Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[S:38]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[S:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=S)o4)cc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in THF (0.6 mL) at −78° C was added thiophosgene (0.010 mL). After stirring for 1 h at −78° C, the reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography, eluting with mixtures of EtOAc in hexanes, to provide the title compound. LC/MS: m/e 562.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.22 (1H, d, J=1.8 Hz), 7.82 (1H, dd, J=8.4, 2.0 Hz), 7.65 (1H, d, J=7.4 Hz), 7.17 (1H, d, J=7.5 Hz), 7.13-7.16 (2H, m), 7.10 (1H, br s), 6.97-6.99 (2H, m), 6.88 (1H, d, J=8.5 Hz), 4.70-4.95 (2H, br), 1.25 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:17][OH:18].O>C(O)C>[OH:18][N:17]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C=O)cc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C=NO)cc([N+](=O)[O-])c1
Yield: 49.1 %

Procedure:
A mixture of methyl 3-formyl-5-nitrobenzoate (0.418 g, 2.0 mmol), hydroxylamine hydrochloride (0.209 g, 3.0 mmol) in ethanol (5.0 mL) was heated at reflux for 2 h. On cooling, the mixture was poured into water and the precipitate collected by filtration. The cake was recrystallized from ethyl acetate-hexane and dried to give 0.22 g (49%) of methyl 3-[(N-hydroxylimino)methyl]-5-nitrobenzoate as an off-white solid, mp 144°-145° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO.O>[N:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:20][CH:21]=1
Reactant: Sc1ccncc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCc2cc(OCCCCSc3ccncc3)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.0 gm of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril were added to a solution of 1.3 gm of 4-mercapto-pyridine and 2.3 gm of a 30% sodium methylate solution in 15 ml of methanol, and the mixture was stirred for 14 hours at room temperature. Subsequently, the reaction solution was diluted with 20 ml of water and the resulting precipitate was recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 10 g.) was added to dry tetrahydrofuran (100 ml.) at 30° C. To the solution was added acetic anhydride (10 ml.) and stirred at the same temperature for 30 minutes. Sodium acetate (3 g.) was added to the solution and stirred at 30° C. for 4 hours. 6 N Hydrochloric acid (10 ml) was dropwise added to the reaction mixture under ice-cooling and the solvent was evaporated in vacuo below 30° C. After adding water into the residue, the mixture was stirred at 20° to 25° C. for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 7 g.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1.[OH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH:14]1([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:21][CH2:22][C@@H:18]([OH:17])[CH2:19]3)=[CH:7][CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(c1ccc(OCCCCl)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCN2CC[C@@H](O)C2)cc1)C1CC1
Yield: 62 %

Procedure:
(4-(3-Chloropropoxy)phenyl)(cyclopropyl)methanone (150 mg, 0.63 mmol), 3-(3R)-hydroxypyrrolidine (55 mg, 0.63 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (62% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1)=[O:17]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Temperature: 150 °C

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19; 100 mg, 0.36 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 79 mg, 0.44 mmol) and DIPEA (190 μl, 1.09 mmol) in dry DMSO (1.2 ml) was sealed and heated at 150° C. for 17 hours. The reaction mixture was filtered through cotton wool and purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O.CN(C=O)C>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(I)ccc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([OH:13])=[N:11][N:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].C[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([O:13][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][N:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1
Reactant: Cc1nnc(O)n1-c1ccc(Cl)cn1
Reactant: CC(C)(C)N=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc(OC(=O)NC(C)(C)C)n1-c1ccc(Cl)cn1
Reaction time: 24 h

Procedure:
19.6 g (0.09 mol) of 4-(5-chloropyridin-2-yl)-5-hydroxy-3-methyl-1,2,4-triazole are suspended in 600 ml of absolute tetrahydrofuran. The mixture is heated to boiling and 20 g (0.2 mol) of tert-butylisocyanate are added, the mixture is heated for 10 minutes and 4 ml of a 5% methanolic sodium methoxide solution are added to the reaction mixture. It is then stirred for 24 hours under reflux conditions, then the suspension is concentrated and the residue is dissolved in methylene chloride and the insoluble components are removed by suction filtering. The organic phase is washed successively with 2 N hydrochloric acid, with sodium hydrogen carbonate solution and with water, dried with magnesium sulphate and evaporated in vacuo. After the addition of ether, 25 g (87% of theory) of the title compound were isolated in the form of crystals, m.p. 132°-134° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[F-].[K+].[C:25]([O:31][CH2:32]Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][C@H:8]1[C:9]([O:11][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of (cis)-1-[(1,1-dimethylethoxy)carbonyl]-4-(phenylmethyl)-L-proline (3.4 g) in dry dimethylformamide (3.0 ml) is added solid potassium fluoride (1.5 g), followed by chloromethyl pivalate (2.0 g). After stirring for 16 hours at ambient temperature the mixture is diluted with water (100 ml) and extracted with ethyl acetate. The ethyl acetate solution is washed with 5% sodium bicarbonate, water, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue (5 g). The oil is chromatographed on silica gel (120 g) eluting with ether/hexane (1:3) to give the product (4.4 g) as an oil that solidifies on standing, melting point 60°-62° C.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[CH2:6]1)[CH:2](C)C.[C:11](OC(=O)CC(CC(C)C)C(O)=O)(C)(C)C.CO>C1COCC1>[CH:1]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[CH2:6]1)([CH3:2])[CH3:11]
Reactant: CC(C)CC1COC(=O)C1
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Preparation of 4-Isobutyl-dihydro-furan-2-one (4): A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0° C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hrs. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (2×50 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyl-dihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) δ0.9 (6H, m); δ1.3 (2H, dd); δ1.5 (1H, m); δ2.1 (1H, m); δ2.6 (2H, m); δ3.6 (1H, m); δ4.4 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:26]([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[O:29][C:26](=[O:28])[CH3:27])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3OC(C)=O)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-1-methyl-indole-2-carboxylic acid ethyl ester (12.86 g, 58.92 mM) and diisopropylethylamine (20.5 mL, 117.84 mM) in CH2Cl2 at 0° C. was added a solution of acetyl salicyloyl chloride in CH2Cl2 over 30 minutes. After the addition was complete the cooling bath was removed and the mixture was allowed to warm to room temperature and stirred at that temperature for 2 hours. The mixture was transferred to a separatory funnel and the solution was washed with 1N HCl (150 mL) and aqueous NaHCO3. The organic fraction was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 47 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.203 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (60 mg, 0.183 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.55 (d, J=5.31 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.31-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.65 (m, 4H), 2.13 (s, 3H). MS (ESI): 783 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25]1([CH2:31][CH:32]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=CCc1ccccc1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CCc2ccccc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with phenyl acetaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-phenethyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 458.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:3]1.[Br:23]Br.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cc(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Br)c(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
7-methyl-5-(pyridin-3-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.28 g, 0.908 mmol) was dissolved in DMF (8 ml). The solution was cooled down to 0° C. Bromine (0.056 ml, 1.09 mmol) was added in dropwise. After 30 min, the reaction mixture was diluted with a aqueous mixture (3:1:4 water, saturated sodium bicarbonate solution and 20% w/w sodium thiosulfate solution, 80 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phase was washed with water (4×60 ml), brine and concentrated to give title compound (0.13 g, 37%). LCMS RT=0.81 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].[CH3:28][O:29][C:30](=[O:35])[CH2:31][C:32](O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:32](=[O:33])[CH2:31][C:30]([O:29][CH3:28])=[O:35])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: COC(=O)CC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (101 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) and malonic acid monomethyl ester chloride (42 mg, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=15 cm, V=5 ml). A yellowish resin was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:12][C:11](=[O:27])[C:10]=1[C:28](=O)[CH2:29][CH3:30]>C(O)C>[CH2:2]([O:4][N:5]=[C:28]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:14][C:9]=1[OH:8])[CH2:29][CH3:30])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Ethoxyamine hydrochloride (0.26 g; 2.7 mmole) and then sodium hydroxide (0.11 g; 2.7 mmole) were added to a solution of 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-propionylcyclohex-2-en-1-one (0.6 g; 1.8 mmole) in absolute ethanol (150 ml). The mixture was stirred at room temperature for a period of 18 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)cyclohex-2-en-1one (0.56 g; 83.2%) as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 5, Example 37.
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.C[Si](C)(C)[N:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:31].Cl[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>C1COCC1>[CH3:42][O:41][C:36]1[CH:35]=[C:40]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][NH:24][C:25]2=[O:31])[CH:39]=[CH:38][CH:37]=1
Reactant: C[Si](C)(C)N1CCCCCC1=O
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2CCCCNC2=O)c1
Reaction time: 0.17 h

Procedure:
To 1.6 M n-BuLi in hexane (31.3 mL, 50 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (8.43 mL, 50 mmol) in anhydrous THF (100 mL) over 5 min. 1-Trimethylsilanyl-azepan-2-one (as described in Step A above) (9.26 g, 50 mmol) in anhydrous THF (20 mL) was added. After stirring the reaction mixture for 10 min a further portion of 1.6M n-BuLi in hexane (31.3 mL, 50 mmol) was added, the mixture stirred for 10 min, and 2-chloroanisole (6.34 mL, 50 mmol) was added. After stirring for 30 min under Ar, the reaction was quenched with H2O, stirred for 30 min, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL) and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1>[CH:1]1([C@@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 35 °C
Reaction time: 22 h

Procedure:
(R)-Methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilypethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22). A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 815 mg) in tetrahydrofuran (THF, 8.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(−)-DuanPhos](BF4) (4.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 35° C. under this hydrogen pressure for 22 h. When HPLC analysis showed that the substrate was almost completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 94.7% ee (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with tetrahydrofuran (THF, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (778 mg) was analyzed by chiral HPLC analysis and result showed a 94.7% of enantiomeric excess favoring the second peak (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22).