Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.Cl.Cl[C:23]1N=C(N2CCOC[C@@H]2C)C2CNCC=2N=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:20]2[CH3:23])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25) using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) as a TFA salt to yield a dark brown oil, which was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([F:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1F

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-fluoro-4-methoxybenz aldehyde. MS (ESI) m/z 517.
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4](=O)[CH3:5].[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[S:10])[NH2:9]>CC(C)=O>[C:3]([C:4]1[N:9]=[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:5]=1)(=[O:7])[CH3:2]
Reactant: CC(=O)C(=O)CBr
Reactant: CC(=O)NCC(N)=S
Solvent: CC(C)=O
Product: CC(=O)NCc1nc(C(C)=O)cs1
Yield: 92.9 %

Procedure:
A suspension of 1-bromo-2,3-butanedione (47 g) and N-[(thiocarbamoyl)methyl]acetamide (30 g) in acetone (600 ml) was refluxed for 3 hours. The resulting precipitate was collected by filtration to afford 4-acetyl-2-(acetylaminomethyl)thiazole (41.8 g).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([CH:13]([CH3:15])[CH3:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:14][CH:13]([C:5]1[S:4][C:3]([CH2:1][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:7][C:6]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: CCOC(=O)c1nc(C=O)sc1C(C)C
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nc(CN2CCOCC2)sc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-formyl-5-(1-methylethyl)-1,3-thiazole-4-carboxylate (150 mg) was dissolved in anhydrous DCM (10 ml) and morpholine (0.064 ml) was added and the mixture stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (280 mg) was added and the mixture stirred at RT for 18 h. Sodium bicarbonate (20 ml) and DCM (20 ml) were added and separated by hydrophobic frit. The solvent was removed in vacuo and purified by column chromatography on silica gel (10 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (77 mg).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[C:11]=1Cl)(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:8][C:7]1[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[C:11]=2[S:1][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC(=O)c1c(Cl)n(C)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc2c(c1C)c1ccccc1n2C
Reaction time: 8 h

Procedure:
450 μl of methyl 2-mercaptoacetate was added to a slurry of 870 mg of (76) and 1.2 g of K2CO3 in 10 ml of MeOH. The reaction was stirred overnight. 30 ml of water was added, stirring continued for 1 hour, and the product filtered off giving 160 mg of product. Recrystallization from MeOH gave 30 mg of (77). M.p. 165.5°-166.8° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: O=C1CN2CCC1CC2
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.C(O)C.[OH-].[Na+]>O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.1 g) was added to ethanol (20 ml), water (10 ml) and 4N aqueous solution of sodium hydroxide (10 ml), stirred at 80° C. for five hours, and the solvent was evaporated in vacuo. 1N Hydrochloric acid aqueous solution was added to the residue at 0° C. and the precipitated solid was washed with water to give the titled compound (1.78 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]2)=[O:8])[CH:3]=1
Reactant: COC(=O)CC1CCN(C(=O)c2cc(C)on2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
Into the reaction flask was added methyl {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetate (2.8 g, 10.0 mmol) and methanol (10 mL) and 3 M of sodium hydroxide in water (10 mL). The mixture was stirred at rt for 2 h. After concentration, the residue was neutralized to pH=7. The mixture was extracted with EtOAc twice. The combined organic layers were dried and concentrated to give the desired product (0.30 g, 11%). LCMS for C12H17N2O4 (M+H)+: m/z=253.1
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cccc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
2,6-dichloroaniline (360 g.) was dissolved in dimethylformamide (1.5 l.) and added to sodium hydride (obtained by washing sodium hydride in mineral oil (214 g; 50%) with petrol) suspended in dimethylformamide (4.1) at 10° C. When the addition was completed the temperature of the mixture was allowed to rise to the ambient temperature and then cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (600 g.) in dimethylformamide (1.5 l.) was slowly added, and the mixture stirred at the ambient temperature for 20 hours. The mixture was poured into salt/iced water (20.1) and the resultant mixture acidified with concentrated hydrochoric acid. The precipitate was collected by decanting off the supernatant liqui and recrystallised from methylated spirit to yield 2(2,6-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 97°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cncc(F)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cncc(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 1.1 g of the crude 5-fluoro-3-pyridinecarbaldehyde, 1.8 g of malonic acid, 0.15 ml of piperidine, and 7 ml of pyridine is stirred at 110° C. for 2 hours. The reaction mixture is concentrated, and 20 ml of water is added. The resulting precipitate is collected and washed with cold water to give 0.5 g of the title compound.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67]([NH:5][CH2:4][CH2:3][F:2])=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: NCCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCCF)c3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 31, method B, using 2-fluoroethylamine hydrochloride (0.70 g, 6.98 mmol), N,N-diisopropylethylamine (2.13 ml, 12.3 mmol), HATU (1.46 g, 3.83 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (3.49 mmol) in DMF (90 mL). The crude product was purified by MPLC on silica gel using EtOAc to provide the title compound as white solid. Yield: 0.74 g (35%). 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.46 (m, 5 H), 1.51 (dd, J=13.28, 3.71 Hz, 2 H), 1.57 (s, 9 H), 3.52 (td, J=26.02, 5.15 Hz, 2 H), 3.86 (dd, J=11.52, 3.52 Hz, 2 H), 4.39 (d, J=7.81 Hz, 2 H), 4.43 (m, 2 H), 6.64 (dd, J=3.32, 1.56 Hz, 1 H), 7.26-7.28 (m, 1 H), 7.80-7.83 (m, 1 H), 7.87-7.93 (m, 2 H), 8.24 (d, J=1.17 Hz, 1 H); MS (APPI) (M+H)+=491.3.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:11][N+:12]([CH3:14])=[CH2:13].[I-]>C1COCC1.CCOC(C)=O>[CH3:11][N:12]([CH2:14][C:8]1[N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:13]
Reactant: C=[N+](C)C
Reactant: Ic1ccc2nccn2c1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cnc2ccc(I)cn12
Yield: 135.3 %

Procedure:
A stirred solution of 6-iodoimidazo[1,2-a]pyridine (2.0 g, 8.2 mmol) and Eschenmoser's salt (5.0 g, 2.7 mmol) in THF (50 mL) was heated to reflux for 24 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual solid was triturated from Et2O, collected by filtration and dried to give the title compound (1.1 g, 45%) as a brown powder. δH (DMSO-d6) 8.67 (1H, m), 7.45 (1H, s), 7.43-7.41 (2H, m), 3.72 (2H, s), 2.14 (6H, s). LCMS (ES+) 302.2 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19]2[C:20]3[N:31]=[N:30][N:29]([C@H:32]4[C@@H:36]5[O:37][C:38]([CH3:41])([CH3:40])[O:39][C@@H:35]5[C@@H:34]([O:42][CH2:43][C:44](O)=[O:45])[CH2:33]4)[C:21]=3[N:22]=[C:23]([S:25][CH2:26][CH2:27][CH3:28])[N:24]=2)[CH:11]=[CH:12][C:13]=1[F:14]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19]2[C:20]3[N:31]=[N:30][N:29]([C@H:32]4[C@@H:36]5[O:37][C:38]([CH3:40])([CH3:41])[O:39][C@@H:35]5[C@@H:34]([O:42][CH2:43][CH2:44][OH:45])[CH2:33]4)[C:21]=3[N:22]=[C:23]([S:25][CH2:26][CH2:27][CH3:28])[N:24]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCC(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
LiAlH4 (0.2 g) was added to THF (10 vol) slowly at 0 to −10° C. To this mixture was added a solution of compound 11a (3 g) in THF (15 mL) slowly over 30 min at 0 to −10° C. The reaction mixture was stirred at 0 to −10° C. for 4-12 hrs. The reaction was monitored by TLC. When the reaction was complete, it was quenched and the product was isolated by routine work up. The filtrate was concentrated under reduced pressure, and compound 12 was isolated as an oily mass; yield 14 g, 70-75%.
Reaction SMILES: [CH2:1]([O:4][NH2:5])[CH2:2][CH3:3].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O>[CH2:1]([O:4][NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CCCON
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydroxhloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure. Boiling point: 88° C./2.5 mmHg
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:21][CH2:20]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH:19]1([C:16]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[O:18][N:17]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CC3)no2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(c2nc(C3CC3)no2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Tert-butyl-4-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylate (1.1 g, 3.8 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was further added thereto. The reaction mixture was stirred at room temperature for 1 hour, neutralized with sodium bicarbonate, and extracted with dichloromethane two times. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (600 mg) as yellowish and transparent oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25](Br)[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:33]([Cu])#[N:34]>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[CH:28]=[C:27]([F:30])[CH:26]=[C:25]([C:33]#[N:34])[C:24]=4[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C#N)c3C[C@H]2O)C1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
According to Scheme 15: A mixture of 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.15 g, 0.303 mmol) and CuCN (54 mg, 0.606 mmol) in dimethylsulfoxide (2 ml) was stirred at 180° C. for 90 min under microwave irradiation. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 27 mg of (1R,2R)-1-[5-acetyl-3-(3-cyano-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-6-fluoro-2-hydroxy-indan-4-carbonitrile (21b). Rt=1.16 min (LC method 4). Detected mass: 442.12 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:13]Br>CO>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: COc1ccc(C(C)=O)cc1Cl
Reactant: BrBr
Solvent: CO
Product: COc1ccc(C(=O)CBr)cc1Cl
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 5.42 mmol) in MeOH (29.5 mL) was added a solution of bromine (0.33 mL, 6.50 mmol) in MeOH (10 mL) at RT. The reaction mixture was then stirred for 2 h, quenched with ice and extracted with DCM (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 70%) as solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC#N>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@H](N)c1ccccc1
Solvent: CC#N
Product: C[C@H](Nc1cc(Cl)ncn1)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of 4,6-dichloropyrimidine (14.9 g, 100 mmole) and (1S)-1-phenylethylamine (13.3 g, 110 mmole) in CH3CN (100 mL) was refluxed for 4 hours. The reaction was partitioned between Et2O (500 mL) and H2O (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel 60 with Hexane/EtOAc 3:1. Pure fractions were combined, concentrated under reduced pressure, and dried under high vacuum to afford the titled compound (18.6 g, 80%) as a yellow oil. 1H NMR (CDCl3): δ 1.57 (d, J=7.0 Hz, 3H), 4.6 (b s,1H), 5.6 (b s,1H), 6.19 (s,1H), 7.34 (m, 5H), 8.30 (s,1H); LC/MS (MH+) 233.62.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:42])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:67]=[C:68]1[CH:72]=[CH:71][C:70](=[O:73])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH2:82])=[O:80]>>[O:73]=[C:70]1[CH:71]=[CH:72][C:68](=[O:67])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH:82][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]([N:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:42])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:80]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
9 mg (9.8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-({(2S)-1-[benzyl(methyl)amino]-1-oxo-3-phenylpropan-2-yl}amino)-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 73) were reacted in analogy to Intermediate 133 with 10 mg (39 μmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide to give 1.8 mg (15% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[S:8])[CH2:6][O:5][C:4]1=[S:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:7](=[S:8])[C:6](=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH3:10])=[CH:19][CH:20]=2)[O:5][C:4]1=[S:9])[CH3:2]
Reactant: COc1ccccc1-c1ccc(C=O)o1
Reactant: CCN1C(=S)COC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN1C(=S)OC(=Cc2ccc(-c3ccccc3OC)o2)C1=S
Yield: 95 %

Procedure:
To a mixture of 3-ethyloxazolidine-2,4-dithione 6 (79 mg, 0.49 mmol), 5-(2-methoxyphenyl)-2-furaldehyde 9 (99 mg, 0.49 mmol) and sodium acetate (201 mg, 2.45 mmol) was added acetic acid (5 mL). As more of the desired product was formed, the reaction mixture color turned to a very red solution. The reaction mixture was refluxed overnight, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography afforded the desired product 2 (M103) in 95% yield (160 mg, purple solid).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2]>[OH-].[Na+]>[N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CNC(=O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
Ethyl N-(2-nitro-3-phenyl-7-benzofuranoyl)glycinate is hydrolyzed by stirring in ethanolic sodium hydroxide solution to provide N-(2-nitro-3-phenyl-7-benzofuranoyl)glycine, m.p. 123°-126° C.