Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:11][N:12]([C+:14]([N:16]([CH3:18])[CH3:17])Cl)[CH3:13]>O>[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:11][N:12]([CH3:13])[C:14]([N:16]([CH3:18])[CH3:17])=[N+:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCNCC
Reactant: CN(C)[C+](Cl)N(C)C
Agent: O=S(=O)([O-])O
Solvent: O
Product: CC[N+](CC)=C(N(C)C)N(C)C
Yield: 82 %

Procedure:
4.20 g (57.4 mmol) of diethylamine are added with stirring and ice-cooling to 6.00 g (25.8 mmol) of bis(dimethylamino)chlorocarbenium hydrogensulfate. The reaction mixture is subsequently stirred for 1 hour at room temperature, and 50 ml of water are subsequently added. The organic phase is separated off, and the aqueous phase is extracted with 50 ml of dichloromethane. The combined organic phases are washed with 20 ml of water, and the solvent is distilled off under reduced pressure. The residue is subsequently dried at 50° C. under reduced pressure (7.0 Pa), giving 5.7 g of viscous N,N,N′,N′-tetramethyl-N″,N″-diethylguanidinium hydrogensulfate, corresponding to a yield of 82.0%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH:11][C:16](=[O:15])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]3[CH:28]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]=4[CH2:34][CH3:35])[N:26]=[CH:25]3)[CH:18]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 153 was prepared from 5-tert-butyl-2-methoxy-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 534 [C33H35N5O2+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O[Li].O.Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To methyl 5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoate (0.450 g, 1.043 mmol) in MeOH/H2O was added LiOH.H2O and stirred at room temperature for 16 h. The mixture was the acidified with HCl (1 N) and extracted with DCM/i-PrOH (3/1) which was dried over Na2SO4 and concentrated to afford the title compound (0.3606 g, 82.84%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]2=[O:20])[CH:4]=[N:3]1.Cl>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:20])[CH:4]=[N:3]1
Reactant: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cc(N2CCNCC2=O)cn1
Temperature: 0 °C

Procedure:
tert-Butyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate (0.058 g, 0.21 mmol) was suspended in ethyl acetate (2 mL), cooled to 0° C., and saturated with gaseous hydrogen chloride. The mixture was warmed to ambient temperature and after 18 hours, concentrated in vacuo. The mixture was treated with sodium bicarbonate (aqueous saturated), washed with a 10% solution of methanol in dichloromethane (3×), filtered, and concentrated in vacuo, providing the titled.
Reaction SMILES: [OH:1][C@@:2]1([C:38](OC)=[O:39])[C@H:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.[OH-].[Na+].Cl.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[C:89]([O:93][NH2:94])([CH3:92])([CH3:91])[CH3:90]>C(OCC)(=O)C.O.C1COCC1.CO>[C:89]([O:93][NH:94][C:38]([C@:2]1([OH:1])[C@H:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:3]1)=[O:39])([CH3:92])([CH3:91])[CH3:90]
Reactant: COC(=O)[C@@]1(O)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: CC(C)(C)ON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of 1-tert-butyl 3-methyl (3R,4R)-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1,3-dicarboxylate (1.59 g, 2.72 mmol), methanol (10 mL), THF (10 mL) and 1N sodium hydroxide (10.9 mL, 4 eq) was stirred overnight. Triethylamine hydrochloride (2.25 g, 16.32 mmol, 6 eq) was added and the resulting mixture was stirred for awhile and then concentrated in vacuo. The residue was dried by azeotropic evaporation with toluene and then dried under high vacuum for 5 h. This crude carboxylic acid was dissolved in DMF (30 mL) and diisopropylethylamine (1.9 mL, 10.88 mmol, 4.0 eq), BOP reagent (1.56 g, 3.54 mmol, 1.3 eq) and O-tert-butylhydroxylamine hydrochloride (512 mg, 4.08 mmol, 1.5 eq) were added. The reaction was stirred overnight, and then diluted with ethyl acetate and water. The organic phase was washed with water three times. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography with 65-70% ethyl acetate/hexane to yield 740 mg (42% in two steps) of tert-butyl (3R,4R)-3-[(tert-butoxyamino)carbonyl]-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1-carboxylate as white solid. MS: (M+H)+=643.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH2:29]>CN(C=O)C>[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: NCc1c(N)cccc1F
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(F)c1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino-6-fluorobenzylamine (60.0 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. 1Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.0 mg, 94%): m.p. 165 (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[O:40]1[C:44]2[CH:45]=[CH:46][C:47](B(O)O)=[CH:48][C:43]=2[O:42][CH2:41]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([C:47]3[CH:46]=[CH:45][C:44]4[O:40][CH2:41][O:42][C:43]=4[CH:48]=3)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Yield: 73.4 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-nitro-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (6.6 g, 10.07 mmol) and benzo[1,3]dioxol-5-yl-boronic acid (3.45 g, 20.14 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-nitro-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (4.8 g, 73%) as a light yellow oil: EI(+)-HRMS m/e calculated for C36H43NO10 (M+Na)+ 672.2779, found 672.2773.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21]OS(C)(=O)=O)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCN3CCCCC3)cc2)cc1

Procedure:
The product from Step 3 (205 mg, 0.4 mmol) was combined with cesium carbonate (197 mg, 0.6 mmol), piperidine (44 mL, 0.44 mmol) in dimethylformamide at room temperature. After four hours the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (120 mg) was obtained.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]([F:20])([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:21])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]([F:20])([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:21]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(N)C(O)CC1
Temperature: 60 °C

Procedure:
A solution of 2-azido-5-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptanol (280 mg, 094 mmol) in THF/water (20 mL/4 mL) was treated with triphenylphosphine (270 g, 1.03 mmol) and the mixture was heated at 60° C. behind a blast screen for 18 hr. The solvents were removed under reduced pressure and the residue was purified via a SCX cartridge washing with MeOH and eluting with 3 N NH3 in MeOH to give 2-amino-5-fluoro-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptanol as a colourless oil. To a solution of this oil (256 mg, 0.94 mmol) in dry DCM (20 mL) at 0° C. was added slowly DIPEA (0.49 mL, 2.82 mmol) followed by trifluoroacetic anhydride (0.16 ml, 1.13 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (20 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamide as a pale yellow oil (130 mg, 38% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07 and 8.06 (2s, 1H), 6.53 (s, 1H), 4.08 and 4.06 (2s, 3H), 4.05-3.92 (m, 2H), 3.06-2.69 (m, 3H), 2.32-1.89 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](=[N:23][NH2:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(B(O)O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][N:23]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccnc(NN=C(c2ccccc2)c2ccccc2)c1

Procedure:
500 mg (3.48 mmol) 2-chloro-4-methoxypyridine, 752 mg (3.83 mmol) benzophenone hydrazone, 469 mg (4.88 mmol) sodium tert-butylate, 15.6 mg (0.07 mmol) palladium(II) acetate, 21.2 mg (0.17 mmol) phenylboronic acid and 43.4 mg (0.07 mmol) racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl are heated in degassed toluene at 90° C. overnight under argon. After cooling, the reaction mixture is poured into water, the aqueous phase is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:14])[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][CH2:4]1.[ClH:15]>>[ClH:15].[ClH:15].[NH2:1][CH2:2][C:3]1([OH:14])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(O)(CN)CC1
Agent: Cl
Product: NCC1(O)CCNCC1

Procedure:
1 g (4.9 mmol) of ethyl 4-aminomethyl-4-hydroxypiperidine-1-carboxylate is heated overnight under reflux with 10 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4O10.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[NH:1]([CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)[C:26]([CH3:27])=[O:28]
Reactant: NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
0.72 g (2.13 mmol) of the aminomethyl compound from step B is dissolved in 6 ml of acetic anhydride at 25° C. and allowed to stand for 1 hour. The solution is diluted with ice water (30 ml) and stirred for 2 hours. The precipitated substance is filtered and, after drying by column chromatography, purified (silica gel, eluant ethyl acetate:benzene=4:1). After the fractions are concentrated by evaporation, 0.65 g of crystalline substance is obtained, which after washing with ethanol yields 0.56 g (70%) of pure title compound with a melting point of 205° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCc4ccccc4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid benzyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and benzyl chloroformate (414 μl, 2.90 mmol). The title compound was obtained as yellow powder (8 mg, 2%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[Na+].O>CC(CC)=O>[C:15]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4])(=[O:16])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 87.5 %

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (25 g) was dissolved in methylethyl ketone (150 mL). NaOAc (12.5 g) was added and the mixture stirred for 48 hours. Water (100 mL) was added and the reaction mixture extracted with DCM. The DCM layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([C:34]([O:36]CC3C=CC=CC=3)=[O:35])[CH3:33])[N:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])[N:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 5.84 g 4-((S)-2-{[5-((S)-1-Benzyloxycarbonyl-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 30 ml ethyl acetate was added under argon 1.0 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (1 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo. Yield: 4.59 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[C:9]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CCc1ncccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ncccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.4 %

Procedure:
To a solution of LiAlH4 (0.94 g) in THF was added ethyl 3-(3-hydroxypyridin-2-yl)propanoate (2.40 g) slowly at 0° C. The reaction mixture was stirred for 5 h at room temperature under N2, then cooled to rt and quenched with water at 0° C. The mixture was filtered. The filtrate was concentrated in vacuo to give the compound as yellow oil (0.95 g, 50%), and the crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 154.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: O=Cc1ccccc1Br
Solvent: CCOCC
Product: OC(Cc1ccccc1)c1ccccc1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 2-bromobenzaldehyde (1 mL, 5.4 mmol) in diethylether (2 mL) was added to a flame dried flask, and flushed with argon. The temperature was reduced to −10° C. and benzylmagnesium chloride was slowly added to the flask via syringe. The reaction was stirred at −10° C. for 1 hour and then stirred at room temperature for 16 hours. The reaction was the poured over ice and acidified to pH 3. It was then extracted with ether (3×40 mL). The organic layers were combined, evaporated, and the resulting residue was purified via silica gel chromatography to produce 520 mg (33% yield) of the title intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: O=C1CNc2ncc(I)cc2N1Cc1cc(Cl)ccc1Cl
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)C(=O)CN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 42 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (62 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (42% yield). M.p.>200° C., LCMS: m/z=564.14 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.37 (2H, m), 1.67 (4H, m), 1.81 (2H, m), 3.22 (6H, m), 3.51 (3H, m), 4.22 (2H, s), 5.23 (2H, s), 7.22 (3H, m), 7.38 (3H, m), 7.55 (3H, m), 8.06 (1H, s).
Reaction SMILES: [Cl-:1].S(Cl)(Cl)=O.[C-]#N.[K+].FC(F)(F)[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1>>[Cl:1][C:12]1[CH:13]=[C:14]([CH2:17][C:18]#[N:19])[CH:15]=[N:16][CH:11]=1
Reactant: [Cl-]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [C-]#N
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: N#CCc1cncc(Cl)c1

Procedure:
Conversion of the hydroxyl group to the chloride using thionyl chloride, followed by the displacement of the chloride by potassium cyanide was performed using the same procedures described for (6-trifluoromethyl-pyridin-3-yl)-acetonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J=2.0 Hz, 1 H), 8.50 (d, J=1.1 Hz, 1 H), 7.73 (s, 1 H), 4.58 (s, 2 H). MS m/z 153.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[O:12])=[CH:8][C:7]=2[CH:13]=1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2oc(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2oc(CO)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
Compound 24 (3.5 g, 19.9 mmol) was dissolved in EtOH (20 mL). NaBH4 (957 mg, 25.87 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (2:1) to give 25 (3.0 g, 85%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 7.36 (1H, d, J=8.90 Hz, H-7), 7.02 (1H, d, J=2.6, H-4), 6.90 (1H, dd, J=6.30 & 2.60, H-6), 6.61 (1H, s, H-3), 4.76 (2H, s, 2-CH2), 3.86 (3H, s, OCH3), 2.16 (1H, bs, OH). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 113.07 (C-7), 111.69 (C-6), 104.34 (C-4), 103.60 (C-3), 58.24 (CH2), 55.92 (OCH3).