Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([F:26])[CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:30][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([F:26])[CH:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccnc(F)c4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccnc(F)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{5-[(2-fluoropyridin-4-yl)methoxy]-3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.27 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.21 g, 82%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16]C(=O)OC(C)(C)C)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOC(C)=O>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH2:16])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(CCCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCN(CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl [(3R)-1-(3-phenylpropyl)-3-piperidinyl]carbamate (880 mg) in AcOEt (1.3 mL) was added 4N HCl—AcOEt (8.8 mL). The mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated. Dichloromethane (10 ml) and saturated sodium bicarbonate (15 ml) was added. Aqueous layer was separated and extracted with dichloromethane. Combined organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give (3R)-1-(3-phenylpropyl)-3-piperidineamine (586 mg) as an yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2cn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 92% pure N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 2.1 mmol), N-methylpiperazine (0.63 g, 6.3 mmol), acetic acid (0.38 g, 6.3 mmol) in dichloroethane (100 mL) was added sodium triacetoxyborohydride (0.67 g, 3.15 mmol) portionwise under nitrogen. The solution was stirred for 20 hr and then quenched by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL), dried (sodium sulphate), filtered and evaporated to leave a sludge which was purified by flash silica gel column chromatography using dichloromethane to 50% MeOH/dichloromethane in 10% increments. F84-96 were combined and evaporated to leave cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.26 g) as a cream foamy glass. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.65 min, 95.2%.1H NMR (d6 DMSO, 400 MHz): 9.17(1H, s), 8.14(1H, s), 8.05(1H, d), 7.28(5H, m), 7.18(1H, m), 7.10(1H, s), 6.99(1H, d), 6.11(2H, bs), 4.67(1H, m), 3.88(3H, s), 2.90(2H, m), 2.73(2H, m), 2.50(7H, m), 2.28(3H, s), 2.06(3H, m), 1.71(2H, m), 1.55(2H, m). F121-138 were combined and evaporated to leave trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.11 g) as a white solid. HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=12.61 min, 96.2%. 1H NMR (d6 DMSO, 400 MHz): 9.16(1H, s), 8.13 (1H, s), 8.04(1H, d), 7.44(1H, s), 7.29 (4H, m), 7.18(1H, m), 7.09(1H, s), 6.97 (1H, d), 6.11(2H bs), 4.53(1H, m), 3.88 (3H, s), 2.93(2H, m), 2.71(2H, m), 2.50 (4H, m), 2.30(5H, m), 2.14(3H, s), 1.89(6H, m), 1.46(2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16]([N:70]2[CH2:75][CH2:74][O:73][CH2:72][CH2:71]2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(Br)cn2)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (3.75 g) is dissolved in toluene (50 ml) and thereto are added tris(dibenzylideneacetone)dipalladium (516 mg), 2-(di-tert-butylphosphino)biphenyl (673 mg), sodium tert-butoxide (813 mg) and morpholine (740 μl), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (2.46 g). MS (m/z): 671 [M+H]+
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:15][C:16]([CH2:21][CH3:22])([CH2:19]O)[CH2:17]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:1]1(=[O:14])[O:13][CH2:17][C:16]([CH3:19])([CH2:21][CH3:22])[CH2:15][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: CCC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCC1(C)COC(=O)CCCCCCCCC(=O)OC1
Temperature: 25 °C

Procedure:
Amorphous poly (2-methyl-2 -ethyl-1,3-propylene sebacate) was prepared by reacting sebacic acid and a 10 mole % excess of 2-methyl-2-ethyl-1,3-propylene glycol in the presence of 0.5 weight % p-toluenesulfonic acid in the same manner as in Example 1. On cooling to room temperature after the polymerization, the poly (MEPS) remained as a clear, tacky fluid. Analysis indicates it has an acid number of 2.40, an hydroxyl number of 19.4, an Mn of 5150 g/mole, an MWD of 1.87 by GPC in chloroform, and a glass transition temperature of about -61°C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:16]=[C:15]4[CH:29]=O)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][OH:26])[CH:16]=[C:15]4[CH2:29][N:38]3[CH2:39][CH2:40][CH2:41][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Reactant: CN1CCCNCC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCCN(C)CC3)c2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a mixture of N-cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide (Example 2c, 0.20 g) and titanium(IV) isopropoxide (2 mL) was added 1-methyl-1,4-diazepane (0.17 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 2 h before adding sodium triacetoxyborohydride (0.38 g). The mixture was stirred at room temperature for 2 h. TFA (5 mL) was added and the mixture stirred at room temperature for 72 h and then evaporated to dryness. The mixture was quenched with 10% aq ammonia (5 ml) and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to afford the title compound (0.055 g) as a white solid.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([C:5]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:6]=1)[CH3:4]>CO>[CH2:3]([C:5]1[C:9]([C:10](=[N:1][OH:2])[NH2:11])=[C:8]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:7]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[N:6]=1)[CH3:4]
Reactant: NO
Reactant: CCc1nn(-c2ccc(O)cc2)c(-c2occc2C)c1C#N
Solvent: CO
Product: CCc1nn(-c2ccc(O)cc2)c(-c2occc2C)c1C(N)=NO
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.3 mL, 4.8 mmol) was added to 3-ethyl-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol) in MeOH (0.6 mL) and the reaction was stirred at 150° C. for 20 min in the microwave reactor. The crude reaction was purified on preparative HPLC to give 3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carboximidamide (3.34 mg, 63%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 327.1 (M+H), 325.23 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.13 (s, 1H), 7.53 (d, 1H, J=1.9 Hz), 7.05 (m, 2H), 6.80 (m, 2H), 6.36 (d, 2H, J=1.9 Hz), 2.83 (q, 2H, J=7.6 Hz), 1.76 (s, 3H), and 1.26 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>ClCCCl.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]#[N:19]
Reactant: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: N#CC1=C(Cl)c2ccccc2OC1c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 25.7 g 4-chloro-3-hydroxyiminomethyl-flav-3-ene and 28.3 g triphenylphosphine in 250 ml 1,2-dichloroethane and 8.7 ml carbon tetrachloride is heated at 60° C. To this solution one adds 12.54 ml triethylamine. The temperature is maintained between 62°-65° C. during the addition and for further 25 minutes. The mixture is cooled to 0° C., filtered and evaporated. The crude material is extracted with hexane. The combined extracts are evaporated and purified by column chromatography on silicagel using a mixture of dichloromethane and hexane as eluant. The pure fraction is evaporated and crystallized in diisopropylether. Pure 4-chloro-3-cyano-flav-3-ene is obtained as pale yellow crystalls; m.p. 99° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.O=[Mn]=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][N:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
A mixture of {6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}methanol (0.96 g) and MnO2 (2.951 g) in AcOEt (50 ml) was refluxed under stirring for 1.5 hour. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29]C)=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][Cl:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl-:44].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:27]([OH:29])=[O:28])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[NH+](CCCl)Cc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a suspension of methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in International patent application publication WO2006/046030) in toluene (0.05 M), were added 10 eq. of 30% w/w aq. NaOH followed by 0.25 eq. of tetrabutylammonium bromide. After stirring for 30 min, 2.5 eq. of N-benzyl-2-chloro-N-methylethanaminium chloride were added, and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue purified by RP-HPLC (WATERS XTERRA prep. C18 column, 5um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried in the presence of HCl to afford the title compound (25%) as a white powder. (ES+) m/z 539 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:10]3[N:15]=[C:14]([C:16]4[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1>[Pd]>[CH2:6]([C:7]1[N:8]=[C:9]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:10]2[N:15]=[C:14]([C:16]3[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([CH3:28])[CH:17]=3)[O:13][C:11]=2[N:12]=1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:34][CH:33]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1OCC(=O)O
Agent: [Pd]
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccccc4)nc3o2)cc(C)c1OCC(=O)O

Procedure:
10 mg of palladium on carbon (10%) were added to a solution of 50 mg of {4-[5-(4-chlorobenzyl)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetic acid, and the mixture was hydrogenated at 5 bar overnight. Three times, another 10 mg of palladium on carbon (10%) were added and the mixture was in each case hydrogenated for a day. For work-up, the catalyst was filtered off through Celite and the solution obtained was concentrated. The residue was purified by HPLC. This gave 7 mg (18%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(C(=O)n2ccc3ccccc32)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3-methylbenzoic acid (1.0 g, 4.65 mmol) and 1H-indole (0.60 g, 5.12 mmol) in DCM (23.3 mL) at RT was added DCC (1.15 g, 5.58 mmol) and 4-dimethylaminopyridine (0.11 g, 0.93 mmol). The reaction was stirred at RT overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-50% Hexene/EtOAC) to yield (2-bromo-3-methylphenyl)(1H-indol-1-yl)methanone as a clear oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH2:11]([C:14]1[C:15]([Cl:24])=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[SH:22])[C:17]#[N:18])[CH:12]=[CH2:13]>CC#N>[CH2:11]([C:14]1[C:15]([Cl:24])=[C:16]([CH:19]=[C:20]([Br:23])[C:21]=1[S:22][CH2:9][CH:8]=[CH2:7])[C:17]#[N:18])[CH:12]=[CH2:13]
Reactant: C=CCBr
Reactant: C=CCc1c(S)c(Br)cc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCSc1c(Br)cc(C#N)c(Cl)c1CC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
In a mixture of crude 3-allyl-5-bromo-2-chloro-4-mercaptobenzonitrile and K2CO3 (1.79 g, 12.9 mmol) in CH3CN (80 mL), allylbromide (1.12 mL, 12.9 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature, and then filtered off. The resulting solution was evaporated and purified by silica gel chromatography to give the desired product 94 (1.1 g, 77.7% overall yield) as a white solid.
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1.Cl>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([N:19]([C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH3:20])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: ClC1=NC(Cl)NC2=C1CCCC2
Reactant: CNc1ccc(OC)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(Cl)nc3c2CCCC3)cc1
Yield: 50 %

Procedure:
A mixture of 2-methoxylcarbonyl cyclohexanone 5.00 g (455 mmol) and urea 6.00 g (100.0 mmol) with 2 mL of ethanol was stirred for 48 h under reflux. After cooling, the formed crude product was washed with water and dried in vacuo to give ca.4 g of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione. A mixture of 5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione 2.00 g (12.0 mmol) and POCl3 10 mL was stirred under reflux for 3 h. After cooling, excess of POCl3 was removed under reduced pressure, and the crude product was diluted with CHCl3, which was poured into ice-water, washed with water, and dried on anhydrous MgSO4. Removal of CHCl3 gave 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline in 95% yield. A solution of 2,4-dichloro-5,6,7,8-tetrahydro-1H-quinazoline 0.615 g (3.0 mmol) and 4-methoxy-N-methylaniline 0.411 g (1.0 mmol) with conc. HCl 0.5 mL in iso-propanol 30 mL was stirred at 23° C. for 16 h. The solution was concentrated under reduced pressure, diluted with CH2Cl2 30 mL, washed with sat. Na2CO3 aqueous solution, and dried on anhydrous MgSO4. After removal of solvents, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 60%) to give titled product in 50% yield, which was further purified with preparative HPLC to give the corresponding TFA salt. 1H NMR (CDCl3, 400 MHz): δ 7.02 (d, 2H, J=9.0 Hz), 6.86 (d, 2H, J=9.0 Hz), 3.83 (s, 3H), 3.40 (s, 3H), 2.73 (t, 2H, J=6.7 Hz), 1.62-1.68 (m, 4H), 1.44-1.49 (m, 2H). m/z: 304.1236 (M+1).
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17].[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: CN
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CC(=O)O
Product: CNC1=C2CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To obtain the corresponding 4-methylamino compound, a suspension of (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate in methanol was mixed with 40% aqueous methylamine and refluxed for 30 minutes. Additional 40% aqueous methylamine was added and refluxing was continued for another 30 minutes. The solvent was then evaporated and the residue was purified as described above for the 4-amino compound to give (20S)-4-(methylamino)-21-hydroxy-20-methylpregn-4-en-3-one.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1=[O:13].[Br-:14].[K+].BrBr>O.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:14][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][C:8]=1[C:11]#[N:12])[N:2]([CH3:1])[C:3](=[O:13])[CH2:4]2
Reactant: CN1C(=O)Cc2ccc(C#N)cc21
Reactant: [Br-]
Agent: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(Br)c(C#N)cc21
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Water (9 mL) was added to 1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (110 mg 0.64 mmol) and the resulting mixture was placed at 70° C. In a separate flask potassium bromide (462 g, 0.26 mmol) in water (12 mL) was treated with bromine (0.100 mL, 1.94 mmol). 6.0 mL of the orange bromine solution was added dropwise to the water and 1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile mixture over ca. 20 minutes. The resulting heterogeneous mixture was permitted to stir at 70° C. for an additional 5 minutes and then cooled to room temperature. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The solution was then further diluted with saturated aqueous sodium thiosulfate. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 3.5%) to provide 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile; MS: (ES+) m/z 250.9 (M+H)+.