Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH3:50])=[CH:41]1>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH2:50][C:29]2([OH:39])[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([Cl:25])[CH:27]=3)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]2=[O:38])=[CH:41]1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.71 (bs, NH) 8.38 (m, 1H), 7.79 (d, 1H), 7.49 (d, 1H), 7.41 (m, 1H), 7.35-7.31 (m, 2H), 7.26 (m, 1H), 6.78 (d, 1H), 5.00 (bs, OH), 3.65 (m, 2H), 3.50 (d, 1H), 3.25 (d, 1H), 1.69 (m, 2H), 0.96 (t, 3H). calculated mass for C21H19ClN2O3, 382.11, observed, 383.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[N:11][C:6]=2[CH:5]=[N:4][N:3]=1.[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=3[CH3:21])[C:26]([NH2:28])=[O:27])=[N:3][N:4]=[CH:5][C:6]=2[N:11]=1
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Oc2ccc3c(Cl)nncc3n2)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(N)=O)cc1-c1nncc2nc(Oc3ccc(F)cc3F)ccc12

Procedure:
A mixture of 5-chloro-2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazine (Example 3, step 5; 130 mg, 0.44 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (144 mg, 0.55 mmol), sodium carbonate hydrate (220 mg, 1.77 mmol), and PdCl2(PPh3)2 (16 mg, 22 μmol) in DME:EtOH:H2O=7:2:3 (2.5 mL) was heated at 130° C. for 30 min in a microwave. The reaction mixture was treated with 5 mL of 1 N NaOH and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, eluted with 40-100% EtOAc in hexanes) afforded the title compound as a tan amorphous solid. MS (ESI, pos.ion) m/z: M+1=393.0
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.CO.[S:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=2)[N:28]=[N:27]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[N:28]=[N:27][S:26][CH:30]=4)=[CH:36][CH:35]=3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: NCc1ccc(-c2csnn2)cc1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (2-5) 0.294 g, 0.766 mmol) in THF (5 mL) and MeOH (5 mL) was added 1-[4-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (0.147 g, 0.766 mmol) and DIPEA (0.495 g, 3.831 mmol). The mixture wsa stirred overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (2 M, 10 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-6% MeOH in CH2Cl2) to give 2-chloro-5-phenyl-6-[4-({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}methyl)phenyl]nicotinonitrile (2-6). 1H-NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.01 (d, J=8.0, 2H), 7.98 (s, 1H), 7.47 (d, J=8.1, 2H), 7.28-7.38 (m, 7H), 7.16-7.18 (m, 2H), 3.84 (s, 2H), 3.83 (s, 2H). LRMS m/z (M+H) Calcd: 494.0, found: 494.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]([C:22]2[C:30]3[CH:29]=[N:28][CH:27]=[N:26][C:25]=3[N:24]([C:31]3([CH2:34][O:35]C4CCCCO4)[CH2:33][CH2:32]3)[CH:23]=2)=[O:21])[CH:17]=[N:18][CH:19]=1.CCCP(O)(O)=O.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]([C:22]3[C:30]4[CH:29]=[N:28][CH:27]=[N:26][C:25]=4[N:24]([C:31]4([CH2:34][OH:35])[CH2:33][CH2:32]4)[CH:23]=3)=[O:21])[CH:15]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: Nc1cncc(C(=O)c2cn(C3(COC4CCCCO4)CC3)c3ncncc23)c1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CC(=O)Nc2cncc(C(=O)c3cn(C4(CO)CC4)c4ncncc34)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
(4-Cyano-phenyl)-acetic acid (6.1 mg, 0.04 mmol) was added to a solution of (5-Amino-pyridin-3-yl)-{7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (15 mg, 0.04 mmol) (Preparation 251) in THF (1 mL). Then 1-propylphosphonic acid cyclic anhydride (0.07 mL, 0.11 mmol) and triethylamine (0.02 mL, 0.13 mmol) were added and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude was dissolved in methanol (1 mL), PTSA (5 mg) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (5×5 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane:methanol 95:5) to afford the title compound as a white solid in 58% yield, 10 mg.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH2:4][CH:5]=[CH2:6])#N.[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:29]>C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:8]=[C:7]([CH:3]([CH:1]=[O:29])[CH2:4][CH:5]=[CH2:6])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC(C=O)c1ccc(Cl)c(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Cyano-4-(3,4-dichlorophenyl)but-1-ene (13 g) (see Preparation 20) was dissolved in anhydrous toluene (100 ml) and cooled to −70° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (50 ml of a 1.5M solution in toluene) was added to the solution over 30 minutes, the mixture stirred at −70° C. for a further 30 minutes and then allowed to warm slowly to −10° C. Water (6 ml) was carefully added (exothermic reaction) before pouring the mixture into a 15% (by weight) aqueous solution of citric acid (500 ml), followed by further addition of toluene (300 ml) and vigorous stirring of the mixture for 30 minutes. The two phases were separated, the organic phase washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 4-(3,4-dichlorophenyl)-4-formylbut-1-ene as an oil (14 g).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[N:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:11]2[NH:10][C:9]=1[CH3:31])=[O:7])[CH3:4]>O.C(O)C>[C:26]([C:25]1[N:24]=[CH:23][N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:9]([CH3:31])[NH:10][C:11]=12)([OH:28])=[O:27]
Reactant: CCOC(=O)C1=C(C)Nc2c(C(=O)OCC)ncn2C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(C)Nc2c(C(=O)O)ncn2C1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 34.4 %

Procedure:
0.17 g of potassium hydroxide in 1.7 ml of water is added to a solution of 1.0 g of 3,8-diethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine in 20 ml of ethanol, and gradually heated followed by stirring at 70° C. for 10 hours. The ethanol is distilled off under reduced pressure, chloroform is added to the resulting oil and extracted with potassium carbonate solution. The water layer is washed with chloroform and adjusted to pH 5-6 with acetic acid. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 0.32 g of 8-carboxy-3-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydroimidazo[1,5-a]pyrimidine, melting at 222° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[NH4+:12].[OH-]>C1COCC1>[Br:1][C:2]1[S:3][C:4]([S:8]([NH2:12])(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=S(=O)(Cl)c1sc(Br)nc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a mixture of 2,4-dibromothiazole-5-sulfonyl chloride (3.17 g, 9.28 mmol) in THF (51.4 mL) was added 33% aqueous NH4OH (24.1 mL, 278 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→20/80) to give 1.7 g (57% yield) of the title compound. as a white solid. LC/MS (FA) ES+ 321, 323, 325. 1H NMR (400 MHz, DMSO-d6) δ: 8.33 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[C:5]2[CH2:20][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Reactant: C1COCCN1
Product: O=[N+]([O-])c1cc(Cl)cc2c(CN3CCOCC3)c(-c3ccccc3)[nH]c12

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole prepared in Step A of Preparation 43 and morpholine were reacted according to the same procedure as Step B of Preparation 43 to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Li+]>CN(C=O)C>[OH:2][C:3]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Temperature: 150 °C

Procedure:
A mixture of the product from step (i) (3.18 g) and lithium chloride (1.96 g) in DMF (30 ml) was heated at 150° C. for 5 h. The mixture was partitioned between diethylether and 2M hydrochloric acid, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 3:1, yield 2.30 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][C@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22])=[N:14][N:13]=[CH:12]2.N([O-])=O.[Na+].[I-:30].[K+]>Cl.O>[I:30][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([O:19][C@H:20]([CH3:25])[C:21]([F:23])([F:24])[F:22])=[N:14][N:13]=[CH:12]3)[CH:4]=1
Reactant: [I-]
Reactant: Cc1ccc(N)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(I)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
To a suspension of 4-methyl-3-(1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazin-6-yl)benzenamine (1.49 g, 4.30 mmol) in 14 mL of 6N HCl at 0° C. was added sodium nitrite (593 mg, 8.59 mmol) in 8 mL of water drop wise. After 20 min at 0° C., a solution of potassium iodide (2.14 g, 12.89 mmol) in 6 mL of water was added slowly. After the brown heterogeneous mixture was stirred at RT for 1 h, it was extracted twice with DCM. The combined DCM layers were washed with 1 N NaOH followed by sat. sodium thiosulfate, dried and concentrated. The brown residue was purified on an ISCO 40 g column (25-55% EtAc in Hexanes) to provide 6-(5-iodo-2-methylphenyl)-1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazine (73% yield, 1.44 g) as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 459.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24]COC)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one (1.5 g, 4.076 mmol) in methanol (25 mL) was added concentrated hydrochloride (5 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure the obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (1 g, 75.7%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccc(O)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
1-[1-(4-Benzyloxybenzoyl)-4-piperidinyl]-3,4-dihyrocarbostyril (4.76 g) is dissolved in methanol (100 ml) and thereto is added 5 % palladium-carbon (1 g). The mixture is stirred at room temperature under 1 atm. under hydrogen atmosphere. After the completion of the reaction, the catalyst is filetered off and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1) and further recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2.5 g) as white powder, m.p. 182°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:33][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:27]=3[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].Br[CH2:35][CH2:36][F:37].[I-].[K+].C(N(CC)CC)C>CN(C=O)C.ClCCl>[F:37][CH2:36][CH2:35][N:30]1[CH2:31][CH2:32][C:27]2[NH:26][C:25]([C:21]3[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=3)[C:4]([N:6]3[CH2:7][CH2:8][CH:9]([C:12]4[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=4)[CH2:10][CH2:11]3)=[O:5])=[N:33][C:28]=2[CH2:29]1
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: FCCBr
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CCN(CCF)C3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 48 h
Yield: 52 %

Procedure:
A mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 88 mg), 1-bromo-2-fluoroethane (150 μl), potassium iodide (50 mg), and triethyl amine (140 μl) in DMF (2 ml) was stirred for 48 hours. The reaction mixture was then diluted with dichloromethane and washed with brine. The organic layer was dried (MgSO4) and concentrated. The residue was purified by prep. TLC using 8% MeOH in DCM to give 51 mg of a white solid (52%). m/z (ES+) 486 (M+H)+. 1H NMR (400 MHz, Chloroform-d) 7.63 (d, 2H), 7.32 (d, 2H), 7.28 and 7.20 (2 singlets, amide rotamers, 1H), 7.00 (s, 1H), 4.93 (m, 1H), 4.67 (dt, J1=47.6 Hz, J2=4.9 Hz, 2H), 3.71 (d, 2H), 3.62 (d, 1H), 3.03-2.71 (m, 8H), 2.43 (d, 3H), 2.29 and 2.19 (2 singlets, amide rotamers, 3H), 2.08-1.89 (m, 2H), 1.85-1.49 (m, 2H), 3.18-3.05 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11](=[C:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[BH4-].[Na+].C1C=CC=CC=1>CO>[OH:22][C@H:6]1[CH2:5][CH2:4][C@@:3]2([CH2:2][OH:1])[C:8]([CH:9]=[CH:10][C:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]=3[CH2:13][CH2:14][C@@H:15]2[OH:21])=[CH:7]1
Reactant: C[C@]12CC[C@H]3C(=C1CCC2=O)C=CC1=CC(=O)CC[C@@]13CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=C[C@@H](O)CC[C@@]13CO
Reaction time: 1 h

Procedure:
To a mixture of 4.5 g of 19-hydroxyandrost-4,6,8(14)-trien-3,17-dione in 40 ml of methanol, which was cooled externally by an ice-bath, was added 1.8 g of sodium borohydride with stirring. Stirring was continued for 1 hour, 450 ml of benzene was added and the mixture was concentrated at reduced pressure to a small volume. Benzene and a small volume of water was added and the mixture was concentrated again. Subsequent filtration and recrystallization of the precipitate from methanol gave 3β,17β,19-trihydroxyandrosta-4,6,8(14)-triene as a white solid, uv max 275 (sh), 285 and 298 (sh) mμ.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:51]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:73])[CH2:64]P(OCC)(OCC)=O)[CH2:59][CH2:58]1)=[O:56])[CH:52]=[CH2:53].[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:64]/[C:63]([N:60]1[CH2:59][CH2:58][N:57]([C:55]([O:54][CH2:51][CH:52]=[CH2:53])=[O:56])[CH2:62][CH2:61]1)=[O:73])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCN(C(=O)CP(=O)(OCC)OCC)CC1
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCN(C(=O)/C=C/[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCC=C)CC1
Yield: 92.6 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 1.5 g, 3.26 mmol), dimethyl sulfoxide (0.65 ml, 9.14 mmol), oxalyl chloride (0.42 ml, 4.90 mmol), triethylamine (2 ml, 14.9 mmol), N-allyloxycarbonyl-N'-(diethylphosphonoacetyl)piperazine (1.24 g, 3.92 mmol) and 60% sodium hydride (130 mg, 3.26 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate) to give the title compound (1.97 g, 92.6% yield).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C:7]2([S:11][CH2:10][CH2:9][S:8]2)[CH2:6]1)=[O:4].[CH3:30][NH:31][CH2:32][C:33](=[O:51])[CH:34]([NH:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:43]([NH:42][CH:34]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:33](=[O:51])[CH2:32][N:31]([CH2:2][C:3]([N:5]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C:7]2([S:11][CH2:10][CH2:9][S:8]2)[CH2:6]1)=[O:4])[CH3:30])(=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1C(=O)CBr)SCCS2
Reactant: CNCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the ester product from part (b) (2.4 g., 4.87 mmole), (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide (0.81 g., 2.43 mmole), prepared as set forth in Example 91(b), and diisopropylethylamine (0.85 ml., 4.87 mmole) in dimethylformamide (20 ml.) is stirred at room temperature overnight. The reaction mixture is poured into water (50 ml.), and extracted with ethyl acetate (3×100 ml.). The combined organic extracts are washed with saturated sodium bicarbonate, 10% potassium bisulfite, and water, dried (Na2SO4), and concentrated into a dark oily residue (2.8 g.). Flash chromatography (200 g. Merck silica gel, 10% ethyl acetate/methylene chloride, 20% methanol/ethyl acetate) affords 1.1 g. of (S)-7-[[[3-(benzoylamino-2-oxo-4-phenylbutyl]methylamino]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester as a yellow oil.
Reaction SMILES: O[C:2]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][C:4](=[O:9])[CH:5]=[CH:6][O:7]C.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[C:10]([C:2]1[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: COC=CC(=O)C=C(O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(=O)cco1
Reaction time: 14 h
Yield: 102.2 %

Procedure:
A mixture of 5-hydroxy-1-methoxy-6,6-dimethyl-hepta-1,4-dien-3-one (Step 1.7) (6.8 g, 36.9 mmol) and TFA (5.65 mL, 74 mmol, 2 eq) in benzene (250 mL) is stirred for 14 h at it and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:0→75:25) provides 5.74 g of the title compound as a yellow oil: ESI-MS: 153.1 [M+H]+; tR=3.21 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 1:1).