Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropanoic acid (5.0 g, 18 mmol) in tetrahydrofuran (50 mL) at 0° C. was added 1.0 M borane-THF complex in THF (55.3 mL, 55.3 mmol). After addition, the reaction mixture was stirred at room temperature for 3 hours, then cooled down with an ice-bath, and quenched by the slow addition of AcOH:MeOH (1:5, 40 mL). Then the mixture was warmed to room temperature for 2 hours. The THF volume was reduced by ½ and the product was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure to give an oil residue which was used directly in the next reaction without further purification. LC-MS found: 168.1 (M−Boc)+.
Reaction SMILES: C([O:4][C:5]([CH3:29])([CH3:28])[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.CS(C)=O.O.C(OCC)C>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([NH:8][C:6](=[O:7])[C:5]([OH:4])([CH3:29])[CH3:28])=[C:10]([C:19]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=3)=[O:20])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(O)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reaction time: 30 h
Yield: 45.8 %

Procedure:
To a suspension of 3-(2-acetoxyisobutyrylamino)-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 360, 251.4 mg, 0.5789 mmol) in methanol (8 ml) and DMSO (20 ml) was added potassium carbonate (45.0 mg, 0.3259 mmol) in water (1 ml) at room tempetature. After stirring for 30 h, the mixture was diluted with diethyl ether (150 ml), and then washed with water (25 ml×3), brine (25 ml) and dried (MgSO4). Removal of solvent gave a crystalline residue, which was recrystallized from ethyl acetate to afford 103.9 mg (45.8%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.Cl.N([O-])=O.[Na+].P(P(O)(O)=O)(O)(O)=O>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=P(O)(O)P(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The reaction is performed in a water/ice bath. 500 mg (2.31 mmol, 1 eq) of 4-bromo-2-methoxy-6-methylaniline is dissolved in a mixture of 7 ml of acetic acid and 3 ml of water, followed by adding 0.8 ml of concentrated hydrochloric acid (37%) and 207 mg (3.00 mmol, 1.5 eq) of sodium nitrite dissolved in 1 ml of water. The mixture is stirred for 30 min and subsequently added to 8 ml of ice-cooled 50% by weight hypophosphoric acid. The reaction is stirred at 0° C. for 8 hours and allowed to stand at RT over night.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1.[NH2:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][C:28]([Br:31])=[CH:29][N:30]=1>C(#N)C>[NH2:24][C:25]1[C:26]([C:32]([NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=2[N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:12][CH2:11]2)=[O:33])=[N:27][C:28]([Br:31])=[CH:29][N:30]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: CC#N
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(NC(=O)c2nc(Br)cnc2N)c1
Yield: 7 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-methoxyphenyl)piperidin-4-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (3 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-methoxyphenyl)piperidin-4-ylcarbamate (7%). LCMS (m/z): 521.1 (MH+); LC Rt=3.63 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc(F)c(F)cc1F
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (0.50 g, 2.8 mmol) in dichloromethane (5 mL) was added N-di-isopropylethylamine (1.8 mL, 1.3 g, 8.5 mmol), WSCDI (0.82 g, 4.2 mmol) and DMAP (0.52 g, 4.2 mmol). After 10 minutes phenylsulfonamide (0.45 g, 4.2 mmol) was added and the reaction left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase chromatography using CH3CN/water as eluent (5:95-95/5 over 30 mins) to yield the title compound (0.60 g, 67%) as a white solid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]2=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][C:29]=3[C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:41])=[O:42])[C:36]([C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[CH:7][N:6]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:5]5=[O:18])=[CH:35][C:29]=3[C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:22][CH:21]=1
Reactant: O=c1c2cc(Br)ccc2ncn1-c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4ncn(-c5ccccc5)c(=O)c4c3)cc12
Temperature: 90 °C
Yield: 8.7 %

Procedure:
To a degassed mixture of 6-bromo-3-phenylquinazolin-4(3H)-one (150 mg, 0.498 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol) in N,N-dimethyl-formamide (4 mL) were added Pd(dppf)Cl2 (15 mg) and K3PO4 (211 mg, 0.994 mmol) under N2. After being heated to 90° C. overnight, the reaction mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)benzofuran-3-carboxamide (10.28 mg, yield: 10%). 1H-NMR (CDCl3, 400 MHz) δ 8.41 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 7.99˜7.92 (m, 3H), 7.88 (t, J=3.6 Hz, 2H), 7.64 (s, 1H), 7.60˜7.52 (m, 3H), 7.46 (d, J=7.2 Hz, 2H), 7.21 (t, J=8.8 Hz, 2H), 5.96 (d, J=4.8 Hz, 1H), 3.18 (s, 3H), 3.00 (d, J=5.2 Hz, 3H), 2.79 (s, 3H). MS (M+H)+: 597.
Reaction SMILES: [O:1]([CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH3:3].C([Li])CCC.[Cl-].[CH2:16]([N:19]([CH2:33][CH2:34][CH3:35])[C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[C:30](I)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21])[CH2:17][CH3:18]>O1CCCC1.C(OCC)C.C(OCC)(=O)C.[Zn]>[CH2:33]([N:19]([CH2:16][CH2:17][CH3:18])[C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([C:6]2[N:5]([CH2:4][O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=2)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21])[CH2:34][CH3:35]
Reactant: CCOCn1ccnc1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccn2COCC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-ethoxylmethylimidazole (J. Am. Chem. Soc. 1978, 100, 3918) (420 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.6 mmol). After 30 min, zinc. chloride (9.9 mL of a 1 M solution in diethyl ether, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.17 g, 3 mmol) followed by palladium(0)tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is diluted with ethyl acetate (50 mL)), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1-5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 8.19 (s, 2H), 5.28 (s, 2H), 3.95 (s, 3H), 3.59 (q, J=7 Hz, 2H), 3.49 (m, 2H), 3.21 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H), 1.25 (t, J=7 Hz, 3H), 0.99 (m, 3H), 0.75 (m, 3H).
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][NH2:41])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl.O>[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([NH:41][CH2:40][C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=1)=[O:42])=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])([CH3:9])[CH3:10]
Reactant: N#Cc1ccc(NC(=O)CN)cc1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)NCC(=O)Nc1ccc(C#N)cc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.4 g of isobutyl chloroformate was added to the n-fixture, and stirred for 1 hour at -20° C. 0.5 g of N1 -(4-cyanophenyl)glycinamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of colorless powder (yield: 49%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.Cl(O)(=O)(=O)=O.[C:32](O[C@@H](C1C(C)=CC2N=C(Br)SC=2C=1OS(C(F)(F)F)(=O)=O)C(OCC)=O)([CH3:35])([CH3:34])[CH3:33]>C(OC(C)(C)C)(=O)C>[C:32]([O:25][C@@H:19]([C:9]1[C:8]([CH3:26])=[CH:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-ethyl 2-(2-chloro-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-hydroxyacetate (0.5691 g, 1.31 mmol) in tert-butyl acetate (65 mL) was added 70% perchloric acid (65 μL, 1.57 mmol). Reaction mixture was stirred for 1.5 h and quenched with solid sodium bicarbonate. Saturated sodium bicarbonate solution was carefully added until basic and mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 15% EtOAc/Hex) to give product contaminated with (S)-ethyl 2-tert-butoxy-2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 5.59 (s, 1H), 4.4-4.1 (m, 2H), 2.55 (s, 3H), 1.20 (s, 9H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:34]=[CH:33][C:10]([NH:11][C:12]3[CH:24]=[C:23]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:22]=[CH:21][C:13]=3[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:11][C:12]3[CH:24]=[C:23]([CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=[CH:21][C:13]=3[C:14]([OH:16])=[O:15])=[CH:33][CH:34]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-morpholinoanilino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 45-80% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-morpholinoanilino)-4-phenethylbenzoic acid 11 mg of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 282.8 %

Procedure:
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (7.99 mmol, 22.6 mmol) was diluted with pyrrolidine (18 mL, 215.6 mmol). The resulting mixture was heated to 80° C. After 3 h, the reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with dichloromethane (200 mL). The organic layer was washed with saturated aqueous citric acid (3×50 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (9.14 g, 100%) as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4]1)=O.O>C1COCC1>[CH3:1][N:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4]1
Reactant: O=CN1CCC(c2ccccc2Cc2ccccc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2ccccc2Cc2ccccc2)C1

Procedure:
A solution of 5.90 g of 1-formyl-3-(α-phenyl-2-tolyl)pyrrolidine of Example 59 in 40 ml of dry THF is added dropwise to a suspension of 2 g LiAlH in 20 ml of dry THF and the mixture is refluxed for 4 hours. After cooling and hydrolyzing with 20 ml of H2O the organic phase is separated and the residue is extracted with ether. The combined organic phase is washed with water, dried (Na2SO4), and concentrated to an oil. This oil is dissolved in 10 ml of acetone and made acidic with a slight excess of HCl/ether. After addition of 200 ml of ether the product is collected and recrystallized from acetone/ether (35/70 ml) to provide 1-methyl-3-(α-phenyl-2-tolyl)pyrrolidine, mp 149.5°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:41][CH2:42][N:37]3[CH2:36][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)cc2)C2CCCc3ccccc32)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg 0.0011 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column by using benzene as eluent, and was concentrated. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether, and filtered under anhydrous conditions to give title compound of formula I. Yield 310 mg. (58.6%).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[CH:22]=[C:23]([CH3:27])[C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:29][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1C
Yield: 70.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(2,4,5-trimethylphenyl)piperazine (249 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (337 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=2)[CH:5]=[C:4]([C:20]2[C:25]([O:26]CC3C=CC(OC)=CC=3)=[CH:24][CH:23]=[CH:22][C:21]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[N:3]=1.Cl>O1CCOCC1.C(OCC)C>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([O:36][CH2:37][CH:38]3[CH2:40][CH2:39]3)=[CH:22][CH:23]=[CH:24][C:25]=2[OH:26])[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=2)[C:7]=1[CH2:8][OH:9]
Reactant: CCNc1ccc(-c2cc(-c3c(OCc4ccc(OC)cc4)cccc3OCC3CC3)nc(N)c2CO)cc1O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNc1ccc(-c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CO)cc1O
Reaction time: 8 h

Procedure:
To a solution of 5-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-(ethylamino)phenol (0.013 g, 0.023 mmol) in 1,4-dioxane (0.5 mL) was added a solution of HCl in 1,4-dioxane (4N, 1.0 mL). After being stirred overnight, the mixture was diluted with diethyl ether. The resulting precipitate was collected by filtration under argon atmosphere, washed with Et2O, and dried under reduced pressure to give 2-[6-amino-4-[4-(ethylamino)-3-hydroxyphenyl]-5-(hydroxymethyl)-2-pyridinyl]-3-(cycloproylmethoxy)phenol. (0.008 g, 76%); LC-MS (m/z=422 M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1.[H-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClCc1ccncc1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Agent: [H-]
Product: COc1ccc(C2=NN(Cc3ccncc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-picolylchloride hydrochloride as described for compound 78, using 12 mmol of sodium hydride instead of 6 mmol. Purified by chromatography (dichloromethane). Crystallized from diethyl ether. M.p. 87°-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([I:8])=[N:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:17])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cnc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: BrCc1cc(Br)cnc1I
Temperature: 80 °C

Procedure:
To a stirred solution of 5-bromo-2-iodo-3-methyl-pyridine (22.5 g, 75.5 mmol, 1 eq) in 1,2-dichloroethane (200 mL) was added NBS (20.16 g, 113.255 mmol, 1.5 eq) followed by addition of AIBN (4.96 g, 30.2 mmol, 0.4 eq) at room temperature in dark. Resulting reaction mixture was heated at 80° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature and quenched with water (150 mL), extracted with DCM (2×150 mL). Combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get dark brownish semi solid (25 g, crude). Crude of title compound was used as such for next reaction. 1H NMR (400 MHz, CDCl3) δ: (Mixture of starting with product): 4.45 (s, 2H), 7.81 (d, J=2.36 Hz, 1H), 8.31 (d, J=2.36 Hz, 1H). LC-MS (m/z): No ionization.
Reaction SMILES: [N+:1](=[C:3]1[C:20](=[O:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[CH2:23][OH:24])=[N-:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[N+:1](=[C:3]1[C:20](=[O:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[CH:23]=[O:24])=[N-:2]
Reactant: C[C@]12CCC(=O)C(=[N+]=[N-])[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CO)CC[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C[C@]12CCC(=O)C(=[N+]=[N-])[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]12

Procedure:
4-Diazo-17β-hydroxymethyl-5αandrostan-3-one is oxidized with pyridinium chlorochromate according to the procedure described in Example 4 to give 4-diazo-3-oxo-5α-androstane-17β-carboxaldehyde. In a similar manner, 4-diazo-17β-hydroxy-5α-androstan-3-one is oxidized with pyridinium chlorochromate to give 4-diazo-5α-androstane-3,17-dione.