Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:33][S:34][C:35]1[S:36][C:37]2[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][C:38]=2[N:39]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:44][C:42]2[CH:41]=[CH:40][C:38]3[N:39]=[C:35]([S:34][CH3:33])[S:36][C:37]=3[CH:43]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a stirred mixture of 4-(benzyloxy)-2-nitroaniline (2.0 g, 8.2 mmol) in TFA (14 mL) at −15° C. was added sodium triacetoxyborohydride (2.84 g, 12 mmol). Then a solution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.9 g, 9.0 mmol) from Step 1 of Example 100 in DCM (10 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. and stir for 2 h. The mixture was partitioned between DCM and water. The organic layer was separated and washed sequentially with saturated aq NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 10% EtOAc in petroleum ether to 100% EtOAc to afford 4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (2.3 g, 64%) as a red-brown solid. 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.33-7.43 (m, 6H), 7.14 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 5.02 (s, 2H), 4.64 (d, J=5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH:29][C:54](=[O:55])[CH2:53][Cl:52])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:54](=[O:55])[CH2:53][Cl:52])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(C=CC(c2ccc(OC)c(NC(=O)CCl)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CCl)c2)c(OC)c1
Yield: 88 %

Procedure:
To a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in toluene, chloroacetyl chloride (10 mmol) in dioxane (10 mL) was added and the solution was refluxed for 2 h. The solution was cooled and the solvent was removed in a rotary evaporator to give 2,4,6-trimethoxystyryl-3-chloroacetamido-4-methoxybenzylsulfone in 88% yield. M.p. 163-165° C. NMR (DMSO-d6) δ 3.83 (s, 3H), 3.84 (s, 6H), 3.85 (s, 3H), 4.14 (s, 2H), 4.22 (s, 2H) 6.08 (s, 2H), 7.11-7.20 (d, 1H vinylic), 6.90-8.33 (m, aromatic), 8.89 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1N1CC2CC1CN2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1N1CC2CC1CN2Cc1ccccc1

Procedure:
5.0 g (124) in 360 mL ethanol and 20 mL water with 4 g NH4Cl and 6.7 iron powder were heated to reflux temperature under 4 hours of mechanical agitation. The reaction solution is filtered over Celite and active carbon, evaporated, absorbed in 100 mL water, brought to pH 10 by means of K2CO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 5 mbar; 160–170° C.): 2.20 g (48.8% of the theoretical yield.) (125) as colorless oil. DC: CHCl3/methanol (9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc(CO)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0° C., and the reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL×3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (ES+) C8H11NO2 requires: 153. found: 154 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52]C)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=4)[CH2:27][CH:26]3[CH2:44][N:51]([CH3:52])[CH3:49])=[O:24])=[CH:18][C:17]=2[CH:46]=1
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CN(C)C)=C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of oxalyl chloride (175 mg) in methylene chloride (1 ml) is added dropwise at -78° C. a solution of dimethyl sulfoxide (215 mg) in methylene chloride (1 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the reaction mixture is added triethylamine (650 mg), then the reaction temperature is raised up to room temperature. To the reaction mixture is then added water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (5 ml). To the mixture are added dimethylamine hydrochloride (200 mg) and sodium cyanoborohydride (130 mg). The reaction mixture is stirred for 48 hours at room temperature and then poured into a 1N NaOH solution, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:methanol ethyl acetate=15:85) to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-dimethylaminomethyl-4-(3,4,5-trimethoxybenzyl) piperazine (200 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 167-169° C.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:24]=[C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([NH:25][C:23]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=2[OH:16])=[C:7]([CH2:6][S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:40])[CH:24]=1)=[O:31]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Oc1cc(CC(=O)O)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)C(=O)Nc1ccc(Oc2cc(CC(=O)O)ccc2O)c(CS(=O)C(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 2 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-hydroxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (1 equivalent).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH2:36]([NH:38][C:39]([NH:33][C:32]1[CH:31]=[CH:30][C:29]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][C:15]([C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)=[CH:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:35][CH:34]=1)=[O:40])[CH3:37]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described in Example 48 4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 534.4
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)=[CH:21][CH:22]=1>FC(F)(F)C(O)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[NH:27][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:25][N:24]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)nc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.4 %

Procedure:
In trifluoroacetic acid (3.3 mL) and water (0.33 mL) was dissolved 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (327 mg), and the solution was stirred at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid, and isopropyl ether was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-[({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (217 mg).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(CCn1ccnc1)c1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC(CCn1ccnc1)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 1.26 g 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml pyridine is treated dropwise with stirring with 0.72 ml of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[3-benzoyloxy-3-(2-naphthyl)-n-propyl]imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give the hydrochloride salt.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:37])(C)(C)C.[C:39](O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:26]=[CH:25][C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH:17]([CH3:39])[CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:38])=[C:10]([CH3:37])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionic acid tert-butyl ester (120 mg) in methylene chloride (1 mL) is added TFA (0.8 mL) and two drops of water. The mixture is stirred for 2 h, and concentrated and purified by reversed phase HPLC (water-acetonitrile with 0.1% TFA). MS (ES): 491.4 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:19])[CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
A solution of 6.00 g of 4-(t-butoxycarbonyl)piperazine-2-carboxamide and 3.28 g of a 37% aqueous formaldehyde solution in 60 ml of methanol was ice-cooled, and 16.66 g of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 24 hours after removing an ice bath. The reaction solution was again ice-cooled, 3.28 g of a 37% aqueous formaldehyde solution and 16.66 g of sodium triacetoxyborohydride were added thereto. After stirring at room temperature for 16 hours, the reaction solution was diluted with ice water, alkalified with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.42 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=1)[C:34]([NH2:36])=[O:35]>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.C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=3)[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC(=O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1C(=O)Cc2cc(-c3cncc(C(N)=O)c3)ccc21
Temperature: 150 °C

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (75 mg, 0.26 mmol) in 12-dimethoxyethane (0.7 mL) was added water (0.3 mL) and ethanol (0.2 ml). The solution was then charged with sodium carbonate (27.6 mg, 0.26 mmol) and 5-bromonicotinamide (CAS#28733-43-9, 53.5 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 9.1 mg, 0.013 mmol). The reaction vessel was sealed and was heated by microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to room temperature, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (methanol-dichloromethane, 0 to 10%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-nicotinamide; MS: (ES+) m/z 268 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 3H), 3.63 (s, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.62 (br. s., 1H), 7.69-7.75 (m, 2H), 8.22 (br. s., 1H), 8.42 (t, J=2.0 Hz, 1H), 8.94 (dd, J=18.9, 1.96 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:8][C:5]1[N:4]=[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)[C:2]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2Br)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2-c2ccncc2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
To a mixture of tert-butyl (1-(5-bromo-2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (229 mg, 0.564 mmol), pyridine-4-boronic acid (76 mg, 0.618 mmol) and Pd(Ph3P)2Cl2 (40 mg, 0.056 mmol) in dioxane (3 mL), aq. Na2CO3 (180 mg, 1.69 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give tert-butyl (1-(2-chloro-5-(pyridin-4-yl)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (80 mg).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C(O)(=O)C.[Br:17]Br>O>[Br:17][C:3]1[C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=2[S:12][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc2[nH]c(=O)[nH]c(=O)c2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A brown glass round-bottom flask was charged with 6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (2.70 g, 14.8 mmol) and glacial acetic acid (30 ml). Bromine (2.70 ml) was added and the mixture stirred at ambient temperature for 4 hours. The resultant mixture was diluted with water (30 ml) and the solid was collected by filtration, washed thoroughly with water and then dried in vacuo to give 5-bromo-6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a brown solid (2.43 g), which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[I-].[Li+].[F:30][C:31]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:32][CH2:33][CH2:34][S:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>CN1CCCC1=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][CH2:41][CH:37]1[CH2:36][S:35][CH2:34][CH2:33][CH2:32][C:31]([F:46])([F:30])[C:42]([F:43])([F:44])[F:45]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Agent: [I-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
A solution of 785.9 mg of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 7 ml of N-methyl-2-pyrrolidinone is mixed with 535.5 mg of lithium iodide and 520 mg of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, and it is stirred for 2.5 hours at a bath temperature of 100° C. Then, it is poured onto water, extracted 3 times with diethyl ether, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 525 mg of pure 11β-fluoro-3-hydroxy-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained. [α]D22=+29.3° (c=0.5% in chloroform).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][CH:8]=1.CN(C)[CH:29]=[O:30].Cl>CCCCCC.O1CCCC1>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1/[CH:14]=[CH:13]/[C:10]1[CH:11]=[CH:12][C:7]([CH:29]=[O:30])=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(C=O)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6M, 28.7 ml) was added dropwise to a solution of (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.0 g) in tetrahydrofuran (140 ml) at -70° C. The mixture was stirred at -70° C. for 15 minutes, and then a solution of N,N-dimethylformamide (4.2 g) in tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at -70° C. for 30 minutes, and then warmed to room temperature. 1N hydrochloric acid (150 ml) was added dropwise, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:2, v/v) gave (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]-benzaldehyde (5.9 g, 54%). The product was recrystallized from ethyl acetate-hexane. Pale brown prisms, mp: 158-159° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]#[N:12])([CH3:3])[CH3:2].[OH:13]O.[OH-].[Na+]>CS(C)=O.O>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]([NH2:12])=[O:13])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.105 g (0.634 mmol) of (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile in 4.9 mL of dimethyl sulfoxide was placed in a 10 mL flask with a magnetic stir bar. After adding 0.60 mL of 35% hydrogen peroxide and 0.097 g (1.2 mmol) of 50% sodium hydroxide solutions the flask was capped and stirred at room temperature for 20 h. The reaction mixture was diluted with 10 mL of water, extracted twice with 10 mL of methylene chloride. The combined methylene chloride layers were back extracted with 3×20 mL of water, dried over magnesium sulfate, and concentrated in vacuo to provide an off-white solid that was further purified by column chromatography (silica gel, 75:25 hexane:ethyl acetate) to provide (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide.