Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=C[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[C:20]([CH3:23])=[CH:21][CH:22]=1.[C:27]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:7]([CH:8]=[O:9])=[CH:2][N:3]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)=[C:19]([CH3:27])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cnc(-c2ccccc2)nc1Cl
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1nc(-c2ccccc2)ncc1C=O
Temperature: 85 °C
Yield: 88.7 %

Procedure:
To a stirred solution of 4-chloro-2-phenylpyrimidine-5-carbaldehyde (50 mg, 0.23 mmol) and 4-chloro-o-toluene boronic acid (48 mg, 0.29 mmol) in dioxane (1 mL) and H2O (0.5 mL) was added Pd(PPh3)4 (26.5 mg, 0.02 mmol), K2CO3 (126.5 mg, 0.92 mmol). The reaction was heated to 85° C. for 6 hrs. After concentration under reduced pressure, the residue was diluted with EtOAc (10 mL) and the organic layer was washed with saturated NH4Cl solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product (70 mg). The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give 4-(4-chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde (63 mg, 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:12]([CH3:24])[NH:11][C:10]([O:25]C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC(O[C:31]1[CH:36]=[CH:35][C:34]([N+]([O-])=O)=[CH:33][CH:32]=1)=O.[C:40](=[O:43])([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:12]([CH3:24])[NH:11][C:10](=[O:25])[N:9]2[C:40](=[O:43])[NH:11][CH2:12][CH2:13][CH:8]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(C)N1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
558 mg (1.50 mmol) of benzyl 4-(3-chlorophenyl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylate and 364 mg (1.81 mmol) of p-nitrophenyl chloroformate were dissolved in 10 ml of dichloromethane. 1 ml of saturated sodium hydrogencarbonate solution was added to the obtained solution at 0° C., and they were stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane and then washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The product was washed with ether and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[F:28])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4ccccc4F)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-fluorobenzoyl chloride gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[C:36](Cl)[N:35]=[N:34][C:33]=2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:36]2[N:35]=[N:34][C:33]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:31][CH:30]=3)[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.13 mmol, 240 mg) in THF (10 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.56 mmol, 200 mg) was added. The resulting mixture was stirred at 50-55° C. over night, then was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][O:26]C4CCCCO4)[C:20]([O:33][CH3:34])=[CH:19][C:18]=3[N+:35]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[H][H].[CH:40](O)=O>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([O:23][CH2:24][CH2:25][OH:26])[C:20]([O:33][CH3:34])=[CH:19][C:18]=4[N:35]=[CH:40]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCOC1CCCCO1
Reactant: [H][H]
Reactant: O=CO
Agent: [Pd]
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.470 g (0.86 mmole) of 4-(3-chloro-phenyl)-2-{4-methoxy-2-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenylamino}-thiazole-5-carboxylic acid amide (VI.44), 0.250 g of 10% palladium on carbon catalyst and 3 mL of 96% formic acid was stirred under 1 atmosphere of hydrogen for 16 hours. The mixture was filtered through diatomaceous earth and the diatomaceous earth pad was washed with formic acid. The filtrate was heated at reflux for 2 hours, cooled and concentrated under reduced pressure. The residue was dissolved in 5 mL of dimethylsulfoxide and 0.20 g of potassium hydroxide in 1 mL of water was added dropwise. The mixture was stirred at room temperature for 30 minutes and then diluted with 50 mL of water. The resulting precipitate was collected by filtration and washed with water to give 0.190 g of 4-(3-chloro-phenyl)-2-[6-(2-hydroxy-ethoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.44a) as a purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([S:22][CH3:23])[CH2:14][CH2:15][C@H:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([S:22][CH3:23])[CH2:14][CH2:15][C@H:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](SC)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS[C@@H]1CC[C@H](C(=O)O)Cc2onc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
0.024 g (0.068 mmol) of methyl cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylthio-4H-cyclohept[d]isoxazole-7-carboxylate was stirred in 5 ml of dioxane and 2 ml of 1N aqueous sodium hydroxide solution were added. The mixture was stirred at room temperature for 1 hour. Water was then added and the solution was partially evaporated. The aqueous solution was acidified with 1N hydrochloric acid and the precipitate was collected, washed with water and dried to give 0.0146 g of cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylthio-4H-cyclohept[d]isoxazole7-carboxylic acid of melting point 241°-242° C.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[N+:16]([C:19]1[C:20]([NH:28][CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)=[C:21]2[S:27][CH:26]=[CH:25][C:22]2=[N:23][CH:24]=1)([O-:18])=[O:17]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[OH:35][C:32]1([CH2:2][C:1]#[N:4])[CH2:31][CH2:30][CH:29]([NH:28][C:20]2[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][N:23]=[C:22]3[CH:25]=[CH:26][S:27][C:21]=23)[CH2:34][CH2:33]1
Reactant: CC(C)NC(C)C
Reactant: O=C1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC1(O)CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
A solution of N,N-diisopropylamine (0.19 mL, 1.4 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. 1.6 M n-butyllithium in hexanes (0.86 mL, 1.4 mmol) was added dropwise, keeping the temperature below 5° C. After the addition was complete, the mixture was stirred for 20 min at 0° C. The mixture was then cooled to −78° C. and acetonitrile (0.072 mL, 1.4 mmol) was added, keeping the temperature below −70° C. After the addition was complete, the mixture was stirred for 20 min at −78° C. and a mixture of 4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanone (0.20 g, 0.69 mmol) in tetrahydrofuran (3 mL)/hexamethylphosphoramide (3 mL) was added, keeping the temperature below −70° C. After the addition was complete, the mixture was stirred for 30 min at −78° C. and then stirred at room temperature for 5 h. The mixture was partitioned between methylene chloride and sat. aq. NH4Cl solution. The organic phase was washed with water, dried over sodium sulfate, concentrated and purified on silica gel column (eluting with 0-30% EtOAc in methylene chloride) to give the desired product (0.11 g, 48%). LCMS calculated for C15H17N4O3S (M+H)+: m/z=333.1. Found: 333.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2C(O)=O)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].O.[OH:34][C:35]1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:35](=[O:34])[C:18]1[CH:19]=[CH:20][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:23])([F:24])[F:22])=[CH:13][CH:17]=1)[CH3:27]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH:19]=[CH:20]N(C)C)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc(Cl)c3)ccnc12
Yield: 43.7 %

Procedure:
A mixture of 13.9 g of 4-amino-5-imidazolecarboxamide hydrochloride, 24.0 g of 3'-chloro-3-dimethylaminoacrylophenone (U.S. Pat. No. 4,209,621, Ex. 50) and 200 ml of glacial acetic acid was heated at reflux for 5 hours. The liquid was evaporated in vacuo to give a yellow solid. The excess acid was neutralized with saturated sodium bicarbonate solution and this mixture was filtered and the solid was washed with water and then was dried. Recrystallization from ethanol-methanol gave 10.2 g of the desired product as yellow crystals, mp 252°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(OC(Cl)=O)C.[NH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1>C(Cl)Cl>[OH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:21][CH2:22]1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: OC1CCNCC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCC(O)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.901 g, 5 mmol) in DCM (25 mL) was added TEA (0.697 mL, 5.00 mmol), EtOCOCl (0.480 mL, 5.0 mmol). This mixture was stirred at 0° C. for 10 mins and then 4-piperidinol (0.506 g, 5.00 mmol) was added. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM (35 mL), washed with HOAc (20 mL, 10%), NaHCO3 (20 mL, 10%), water (20 mL), dried over Na2SO4, filtered and concentrated and purified by CombiFlash chomatograph to afford the title compound (0.696 g, 53%). LC-MS m/z 264 (M+H)+.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][NH:17][S:16]1(=[O:22])=[O:21])[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:16]1(=[O:22])=[O:21])[CH2:9]2
Reactant: BrCc1ccccc1
Reactant: O=C(CN1CCCNS1(=O)=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCN(Cc2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To N-(adamantan-2-yl)-2-(1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide hydrochloride (50 mg, 0.135 mmol) in DMF (1 mL), were added K2CO3 (93.3 mg, 0.675 mmol) and (bromomethyl)benzene (46.2 mg, 0.27 mmol). The reaction mixture was agitated for 4 hr at room temperature and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield N-(adamantan-2-yl)-2-(6-benzyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide (53 mg, 94%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.72-7.69 (brd, 1H), 7.39-7.28 (m, 5H), 4.17 (s, 2H), 3.86-3.83 (m, 1H), 3.79 (s, 2H), 3.46-3.42 (m, 2H), 3.17-3.14 (m, 2H), 1.93-1.89 (m, 2H), 1.80-1.67 (m, 12H), 1.52-1.48 (m, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]1([CH:10]2[CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[O:13][B:12]([CH:21](Cl)[CH2:22][CH:23]([CH3:28])[C:24]([CH2:26][CH3:27])=[CH2:25])[O:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1>[CH:4]1([CH:10]2[CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[O:13][B:12]([CH:21]([CH3:1])[CH2:22][CH:23]([CH3:28])[C:24]([CH2:26][CH3:27])=[CH2:25])[O:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[Mg]Br
Reactant: C=C(CC)C(C)CC(Cl)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Solvent: C1CCOC1
Product: C=C(CC)C(C)CC(C)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Reaction time: 20 h

Procedure:
Methylmagnesium bromide (3.0 M in ether, 13.3 mL, 40 mmol) was added to a stirred solution of [4R-[2(S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(5-chloro-2-ethyl-3-methylpenten-5-yl)-1,3,2-dioxaborolane (15.2 g, 40 mmol) in THF (250 mL) at -78° C. over a period of 20 min. The bath was allowed to warm to 20°-25° C. and the reaction mixture was stirred for 20 h. The solution was concentrated under vacuum and ether (200 mL) was added to the residue. The ethereal solution was washed with saturated aqueous ammonium chloride (2∞200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to liquid [4R-[2(S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(2-ethyl -3,5-dimethylpenten-5-yl)-1,3,2-dioxaborolane (12a) (13.8 g, 96%); 300 MHz 1H-NMR (CDCl3) δ0.84-2.27 (m, 37), 3.81 (m, 2), 4.68 and 4.74 (AB, 2); 75 MHz 13C-NMR (CDCl3) 12.3, 16.2, 20.2, 25.9, 26.0, 26.4, 27.4, 28.28, 28.34, 39.2, 39.5, 43.0, 83.2, 106.7, 156.3). HRMS: calcd for C23H41BO2 (M+) 360.3200, found: 360.3199.
Reaction SMILES: [CH3:1][C@@:2]1([F:22])[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:21])[C@:16]1([CH3:17])[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[BH4-].[Na+]>[Pd]>[CH3:1][C@@:2]1([F:22])[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@@H:3]1[OH:21])[C@:16]1([CH3:17])[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH3:1][C@@:2]1([F:22])[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@H:3]1[OH:21])[C@:16]1([CH3:17])[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@](C)(F)C[C@@H]12
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C[C@@](C)(F)[C@H]2O
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@](C)(F)C[C@@H]12

Procedure:
Similary, catalytic hydrogenation over 5% palladium on carbon of the 16β-methyl-16α-fluoro-5-androsten-17-one produced in Example 5 followed by treatment with sodium borohydrid affords 16β-methyl-16α-fluoro-5α-androstan-17α-ol and 16β-methyl-16α-fluoro-5α-androstan-17β-ol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:33].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:66]=[O:67].[CH2:69]([OH:71])[CH3:70]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:69]([O:71][C:66]([C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:34])=[C:6]([F:33])[CH:7]=3)=[CH:22][CH:21]=2)[C:16]([CH3:31])([CH3:32])[CH2:17][CH:18]=1)=[O:67])[CH3:70]
Reactant: CCO
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1F
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)c(F)c3)ccc21

Procedure:
Following General Procedure E and using [4-(8,8-dimethyl-5-trifluoromethanesulfonyloxy-7,8-dihydro-naphthalen-2-ylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester (Intermediate 203, 0.32 g, 0.65 mmol), palladium acetate (0.015 g, 0.064 mmol), 1,3-bis(diphenylphosphino)propane (0.027 g, 0.064 mmol), N,N-dimethylformamide (55 mL), ethanol (2 mL) and triethyl amine (2 mL) followed by flash column chromatography over silica gel (230–400 mesh) using 5–15% ethyl acetate in hexane as the eluent the title compound was obtained (0.15 g, 55%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[I-:11].[Na+].NCCN.N>[Cu]I.O.O1CCOCC1>[I:11][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: NCCN
Solvent: C1COCCO1
Solvent: O
Product: OCCc1ccc(I)cc1

Procedure:
0.474 g (2.48 mmol) of copper (I) iodide, 5 g (24.86 mmol 2-(4-bromophenyl)ethanol and 7.45 g (49.73 mmol) of sodium iodide are successively added to a flask under an argon atmosphere. Then 0.438 g (4.97 mmol) of dimethylenediamine and 25 mL dioxane are added and the reaction mixture is refluxed for 14 hours. Then the reaction mixture is combined with 20 mL concentrated ammonia solution at ambient temperature, with 100 mL of water diluted and extracted with dichloromethane. The organic phase is extracted three times with water and dried over sodium sulfate. Yield: 5.4 g (87.5% of theory); C8H9IO (M=248.06); calc.: molecular ion peak (M)+: 248; found: molecular ion peak (M)+: 248; Rf value: 0.6 (silica gel, dichloromethane/ethanol (10:1)).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)=O.S(C)C>C1COCC1>[F:1][C:2]([F:19])([F:20])[CH2:3][NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)CC2
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)[C@H](NCC(F)(F)F)CC2
Yield: 43 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2,2,2-trifluoroacetamido)-2,3-dihydro-1H-indene-5-carboxylate (1.8 g, 6.27 mmol, 1.0 eq.) in THF (30 ml) is added BH3.Me2S (0.9 ml, 9.4 mmol, 1.5 eq.) drop wise and the reaction mixture is heated at reflux for 2 h. The reaction mixture is then quenched with MeOH (0.5 ml) and then partitioned between water (30 ml) and ethyl acetate (100 ml). The organic layer is washed with brine (30 ml), dried over anhydrous Na2SO4 and evaporated to get the crude which is purified by column chromatography (silica gel; 4% ethyl acetate/hexanes) to yield the desired compound as a colourless oil. Yield: 43% (730 mg, 2.67 mmol).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[OH2:26]>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:26][CH2:3][CH2:2][CH2:1][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[O:14][CH2:1][C:4]2[CH:13]=[CH:12][CH:11]=[CH:6][CH:5]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: C=CCc1ccc2ccccc2c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2ccc3ccccc3c2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of the product of Example 118 Part C (9.10 g. 0.031 mole) in pyridine (150 mL) was stirred at 0° and treated with p-toluenesulfonyl chloride (6.70 g, 0.035 mole). then stirred for 16 hours at room temperature. The solution was poured into water. ,and the mixture extracted with ethyl acetate. The resulting oil was chromatographed with 4:1 hexane/ether to provide the title compound (3.20 g, 23%) as an oil.