Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[NH:22]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[N:2][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-n2ccnc2)n(CCCCC#N)c2ccccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(-n2ccnc2)n(CCCCc2nnn[nH]2)c2ccccc12

Procedure:
A mixture of 600 mg of 1-(4-cyanobutyl)-3-methyl-2-(1-imidazolyl)indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of dimethylformamide is heated at 120° overnight. After cooling the mixture is filtered and the filtrate diluted with ca. 25 ml of water. After the pH is adjusted to 10-11 with 3N NaOH, the solution is washed with ether to remove unreacted nitrile. The aqueous phase is adjusted to pH 5-6 with 2N HCl and extracted with ethylacetate. The extract is washed with water, dried over magnesium sulfate and concentrated in vacuo. The solid residue is slurried in petroleum ether and collected to give 1-[4-(5-tetrazolyl)-butyl]-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC.[Cl-].[Li+].CN(C)C=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1cc(C(=O)O)cc(-c2ccco2)c1)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 7 h
Yield: 71 %

Procedure:
A mixture of methyl 3-bromo-5-[methyl(methylsulfonyl)amino]benzoate obtained in Reference Example 15 166 mg (0.5.0 mmol), tri-n-butyl(2-furyl)stannane 0.18 mL (0.55 mmol), lithium chloride 42 mg (0.10 mmol), tetrakistriphenylphosphine palladium(0) 29 mg (0.025 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 100° C. under argon atmosphere for 7 hours. The mixture was diluted with a mixed solvent of ethyl acetate/toluene=1:1 and washed twice with water. After drying of the mixture on magnesium sulfate, the mixture was concentrated and the residual oil was purified by a column chromatography on silica gel (eluted with hexane/ethyl acetate=2:1→1:1). The resulting solid was dissolved in a mixture of 2N aqueous sodium hydroxide solution (2 mL), methanol (2 mL) and tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated and thereto added water and the mixture was washed with a mixed solvent of hexane/ethyl acetate=1:1. The aqueous layer was adjusted by adding 1N hydrochloric acid to pH=3 and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 105 mg (0.355 mmol) of the title compound (yield: 71%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
4-Methoxybenzenesulfonyl chloride (0.04 mL, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 39 (61 mg, 67% yield) as a yellow solid. LC-MS (M+H=379, obsd.=379).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.[CH2:32]([N:34]([CH2:37][CH2:38]Cl)[CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH2:36][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23])[CH3:33]
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(Diethylamino)ethyl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and N,N-diethylaminoethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(OCCCCBr)cc1
Product: CCN(CCO)CCCCOc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester with 2-ethylaminoethanol yielded (4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 421 (MH+).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[C:17]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[CH:26][C:27](OC)=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CO>ClCCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:26][C:27]([NH:16][C:15]2[C:6]([Cl:5])=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:28])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1
Reactant: Nc1cc2ccccc2nc1Cl
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C=CC(=O)Nc2cc3ccccc3nc2Cl)cc1

Procedure:
A solution of trimethylaluminum (2.0 M, 0.61 mL, 1.22 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylcinnamate (0.241 g, 1.11 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours. The solution was cooled and treated with methanol (˜1 mL). The product was preabsorbed on silica gel and eluted with 20% ethyl acetate in hexane, to give the product as a colorless solid, 0.288 g (71%). MS: m/z 365 (MH+). 1H NMR (DMSO-d6): δ 1.31 (m, 9 H), 7.16 (d, 1 H), 7.50 (d, 2 H), 7.59-7.69 (m, 4 H), 7.75 (t, 1 H), 7.95 (d, 1 H), 8.05 (d, 1 H), 8.94 (s, 1 H), and 9.97 (s, 1 H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@H:8]2[CH2:10][C:11](=O)[CH2:12][C@H:7]2[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:5]1[CH2:9][C@H:8]2[CH2:10][C:11](=[N:15][OH:16])[CH2:12][C@H:7]2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCN1C[C@H]2CC(=O)C[C@H]2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCN1C[C@H]2CC(=NO)C[C@H]2C1

Procedure:
A suspension of (3aS,6aR)-2-butylhexahydrocyclopenta[c]pyrrol-5-one (0.467 g, 2.58 mmol), hydroxylamine hydrochloride (0.430 g, 6.19 mmol) and sodium acetate (0.842 g, 6.19 mmol) in ethanol (21 ml) and water (7 ml) is heated to reflux for 1 hour. The ethanol is evaporated and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase is washed with brine, dried (MgSO4) and evaporated to afford (3aS,6aR)-2-butylhexahydrocyclopenta[c]pyrrol-5-one oxime, MH+197.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Cl)=[CH2:12].C1COCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])[CH:11]=[CH2:12]
Reactant: C=C[Mg]Cl
Reactant: Cc1cccc(C=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C)c1O
Temperature: 17.5 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxy-3-methylbenzaldehyde (48.78 g, purity: 40.7%, 0.146 mol) was dissolved in toluene (100 ml), and the mixture was added to a reactor under a nitrogen atmosphere. After the mixture was cooled to 0° C. in ice-water, a solution of vinyl magnesium chloride in THF-toluene (1.77M, 182 ml, 0.32 mol, THF:toluene=1:1 (v:v)) was added thereto over 15 minutes such that the temperature of the mixture did not exceed 25° C. After the mixture was stirred at 15-20° C. for 2 hours, it was cooled to 0° C. A 20% aqueous ammonium chloride solution (250 ml) was added thereto. After the mixture was stirred at 25° C. for 1 hour, the solution was separated. The organic layer was concentrated to obtain 32.36 g (purity: 73.5%, 0.145 mol) of 2-(1-hydroxy-2-propenyl)-6-methylphenol as an orange-colored oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH:31]([CH2:39][N:40]([CH3:42])[CH3:41])[CH2:30]2)=[O:28])=[CH:21][CH:20]=1.C(B(CC)[C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1)C.O>C1(C)C=CC=CC=1.C(O)C.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>[C:7]1([CH3:17])[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[CH3:41][N:40]([CH2:39][CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:29]([C:27](=[O:28])[CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[CH:20][CH:21]=2)[CH2:30]1)[CH3:42]
Reactant: CN(C)CC1Cc2ccccc2N(C(=O)CCc2ccc(Br)cc2)C1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CC1Cc2ccccc2N(C(=O)CCc2ccc(-c3cccnc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
2M Aqueous sodium carbonate solution (1.25 ml) was added to a suspension of 1-[3-(4-bromophenyl)propanoyl]-3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline p-toluenesulfonate (400 mg) in toluene (10 ml) and ethanol (1.25 ml), which was stirred at room temperature for 10 minutes. Diethyl(3-pyridyl)borane (154 mg) and tetrakis(triphenylphosphine)palladium (24 mg) were added to the reaction mixture, which was heated under reflux under an argon atmosphere for 14 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane/ethyl acetate=10/1 to 2/1), which was converted into its p-toluenesulfonate. The mixture was recrystallized from ethanol-IPE to give the entitled compound (250 mg).
Reaction SMILES: BrCCCCCCCCOC1C=CC([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=CC=1.O.C(OCC)(=O)C.[ClH:33]>CC1OC(C)CNC1>[ClH:33].[C:21]([OH:23])(=[O:22])[C:20]1[CH:24]=[CH:25][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: CC1CNCC(C)O1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1

Procedure:
A suspension of 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g) in 2,6-dimethylmorpholine (3.06 ml) was refluxed for 30 minutes. The reaction mixture was added to mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-2,6-dimethylmorpholin-4-yl)octyloxy]phenyl]benzoic acid hydrochloride (0.95 g).
Reaction SMILES: N1C=CN=C1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:31]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:13]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]2)=[CH:25][CH:24]=1)([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: O=C1CCC(c2ccc(O)cc2)(c2ccccc2F)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(c3ccccc3F)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (128 mg, 1.9 mmol) was added to a solution of 6 (214 mg, 0.75 mmol) and TBDMSCl (136 mg, 0.90 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight. NaHCO3 (10 mL, saturated aqueous solution) was added and the mixture was extracted with EtOAc (2×40 mL). The combined organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The concentrate was dissolved in EtOAc (50 mL) and the solution was washed with MgSO4 (4% aqueous solution). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. Yield of crude: 394 mg (>100%) as a thick oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2([OH:19])[C:14]([O:16]CC)=[O:15])=[CH:6][CH:5]=1>CS(C)=O.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2([OH:19])[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(O)CCCc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C1(O)CCCc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
NaOH (10M, 1 mL) was added to a solution of 7-chloro-1-hydroxytetraline-1-carboxylic acid, ethyl ester (0.8 g; 3.1 mmol; from step (iii) above) in DMSO (20 mL), and the mixture was heated to 100° C. for 3 hours. The resultant mixture was diluted with crushed ice (40 g) and brine (40 mL), and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with 2M HCl and extracted with EtOAc (2×40 mL). The combined organic layer was dried (Na2SO4) and concentrated. Yield 0.22 mg (30%).
Reaction SMILES: [CH:1]1([CH:7]([C:13]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7](=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C1CCCCC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Yield: 93 %

Procedure:
A mixture of ethyl 2-cyclohexyl-3,3-bis(4-fluorophenyl)-3-hydroxypropionate (15.0 g, 38.6 mmol) and p-toluenesulfonic acid (2.5 g) in 250 mL of toluene was heated at reflux for 2 hours. The mixture was cooled, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 13.3 g of the title compound; m.p. =50°-55° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.I[CH3:16].[OH-].[Na+]>CS(C)=O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:16])[CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portions to a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), iodomethane (11.8 g, 168 mmol) and dimethylsulfoxide (150 ml). The mixture was stirred at room temperature overnight. Sodium hydroxide (200 ml, 1 M) was added, and the mixture was filtered. Yield 25.1 g, 95%. Mp 76-82° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]1([C:15]#[N:16])[C:10]([O:12]CC)=[O:11].[OH-].[K+]>>[CH3:17][C:2]1([CH3:1])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]1([C:15]#[N:16])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1C(C)(C)C1(C#N)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C1C(C)(C)C1(C#N)C(=O)O
Yield: 90.6 %

Procedure:
A mixture of 2 g of ethyl 2,2-dimethyl-3-ethoxycarbonyl-1-cyano-cyclopropane-1-carboxylate (prepared as in U.S. Pat. No. 3,397,223) and 4.71 g of 10% ethanolic potassium hydroxide was stirred under an inert atmosphere for 15 hours and the ethanol was then evaporated under reduced pressure. The residue was washed with ether and was then taken up in ether. The pH of the solution was adjusted to 3 by addition of dilute sulfuric acid and the decanted ether phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 1.6 g of 2,2-dimethyl-3-ethoxycarbonyl-1-cyano-cyclopropane-1-carboxylic acid with a melting point of ≃130° C. (decomposition).
Reaction SMILES: C(O)(=O)C.[O:5]([CH:13]1[CH2:30][CH2:29][C@@:28]2([CH2:31][OH:32])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C:22]2=[O:33])[CH2:14]1)[Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([O-])(=O)C>>[O:5]([CH:13]1[CH2:30][CH2:29][C@@:28]2([CH2:31][OH:32])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[OH:33])[CH2:14]1)[Si:6]([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1

Procedure:
Substituting 3-t-butyldimethylsiloxy-19-hydroxy-5-androsten-17-one acetate and 19-hydroxy-3β-(4'-tetrahydropyranyloxy)-5-androsten-17-one acetate for the 19-hydroxy-3β-(2'-tetrahydropyranyloxy)-5-androsten-17-one, acetate above results in the preparation of 3-t-butyldimethylsiloxy-5-androsten-17β,19-diol and 3β-(4'-tetrahydropyranyloxy)-5-androstene-17β,19-diol, respectively.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH2:6][C:7](=O)[CH2:8][CH3:9].[NH2:11][C:12]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[CH:20][C:13]=1[C:14](OC(C)C)=[O:15].Cl>C1(C)C(C)=CC=CC=1.CO>[CH2:8]([C:7]1[NH:11][C:12]2[C:13]([C:14](=[O:15])[C:6]=1[CH3:5])=[CH:20][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=1)=[C:22]([CH3:24])[CH:23]=2)[CH3:9]
Reactant: Cc1cc(N)c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Reactant: CCC(=O)CC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Temperature: 25 °C
Yield: 83 %

Procedure:
Aluminum chloride (30.0 g) and 125 ml of xylene were added into a 1000-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and Dean-Stark device under a nitrogen gas stream. 3-Pentanone (58.1 g) was added dropwise thereto with stirring at 10° C. or below. Subsequently, 60.55 g of isopropyl 2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate dissolved in 250 ml of xylene was added dropwise thereto at room temperature, and the mixture was heated under reflux for 6 hr. A mixture composed of 5.0 g of aluminum chloride, 65 ml of xylene, and 9.69 g of 3-pentanone was added into the reaction solution, and the mixture was further heated under reflux for 18 hr. After the completion of the reaction, the reaction solution was allowed to cool at room temperature. The reaction solution was added little by little to 150 ml of a 5% aqueous hydrochloric acid solution prepared in a separate 1000-ml glass flask. Further, 150 ml of methanol was added thereto, and the mixture was heated under reflux for about one hr. The reaction mixture was allowed to cool at room temperature and was collected on a suction filter. The reaction mixture was washed with an aqueous methanol solution and was dried to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one as a light brown solid (51.33 g, yield: 90.7%).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([O:9][C:10](=[O:13])[CH2:11][OH:12])=[O:8])(=O)C.[OH-].[NH4+].Cl>O>[SH:4][CH2:5][CH2:6][C:7]([O:9][C:10](=[O:13])[CH2:11][OH:12])=[O:8]
Reactant: CC(=O)SCCC(=O)OC(=O)CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(CO)OC(=O)CCS

Procedure:
O-(3-acetylthiopropanoyl)glycolic acid from Example 1 (1.3 g), under a blanket of argon is treated for fifteen minutes with a cold solution of 7 ml of water and 7 ml of concentrated ammonium hydroxide. This is chilled, acidified with concentrated hydrochloric acid and extracted into ethyl acetate, yield: 1.2 g. This product O-(3-mercaptopropanoyl)glycolic acid is chromatographed on DEAE Sephadex A25 (Polidextrane anion exchange resin) with a linear gradient of ammonium bicarbonate. The desired fractions (45-70; U.V. peak at 254 nm.) are pooled, concentrated and lyophilized. This ammonium salt of O-(3-mercaptopropanoyl)glycolic acid is converted to the free acid by treatment with Dowex 50WX2 cation exchange resin, yield 320 mg. The O-(3-mercaptopropanoyl)glycolic acid is converted to the dicyclohexylamine salt by dissolving in ether and precipitating by the addition of dicyclohexylamine, m.p. 143°-144°.