Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[NH2:43])[CH2:33][CH2:32]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:43][C:42]3[CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=[C:40]([O:39][CH2:38][CH2:37][N:34]4[CH2:33][CH2:32][O:31][CH2:36][CH2:35]4)[CH:41]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Nc1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN4CCOCC4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (70.9 mg, 0.172 mmol) and 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (50 mg, 0.172 mmol) in pyridine (5 mL) was added T3P® (50% in EA, 0.3 mL) dropwise and the mixture was stirred at 25° C. for 1 h. The mixture was quenched with cold water (20 mL), extracted with DCM/MeOH (10:1, v/v, 20 mL×3). The organic layer was dried over Na2SO4 and concentrated to give an off white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide (80 mg, 0.111 mmol, 64.5% yield): 1H NMR (400 MHz, CD3OD): δ 7.94 (d, J=1.8 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.45-7.35 (m, 6H), 6.95-6.88 (m, 3H), 5.35 (s, 2H), 4.20-4.10 (m, 4H), 3.80 (s, 2H), 3.78 (s, 3H), 3.73-3.66 (m, 4H), 2.81 (t, J=5.4 Hz, 2H), 2.59 (d, J=4.2 Hz, 4H), 1.41 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 684 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=[O:11])[CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[C:14]1([CH:24]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:12])=[O:11])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCC(=O)OC
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=Cc1cccc2ccccc12)C(=O)O
Yield: 42.8 %

Procedure:
8.17 g (0.19 mole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 25 g (0.16 mole) of dimethyl glutarate and 23.4 g (0.16 mole) of 1-naphthaldehyde dissolved in 200 ml of anhydrous methanol. The mixture was heated under reflux for 30 minutes, after which 190 ml (0.19 mole) of a 1N aqueous solution of sodium hydroxide were added to it, and the mixture was again heated under reflux for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with water and washed with diethyl ether. The aqueous layer was acidified and then extracted with diethyl ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then diisopropyl ether was added to the residue to precipitate crystals, which were collected by filtration to give 18.5 g of 2-(1 -naphthylmethylene)glutaric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:5]=[CH:4][C:3]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCC[C@@H](CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC[C@@H](COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 81.5 %

Procedure:
850 mg of (R)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 50 ml THF were treated with 810 mg of triphenylphosphine, 470 mg of methyl 4-hydroxybenzoate and 0.49 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 1 g of (R)-methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoate as a colorless oil, [α]D=−23.3 (c=0.307, in CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.I[CH2:14][CH3:15].C(N1C2C=C(N)C=CC=2N=C1)C>>[CH2:14]([N:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][C:6]=2[N:10]=[CH:9]1)[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: CCn1cnc2ccc(N)cc21
Product: CCn1cnc2cc(N)ccc21

Procedure:
In accordance with Example 68 (Step 2), 5-nitrobenzoimidazole was used instead of 4-nitro-1H-indole, and iodoethane was used instead of (S)-tetrahydrofuran-3-yl methanesulfonate to obtain 1-ethyl-1H-benzo[d]imidazol-5-amine (317 mg) and 1-ethyl-1H-benzo[d]imidazol-6-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]3=[O:22])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]3=[O:22])=[CH:8][CH:9]=1
Reactant: CCCCCN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example 3, a solution of 5.3 g of 1-(4-nitrophenyl)-3-n-pentyl-3-azabicyclo[3.1.0]hexane-2,4-dione in 150 ml of ethanol is hydrogenated in the presence of 0.25 g of 5% palladium on carbon and worked up, affording the title compound which melts at 113°-115° C. after recrystallisation from ethyl acetate/petroleum ether.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][N:8]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[NH2:3][C:4]1[S:5][C:6]([S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:24])=[CH:7][N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2ccccn2)s1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2ccccn2)s1
Yield: 106.5 %

Procedure:
To a solution of 2-amino-5-(2-pyridylthio)thiazole dihydrochloride (4.0 g) in chloroform (100 ml) was dropwise added the solution of 3-chloroperbenzoic acid (5.0 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(2-pyridylsulfinyl)thiazole (3.4 g, yield: 78.9%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:30][C:29]=2[CH:40]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:38])[CH3:39])[C:34]([O:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:4]=3)=[O:35])=[CH:30][C:29]=2[CH:40]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1ccc(F)c(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for about 1 hour and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography, gives 4-fluoro-3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[F:18])C>ClC(Cl)C>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[F:18]
Reactant: CN(C)CCCCCOCc1cc(Br)ccc1F
Solvent: CC(Cl)Cl
Product: CNCCCCCOCc1cc(Br)ccc1F

Procedure:
In a 25 ml flask, under a nitrogen atmosphere, N,N-dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine (696 mg, 1.87 mmol) was dissolved in dichloroethane (6.0 ml). To this solution ACE•Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction mixture was refluxed for twenty hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: CS([N:5]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[C:7]2([CH2:11][CH2:10][N:9]([CH2:12]/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:8]2)[CH2:6]1)(=O)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:7]3([CH2:11][CH2:10][N:9]([CH2:12]/[CH:13]=[CH:14]/[C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)[CH2:8]3)[CH2:6][NH:5][C:27]2=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2cc(Cl)ccc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(/C=C/CN2CCC3(CNc4ccc(Cl)cc43)C2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A solution of 1-methanesulfonyl-5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] obtained in Step D (256 mg) in toluene (25 ml) under argon was treated with sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al, 65% in toluene, 0.67 ml) and the reaction mixture was stirred at 100° C. for 1 hour, cooled to room temperature, quenched by addition of ethyl acetate (10 ml), stirred for 15 min and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent ethyl acetate methanol 95:5) to afford 5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (157 mg) as a yellow oil, which was characterised by its mass and NMR spectra.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[CH3:42][C:39]1[CH:38]=[CH:37][C:36]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)([OH:35])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:24][CH:23]=3)[OH:21])[CH2:13][CH2:12]2)=[CH:41][CH:40]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccc(C)cc3)c3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(CCCC(O)c3ccc(C(C)(C)C(=O)O)cc3)CC2)cc1
Yield: 34.7 %

Procedure:
To 350 mL of methanol in a 1 L round bottom flask equipped with a mechanical stirrer was added 5.3 g (9.8 mmol) of methyl 4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 9, 5.1 g (0.13 mol) of solid sodium hydroxide, and 100 mL of water. The mixture was heated to reflux for 3 hr. After cooling, the methanol was removed in vacuo, and 6 N hydrochloric acid was added dropwise until the solution was no longer basic (pH=7). The solution was extracted three times with ethyl acetate. The organic layers were combined and a white crystalline solid precipitated out of solution. The solid was washed with ether to provide 1.8 g (34%) of 4-[4-[4(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid, as the dihydrate, mp 208-215 C. Analysis. Calcd. for C34H43NO4-2(H2O): C, 72.18; H, 8.37; N, 2.47. Found: C, 72.02; H, 8.36; N, 2.41.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[NH:34]1C=N[N:36]=[N:35]1>>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:13]2[C:5]3[O:4][C:3]([C:1]4[NH:36][N:35]=[N:34][N:2]=4)=[CH:8][C:7](=[O:9])[C:6]=3[CH:10]=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: c1nnn[nH]1
Reactant: N#Cc1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Product: O=c1cc(-c2nnn[nH]2)oc2c(COc3ccc(OCc4ccc5ccccc5n4)cc3)cccc12

Procedure:
When the nitrile of Example 12, Step 7 is replaced with the cyano product from Example 33, Step 4 above, 5- 8-(4-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1- benzopyran-2-yl)tetrazole is obtained; m.p. >250° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH2:16][CH:15]=[C:14]1[CH2:13][C:12](=[O:28])[CH:11]=[CH:10]2.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C@@H:21]([OH:27])[CH2:20][CH2:19]4)[CH2:16][CH:15]=[C:14]1[CH2:13][C@@H:12]([OH:28])[CH:11]=[CH:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)C=C[C@@]43COC3CCCCO3)[C@@H]1CCC2=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43COC3CCCCO3)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A tetrahydrofuran solution of 19-tetrahydropyranyloxy-1,5-androstadiene-3,17-dione is added under nitrogen to a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran. After stirring overnight at room temperature, an aqueous solution of potassium tartrate is added with stirring to form a readily filterable white solid. The reaction mixture is filtered, the filtrate dried over magnesium sulfate and the solvent removed by evaporation. The residue which remains is crystallized from an acetone solution to yield 19-tetrahydropyranyloxy-1,5-androstadiene-3β,17β-diol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:20]([NH2:21])=[N:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:20]([NH:21][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:19][C:13]=2[N:14]=1
Reactant: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)ccc(Cl)c1Cl

Procedure:
The procedure of Example 2 was followed to react 0.30 g of 6-(2,3,6-trichloro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 85 with tert-butyl isocyanate (0.108 mL). The product is purified by medium pressure chromatography (MPLC) using silica gel and eluting with 1:1 CHCl3 :EtOAc to afford the title compound; mp 329°-330° C., CIMS (1% ammonia in methane): m/z (relative intensity) 439 (MH+ -1, 3), 441 (MH+ +1, 3), 84 (100).
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N1CCNCC1)CC1C=CC=CC=1.[CH:41]1([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:51][CH2:52]2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCC(CCCN2CCNCC2)CC1
Reactant: Clc1cc(Br)ccc1OCc1ccccc1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 100.4 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene was replaced with 1-benzyloxy-4-bromo-2-chlorobenzene (861 mg), and l-phenethylpiperazine was replaced with 1-(3-cyclohexylpropyl)piperazine (730 mg). Whereby obtained crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=10:1) to provide 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine (1.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:47])([CH2:41][N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C@H:22]([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[O:27][CH2:26]1)[CH3:23]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:47])([CH2:41][N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C@H:22]([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[O:36])=[CH:39][CH:40]=2)[O:27][CH2:26]1)[CH3:23]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: Cc1ccc(N)cc1
Agent: C[Al](C)C
Product: Cc1ccc(NC(=O)c2ccc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)cc2)cc1

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available p-toluidine (128 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (166 mg, yield 96%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7](O)(=[O:16])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CCOCC>[CH2:7]([OH:16])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCC/C=C/CO
Reaction time: 1 h

Procedure:
A 500 ml flask with a reflux condenser, mechanical stirrer and a dropping funnel, and protected from moisture with a drying tube is charged with LiAlH4 (6.1 g, 0.16 mole) and 200 ml ether. A solution of trans-2-nonenoic acid (7.8 g, 0.05 mole) in 25 ml ether is added at a rate to maintain refluxing. Refluxing is continued for 1 hour and the mixture cooled. Exess reagent is destroyed by the addition of ethyl acetate (5 ml) followed by acidification with 5M HCl. The organic layer is separated, washed with water, dried and distilled under vacuum to give trans-2-nonenol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([Cl:37])=[CH:6][CH:7]=[C:8]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].[Cl-].[NH4+]>CN(C)C=O>[Cl:3][C:4]1[C:5]([Cl:37])=[CH:6][CH:7]=[C:8]([C:10]2[N:11]([S:39]([CH3:38])(=[O:41])=[O:40])[C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=1
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)c(Cl)c3)[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)c(Cl)c3)n(S(C)(=O)=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 13 mg, 0.3 mmol) was added to a solution of 1-{3-[2-(5-chloro-4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 85, 52 mg, 0.1 mmol) in N,N-dimethylformamide (1 mn) and the mixture was stirred at room temperature for 5 min. Methanesulfonyl chloride (10 μl, 15 mg, 0.13 mmol) was added and the mixture was stirred at room temperature for 10 min. Further sodium hydride (60% dispersion in mineral oil, 50 mg, 1.2 mmol) and methanesulfonyl chloride (20 μl, 30 mg, 0.26 mmol) were added and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with aqueous ammonium chloride (10%, 10 mL) dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (50:50) to give the title compound as a colorless glass (30 mg, 51%). 1H NMR (360 MHz, CDCl3) δ8.04 (1H, d, J 8.8 Hz), 7.62 (1H, d, J 2.1 Hz), 7.45 (2H, d, J 8.5 Hz), 7.37 (2H, d, J 8.5 Hz), 7.36 (1H, dd, J 8.8, 2.1 Hz), 7.03 (1H, t, J 7.7 Hz), 6.94-6.85 (3H, m), 3.87 (3H, s), 3.75 (2H, m), 3.38 (2H, m), 2.98-2.86 (6H, m), 2.81 (3H, s), and 2.45 (2H, m). m/z (ES+) 586, 588 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](OC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A solution of methyl 3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)propionate (117 g, 0.4 mol) in 200 ml of anhydrous ether was added dropwise to a mixture of lithium aluminum hydride (17 g, 0.45 mol) and anhydrous ether (800 ml) under an inert atmosphere with ice-water cooling. After the addition was completed, the reaction mixture was heated at reflux temperature for one hour, then cooled to room temperature. To the cooled mixture was added dropwise 80 ml of 3% sodium hydroxide aqueous solution with vigorous stirring and with ice-water cooling. After the addition was completed, the mixture was stirred at room temperature for 30 minutes. A white precipitate was separated by filtration and washed with ether. The filtrate and washings were combined and evaporated. The residue was vacuum distilled to give 101 g (95%) of the product.