Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:22]N1C(=O)CCC1=O>C(#N)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:22])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Cl)cc21
Reaction time: 8 h
Yield: 391.8 %

Procedure:
A solution of N-trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g, 1.99 mmol) in acetonitrile (20 mL) was treated with N-chlorosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 60 C. The product mixture was concentrated, diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.421 g of a clear oil. MS calculated for C15H17ClF3NO2+H: 336, observed: 336.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:17])=[CH:18][CH:19]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Agent: Br
Product: Nc1ccc(CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 20 g (78 mmol) of 4-[2-[3,4-dimethoxyphenyl)ethyl]aniline which is prepared in Preparation 1 above and 300 ml of of 48% hydrobromic acid is stirred at reflux under nitrogen for seven hours and at room temperature overnight. The resultant precipitate is collected, washed with ether, and redissolved in 1N.NaOH. The solution is acidified to pH 6 with glacial HOAc and the resultant precipitate is collected as crude product. Recrystallization from H2O and then from MeOH yields the 4-[2-(3,4-dihydroxyphenyl)ethyl]benzenamine as an acetate salt; yield, 13.4 g (76%), mp 216°-218° C.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: CC(O)CCC(=O)[O-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
80 g (0.57 mol) of sodium 4-hydroxypentanoate and 184.1 g (0.57 mol) of tetrabutylammonium bromide are suspended in 1.2 liters of abs. dimethyl formamide and the suspension is stirred for 15 minutes at room temperature. Then 67.8 ml (0.57 mol) of benzyl bromide are added dropwise and the reaction mixture is stirred for 15 hours at room temperature. The solution so obtained is diluted with water and extracted three times with ether. The organic phases are washed once with water and once with brine. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives 63.1 g of benzyl 4-hydroxypentanoate of b.p. 139°-140° C./2.10-2 torr as a colourless oil.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][C:7]([NH2:22])=[C:6]([NH2:23])[CH:5]=1.[C:24](=S)=[S:25].CC(O)=O>CCO.O>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:9]2[C:4]([Cl:3])=[CH:5][C:6]3[NH:23][C:24](=[S:25])[NH:22][C:7]=3[CH:8]=2)=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: S=c1[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc2[nH]1
Temperature: 110 °C

Procedure:
A 2 mL Biotage™ microwave was charged with solid KOH (18.0 mg, 0.326 mmol), water (0.2 mL), a solution of compound 2-2 (64.0 mg, 0.217 mmol) in EtOH (1.2 mL) and carbon disulfide (65 uL, 1.1 mmol). The vial was capped and stirred at rt until KOH dissolved then heated in a microwave synthesizer (Biotage Initiator™) at 110° C. for 10 min. Contents of the vial were transferred to a 20 mL scintillation vial, diluted with water (6 mL) and acidified by a dropwise addition of 10% aqueous AcOH. The resulting suspension was centrifuged, the supernatant was decanted and the resulting brownish precipitate was washed with 10% aqueous AcOH (3 mL) and water (three times, 3 mL). The precipitate was then dissolved in EtOAc and passed through a short plug of neutral alumina. The EtOAc solution was evaporated to dryness in vacuo to give the crude product as yellow solid. LR-MS (API-ES): calculated for C19H13ClN2S 336.1, observed m/e 337.0 (M+H)+ (Rt 3.12 min). The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:12])[CH2:10]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]1[CH:18]2[CH2:19][C:20]3([NH2:23])[CH2:22][CH:16]([CH2:17]2)[CH2:15][CH:14]1[CH2:21]3>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:12])[CH2:10][NH:23][C:20]23[CH2:19][CH:18]4[CH2:13][CH:14]([CH2:15][CH:16]([CH2:17]4)[CH2:22]2)[CH2:21]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: OC(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: Cl
Product: OC(CNC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
27 g (0.1 mol) of 1-(3,4-dichlorophenyl)-2-bromoethanol are added to a solution of 30 g (0.2 mol) of 1-adamantamine, 0.1 g of KI and 100 ml of ethanol; the mixture is stirred for 48 hours at 20° C. and 6 hours under reflux.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (25 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.687 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.92 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.1-2.9 (m, 6H), 2.75 (m, 1H), 2.60 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated for C12H16BrNO+H: 270, observed: 270.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:2]2.[Br:30][CH2:31][C:32]([NH:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)=[O:33]>C(#N)C>[Br-:30].[OH:28][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:10]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH2:31][C:32](=[O:33])[NH:34][C:35]3[CH:39]=[CH:38][O:37][N:36]=3)([CH2:6][CH2:5]2)[CH2:2]1)=[O:29]
Reactant: O=C(CBr)Nc1ccon1
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Solvent: CC#N
Product: COc1cccc(C(O)(C(=O)OC2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2cccc(OC)c2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]-oct-3-yl)ester (Intermediate K) (0.25 g, 0.63 mmol) in acetonitrile (10 ml) is added 2-bromo-N-isoxazol-3-yl-acetamide (0.15 g, 0.73 mmol) and the reaction mixture stirred at room temperature for 3 hours. The resulting precipitate is removed by filtration and the mother liquor is left at room temperature for 72 hours to crystallise. The crystals are filtered and dried in vacuo to yield the titled compound as a solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:35]([CH2:38][C:39]([O:41]CC)=[O:40])=[C:36]=[S:37]>C(Cl)(Cl)Cl>[C:39]([CH2:38][NH:35][C:36]([C:11]1[C:12](=[O:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:25])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[OH:14])=[S:37])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Reactant: CCOC(=O)CN=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCn1c(O)c(C(=S)NCC(=O)O)c(=O)n(C2CCCCC2)c1=O
Reaction time: 168 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330 mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethyl isothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) was stirred for 7 days. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was purified by flash chromatography (hexane-20% ethyl acetate in hexane) to give the title compound as a clear oil (250 mg, 60%). The diester was dissolved in ethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). The mixture was stirred overnight, taken up in ethyl acetate and washed with 1 molar hydrochloric acid (×2), dried and evaporated. Crystallization from acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1 H), 12.50 (s, 1 H), 12.03 (br s, 1 H), 4.71 (m, 1 H), 4.35 (d, J=5.05 Hz, 2H), 3.84 (t, J=7.20 Hz, 2 H), 2.10-2.38 (m, 4 H), 1.80 (d, J=12.63 Hz, 2 H), 1.42-1.71 (m, 7 H), 1.21-1.42 (m, 4 H), 1.01-1.22 (m, 1 H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][CH2:17]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][C:16]3([O:20][CH2:19][CH2:18][CH2:17]3)[CH2:21][CH2:22]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:31]1[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=[C:30]1[CH3:29])=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCC3(CCCO3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCCO4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 8-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-1-oxa-8-azaspiro[4.5]decane and 2-methybenzimidazole were reacted to give 370. LCMS m/z: 503.2 (MH+)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=2)=[N:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29](OCC)=[O:30])[NH:23][C:22]2=[O:34].C(N(C(C)C)CC)(C)C.C(O)C>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][S:6][C:3]3[N:4]=[CH:5][NH:1][N:2]=3)[CH:11]=1)=[O:30])[NH:23][C:22]2=[O:34]
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Reactant: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(OCCSc2nc[nH]n2)c1)c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A suspension of 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (318 mg, 1.27 mmol), ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 52 (100 mg, 0.423 mmol) and diisopropylethylamine (0.442 mL, 2.54 mmol) in THF (9 mL)-ethanol (3 mL) was stirred at 90° C. for 2 days. The reaction solvent was evaporated under reduced pressure, and the residue was extracted with 0.1N hydrochloric acid and THF-ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was crystallized from toluene-ethanol, and the obtained crude crystals were recrystallized from THF-IPE to give the title compound as a white powder (45.7 mg, 25%).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C@H:15]2[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:7]([O:12][CH3:13])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[Cl:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C@H:15]1[C@H:14]([C:6]2[C:7]([O:12][CH3:13])=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=2[O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2[Cl:26])[CH2:18][CH2:17][N:16]1[CH3:19])(=[O:24])[CH3:23]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(O)c1C(C)=O
Reactant: O=C(O)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC(=O)c2cccnc2Cl)c1C(C)=O

Procedure:
(+/−)-trans-Acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-ylmethyl ester (1.65 g, 4.7 mmol) was reacted with 2-chloro-pyridine-3-carboxylic acid (2.44 g, 15.49 mmol) in the presence of dry pyridine (25 mL) and POCl3 (2.1 mL, 23.43 mmol) using the conditions described in example 52 to get trans-2-Chloro-nicotinic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester. This was converted in situ to the title compound(66) using NaH (1.29 g, 26.86 mmol) in 1,4-dioxane (25 mL) as described in example 26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:33]1C=CC(C(C2(C)CCNCC2)=O)=CC=1.C(OC(=O)N[C@H]1CC[C@H](CC=O)CC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([CH3:33])[CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reactant: CC1(C(=O)c2ccc(F)cc2)CCNCC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C)(C(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
According to the procedure described for the synthesis of Trans-(4-{2-[4-(4 Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (intermediate E, example 1), the title compound was synthesized from (4-Fluoro-phenyl)-(4-methyl-piperidin-4-yl)-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester. MS (m/e): 447.4 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].Br.[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([O:16]C1C=CC=CC=1)=O)=[O:7]>C(O)C.O>[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([NH:2][CH3:1])=[O:16])=[O:7]
Reactant: CN
Reactant: COC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Agent: Br
Solvent: CCO
Solvent: O
Product: CNC(=O)Nc1snc(C)c1C(=O)OC

Procedure:
A warm solution of methyl 3-aminocrotonate (prepared according to the method of Conrad and Epstein, Chemische Berichte, 1887, 20, 3054, 10.4 g.) in toluene (20 ml.) was added with stirring to a solution of phenoxycarbonylisothiocyanate (16 g.) in toluene (50 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 11/2 hours at ambient temperature, filtered and the solid residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-methoxycarbonyl-N-phenoxycarbonylthiobutyramide (8.6 g.) in the form of an orange solid, which was then dissolved in ethyl acetate (100 ml.). To this solution, a solution of bromine (1.67 ml.) in ethyl acetate (5 ml.) was added over 15 minutes at 2°-5° C. The mixture was stirred at ambient temperature for 11/2 hours and the solid product filtered off to give 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.6 g.) m.p. 170°- 173° C. A solution of methylamine in ethanol (30% w/v; 20 ml.) was added to 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.0 g.). The mixture was heated under reflux for 15 minutes, diluted with water (30 ml.), filtered and the solid residue dried at 100° C., to give 1-(4-methoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (4.1 g.), m.p. 236°-237° C.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[OH2:9].[CH2:10]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1)[CH:11]=[CH2:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O.CC(C)=O>[OH:9][CH:11]([CH2:12][OH:5])[CH2:10][O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:38])[CH2:21][CH2:22][C@@H:23]2[C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)[CH2:15]1
Reactant: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H](OCC(O)CO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reaction time: 20 h

Procedure:
To a mixture of 0.70 g of N-Methylmorpholine-N-oxide, 6.5 ml of water, 13.7 ml of acetone and 1.64 ml of a 0.06 M ethereal osmium tetroxide solution, 2.0 g of 3β-prop-2-enoxy-17β(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex.2, dissolved in 29 ml of tert-butanol were added at room temperature. The mixture was left on standing for 20 hrs, 50 ml of a saturated sodium hydrosulfite solution and 2.0 g of celite were added, the mixture was stirred for 2 hrs and then filtered. The organic solvent was distilled under reduced pressure, the aqueous phase was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 20/80 as eluant to give 1.8 g of 3β-(2,3-dihydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4 and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]-propyl]-4-piperidinyl-1,2-benzisoxazole as a beige solid, m.p.=156-158° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14]C(C3C=CC=CC=3)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:25]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27][CH2:28][CH3:29])=[O:26].[C:50]1([CH3:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14]/[C:56](/[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:30]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccccc2)CCN(C)C1
Reactant: Cc1ccccc1
Product: CCOC(=O)/C=C(/Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccccc1
Temperature: 100 °C

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-phenylethanone (100 mg, 3 mmol) was dissolved in 3 mL of toluene. (Carbethoxymethylene)triphenylphosphorane (200 mg, 0.56 mmol) was added and the reaction mixture was heated at 100° C. overnight. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100-200) eluting with 2% MeOH-DCM. 1H NMR (CDCl3, oxalate salt) δ (ppm): 7.70 (m, 1H), 7.50 (m, 2H), 7.38 (m, 3H), 7.20 (m, 1H), 7.10 (m, 1H), 5.30 (m, 1H), 4.80 (s, 2H), 3.90 (m, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 2.0 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:27][C:28](=[CH2:30])[CH3:29].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:28]([CH3:30])([CH3:29])[CH3:27])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Temperature: -50 °C
Yield: 67.8 %

Procedure:
To a stirred suspension of 10 g of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 250 mL dry diethyl ether cooled at -50° C. was slowly added 60 mL of liquid isobutylene (previously condensed from gaseous material in a dry ice-alcohol bath). With continued stirring and cooling, 50 mL of concentrated H2SO4 was added slowly and carefully. The mixture was then sealed in a stainless steel Parr container and stirred at -30° C. for 40 hours. After releasing the pressure, the mixture was added slowly and carefully to excess saturated NaHCO3 solution. The aqueous mixture was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 7.8 g (67.8%) of the title compound, m.p. 143°-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH2:18][CH2:19][S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of 4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-3,4-dihydro-1H-pyrazine-2-one (0.3 g, 1 mmol) in CH2Cl2 is added Et3SiH (1.57 ml, 10 mmol). The resulting solution is cooled to 0° C. and CF3CO2H (2.2 ml, 30 mmol) is added dropwise. The mixture is stirred 16 hours at room temperature, washed with a saturated aqueous NaHCO3 solution, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography on silica gel eluting with a gradient of 50% AcOEt:Hexane to 100% AcOEt. The title compound (0.138 g, 46% yield) is obtained as an oil.