Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)=O.[OH-].[Na+]>CCCCCC.C1COCC1>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(CSC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
0.8 g (0.02 mol) of sodium hydride (60% dispersion in oil) was washed three times with hexane and suspended in 20 ml of THF. 2.24 ml (0.019 mol) of benzyl mercaptan in 12 ml of THF were added dropwise at 0°. The mixture was stirred at room temperature for 15 min. and subsequently 0.95 g (0.0037 mol) of 1-benzylpiperidin-4-yl methanesulfonate in 10 ml of THF was added dropwise. The reaction mixture was boiled at reflux for 22 hrs. and then poured into 200 ml of 2N aqueous NaOH. The inorganic phase was extracted with ether and the combined organic phases were washed with 2N aqueous NaOH and dried over magnesium sulfate. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:1) as the eluent. 0.444 g (40%) of 1-benzyl-4-benzylsulfanylpiperidine was obtained as a yellow oil. MS: me/e (% basic peak)=297 (C19H23 NS+, 1.4), 206 (62), 174 (23), 91 (199).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)[CH3:2].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:11][CH:15]=[CH:14]2)[CH3:2]
Reactant: CCSCc1ccccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSCc1cccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 7.40 g (37.5 mmol) of the compound from Example 3A in 195 ml of tetrahydrofuran was added dropwise to 134 ml (93.8 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran under argon at −78° C., and the mixture was stirred at −78° C. for 2 h. The reaction mixture was then slowly added to an ice-cold, saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to result in 4.98 g (69% of theory) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:25]>>[CH3:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][CH:9]=[O:8])[C:15](=[O:25])[CH:16]=[CH:17]2
Reactant: Cc1ccc2c(ccc(=O)n2CC2OCCO2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(ccc(=O)n2CC=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 3 mL of a 90% aqueous trifluoroacetic acid solution, 243 mg of 1-(1,3-dioxolan-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydroquinoline was dissolved, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the resultant solution was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 236 mg of a pale yellow oily substance, (6-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]CC2C=CC=CC=2)=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCO)cc1
Reaction time: 4 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 145 mg) in methanol (4 ml), a solution of Compound 25 (655 mg, 0.868 mmol) in methanol (6 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for 4 hours. After a nitrogen atmosphere was restored, ethyl acetate (about 10 ml) was added, and this was followed by filtration on silica gel and washing with an ethyl acetate solution containing 10% methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 26.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:13]=[CH:12][C:11]([NH:14]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 6-(morpholinomethyl)pyridin-3-ylcarbamate (115; 1.20 g, 4.1 mmol) in dichloromethane (20 mL) was added TFA (6.0 mL). The resulting reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the residue to adjust the pH=9. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 6-(morpholinomethyl)pyridin-3-amine 116 (450 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH:7]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: N#Cc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1ccc(Nc2cc(Cl)ccc2N)nc1
Temperature: 100 °C

Procedure:
To a well stirred solution of step 1 intermediate (2.5 g, 9.1 mmol) in ethanol (45 ml), aqueous solution of ammonium chloride (4.87 g, 91.0 mmol) was added and the reaction mixture was refluxed at 100° C. After 15 minutes iron powder (1.5 g, 27 mmol) was added to it portionwise and was further refluxed for 2 h. After the completion of reaction, excess of ethanol was evaporated under reduced pressure; the reaction mixture was diluted with chloroform (200 ml) and filtered through celite bed. The combined organic layers were washed with water (2×50 ml) and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield 1.8 g of the product.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.[CH3:30][NH:31][CH3:32]>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:31]([CH3:32])[CH3:30])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CNC
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4CCC(=O)C4)ccc23)C1
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(C4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (1-hydroxy-3-methylcyclohexyl methyl)-amide, and dimethylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm (VTNMR: 80° C.): 8.26-8.24 (m, 1H), 8.11-8.09 (m, 1H), 7.97-7.94 (m, 1H), 7.73-7.70 (m, 1H), 7.56-7.54 (m, 1H), 3.87-3.85 (m, 1H), 3.46-3.33 (m, 3H), 2.77-2.49 (m, 1H), 2.25-1.34 (m, 20H), 0.87-0.77 (m, 1H). m/z: 444.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:16]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:16])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(N)c1NCCO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(N)c1NCCO
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of methyl 3-amino-2-[(2-hydroxyethyl)amino]benzoate (114.1 mg, 0.543 mmol) in dichloromethane (2.7 mL) was added N-chlorosuccinimide (14.5 mg, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 hr and at 30° C. for 0.5 hr. Aqueous sodium sulfite was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (29.0 mg, 0.12 mmol, 22%) as an orange amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[OH2:13]>OO.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([OH:13])[CH:7]=1
Reactant: O
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: OO
Solvent: CCO
Product: COc1ccc(Cl)cc1O

Procedure:
A solution of 5-chloro-2-methoxy benzeneboronic acid (1.9 g, 10 mmol) in hydrogen peroxide (2.04 ml, 30% solution) and ethanol 40 ml was refluxed for 30 min. Water was added and the product was extracted with two portions of ethyiacetate. Drying over magnesium sulfate and evaporation of the solvent gave the product as an oil. Yield 1.05 g, 65%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[O:20][C:19]([CH:21]2[O:26][CH2:25][CH2:24]C[O:22]2)=[CH:18][CH:17]=1)CCC>CN(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>[O:26]1[CH2:25][CH2:24][O:22][CH:21]1[C:19]1[O:20][C:16]([N:3]2[CH:2]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:17][CH:18]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccc(C4OCCO4)o3)cc2c1
Reaction time: 0.25 h

Procedure:
10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1979, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh3)4 is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1,3-dioxane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)=[CH2:2].C1CCCCC1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C([Li])CCC.CO>[CH2:17]([N:19]([CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: C=Cc1ccc(C=C)cc1
Reactant: CCNCC
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCCCC1
Product: C=Cc1ccc(CCN(CC)CC)cc1
Temperature: 50 °C
Yield: 71.4 %

Procedure:
In a 200 ml three necked flask were placed 26 g of p-divinylbenzene and 40 ml of cyclohexane, and to the mixture were further added 40 ml of a cyclohexane solution of an amide-amine complex prepared from 14.8 g of diethylamine and 0.512 g of n-butyllithium. The mixture thus obtained was heated at 50° C. for 3 hours with stirring. Then the reaction solution was added with 10 ml of methanol and subjected to distillation to give 29.0 g of p-diethylaminoethylstyrene having a boiling point of about 84° C./1 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:4]([CH3:21])[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([CH3:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:8][C:6]1[CH:7]=[C:2]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH:3]=[C:4]([CH3:21])[C:5]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1cc(Br)cc(C)c1-n1ccnc1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)cc(-c2cc(C)c(-n3ccnc3-c3ccc(F)cc3)c(C)c2)c1
Yield: 91.5 %

Procedure:
8.5 g (24.6 mmol) N-(4-bromo-2,6-dimethylphenyl)-2-(4-fluorophenyl)imidazole, 4.43 g (29.5 mmol) 3,5-dimethylphenylboronic acid, 0.17 g (0.74 mmol) palladium (II) acetate, 9.17 g (66.5 mmol) potassium carbonate and 0.65 g (2.46 mmol) triphenylphosphine were refluxed in 350 mL 1,2-dimethoxyethane and 130 mL water for 18 hours under N2 atmosphere. The cooled mixture was then transferred to a separatory funnel whereupon the water was removed. The organic material was then enriched with ethyl acetate and extracted from water. The organic layer was dried over anhydrous MgSO4, filtered and evaporated of solvent to give a light residue. The residue was then purified on a silica gel column using 50% ethyl acetate/hexanes as eluent. The pure fractions were evaporated of solvent the solids collected on a funnel with hexanes to give 8.34 g N-(2,6-dimethyl-4-{3,5-dimethylphenyl}phenyl)-2-(4-fluoro phenyl)imidazole as a bright white solid. MS confirmed.
Reaction SMILES: COC1C(C(OCC)=O)=C(CC(OCC)=O)N(C)C=1.[CH3:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[C:23]([C:25]1[N:29]([CH3:30])[C:28]([CH2:31][C:32]([O-:34])=[O:33])=[C:27](C(OCC)=O)[C:26]=1[O:40][CH3:41])=[O:24].CC1C=CC=CC=1C(C1N(C)C(CC(O)=O)=C(C(O)=O)C=1OC)=O>C(O)(C(F)(F)F)=O>[CH3:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[C:23]([C:25]1[N:29]([CH3:30])[C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][C:26]=1[O:40][CH3:41])=[O:24]
Reactant: CCOC(=O)c1c(OC)c(C(=O)c2ccccc2C)n(C)c1CC(=O)[O-]
Agent: CCOC(=O)Cc1c(C(=O)OCC)c(OC)cn1C
Agent: COc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)n(C)c1C(=O)c1ccccc1C
Yield: 50 %

Procedure:
Following substantially the procedures as described in Example 1, Steps C-E, crude ethyl 4-methoxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate is converted to about 16 mmole of 5-(o-methylbenzoyl)-4-methoxy-3-ethoxycarbonyl-1-methylpyrrole-2-acetate followed by hydrolysis to 5-(o-methylbenzoyl)-4-methoxy-3-hydroxycarbonyl-1-methylpyrrole-2-acetic acid which in turn is decarboxylated in neat TFA according to procedure of Example 2 to afford an overall 50% yield of 5-(o-methylbenzoyl)-4-methoxy-1-methylpyrrole-2-acetic acid.
Reaction SMILES: O.[OH-].[Li+].C([O:7][C@@H:8]([C:10]1[N:11]=[N:12][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[N:14]=1)[CH3:9])(=O)C>O1CCCC1.O>[CH3:21][C:17]1[CH:16]=[C:15]([N:13]2[N:12]=[N:11][C:10]([C@H:8]([OH:7])[CH3:9])=[N:14]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)O[C@H](C)c1nnn(-c2cccc(C)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-n2nnc([C@@H](C)O)n2)c1
Yield: 98.4 %

Procedure:
Lithium hydroxide monohydrate (16.68 g, 400 mmol) was added to a stirred solution of (1R)-1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethyl acetate (46.6 g, 190 mmol) in tetrahydrofuran/water (1:1, 750 mL). After 3 hour reaction time the mixture was concentrated to half volume. Brine (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title product (38.18 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[C:8]=2[CH2:7]1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[S]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(n3c4c(cccc24)CCC3)C(c2ccccc2)N1
Agent: [S]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c3cccc4c3n(c2c(-c2ccccc2)n1)CCC4
Reaction time: 8 h
Yield: 58.9 %

Procedure:
3.6 g (10 mmol) of 10-ethoxycarbonyl-8-phenyl-5,6,8,9,10,11-hexahydro-4H-pyrido[4',3':4,5]pyrrolo[3,2,1-ij]quinoline (a mixture of isomers), obtained analogously to the method of example I a) to c) were boiled while stirring for 8 hours together with 0.8 g (25 mmol) of sulphur in 25 ml of xylene. Another 0.2 g of sulphur were added and boiling with stirring was carried out for another 8 hours. The reaction mixture was evaporated in vacuum and chromatographed over 150 g of silicagel using methylene chloride with 10% by volume of ethyl acetate as an eluent. The desired fraction was evaporated in vacuum. The residue was crystallised from 10 ml of ethyl acetate. 2.1 g (59%) of the desired product were obtained having a melting-point of 173°-174° C,
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH3:19])[S:15][N:14]=1.C(OC(C)C)(C)C>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH3:19])[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: CSc1nc(O)ns1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CNC(=O)n1sc(SC)nc1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
0.1 ml of triethylamine and 5 ml of methyl isocyanate were added to a solution of 7.5 g of 3-hydroxy-5-methylthio-1,2,4-thiadiazole in 50 ml of tetrahydrofuran and after stirring at 20° C for 3 hours, 25 ml of isopropyl ether were added. The mixture was vacuum filtered and the recovered crystals were washed, dried and crystallized from acetone to obtain 5.2 g of 2-(N-methylcarbamoyl)-5-methylthio-1,2,4-thiadiazole-3-one melting at 144° C.
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C@@H:17]2[OH:26])[CH2:9][CH2:8]1)(=O)C.O>CO>[N:27]1([C@H:16]2[CH2:15][C@H:14]3[C@H:13]4[C@H:22]([CH2:21][CH2:20][C@:18]3([CH3:19])[C@H:17]2[OH:26])[C@:23]2([CH3:25])[C@H:10]([CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:24]2)[CH2:11][CH2:12]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)O[C@@H]1CC[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]34)[C@@]2(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](O)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Sodium hydroxide solution (60 ml; 4N) was added to a solution of 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol 2-acetate (25.49 g) in methanol (120 ml) and the mixture was heated under reflux for 1 h. When the solution had cooled to room temperature, water (200 ml) was added to precipitate the product, which was filtered off and washed with water (3×200 ml). A solution of the crude solid in diethyl ether (150 ml) was washed neutral with water (2×200 ml), dried (MgSO4) and evaporated to dryness. Crystallisation of the resulting white solid from methanol acetone afforded 16β-(1-piperidinyl)-5α-androstane-2β,17β-diol (17.51 g), m.p. 215°-219° C.; [α]D +36.1° (c 0.48 in CHCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[N+]=[N-])=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:31][O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]4[CH:30]=[CH:29][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:31][O:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccc(F)cc4)o3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccc(F)cc4)o3)CC2)cc1

Procedure:
A solution of 4-(2-{4-[5-(4-Fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-ethyl)-benzyl azide (2.25 g, 4.3 mmol), prepared as in Part B, in EtOH (80 mL) is treated with 10% Pd/C (400 mg) and hydrogenated at 50 psi for 12 h. The catalyst is removed by filtration through celite, and the solvent evaporated to afford the title compound as off-white solids, which is used in subsequent reactions without purification.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[S:12][C:11]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][CH:9]=1)=[O:7])C.Cl>CCO.O>[C:14]1([S:13][C:11]2[S:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9][N:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc(Sc2ccccc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(Sc2ccccc2)s1
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
Potassium hydroxide (1.58 g, 28.2 mmol, 10 eq) is added to a solution of 2-phenylsulfanyl-thiazole-5-carboxylic acid ethyl ester (0.748 g, 2.82 mmol, 1 eq) in EtOH (15 mL) and water (10.5 mL). The reaction is stirred for 1.5 hours, diluted with water (30 mL) and EtOH (30 mL), and acidified by addition of 3 N HCl until a white precipitate forms. The precipitate is filtered and purified by recrystallization from water and EtOH to give the product as a white crystalline solid (0.307 g). MS (ESI) for C10H7NO2S2 m/z 235.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13]OC(OC)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (5.0 g, 22 mmol) in MeOH (10 mL) was added 2,2-dimethoxypropane (3.4 g, 33 mmol) and 4-methylbenzene-1-sulfonic acid (2.0 mg, 0.010 mmol). The resulting solution was stirred overnight at 55° C. and allowed to cool to rt. The resulting mixture was concentrated under reduced pressure and poured into water (100 mL). The solids were collected by filtration and washed with hexanes (2×20 mL) to obtain compound 50a as a gray solid. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.54-7.51 (m, 2H), 7.35-7.28 (m, 2H), 5.18-5.16 (m, 1H), 3.793 (s, 3H), 3.51-3.49 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10]Cl)[N:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[N+:13]=[N-:14]
Reactant: N#Cc1ccc(CCl)nc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])nc1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-6-chloromethyl-3-cyanopyridine (600 mg, 3.21 mmol) and sodium azide (229 mg, 3.53 mmol) in DMF (12 mL) were stirred at 50° C. for 30 min. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2 times) and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (chloroform) to give the title compound as an oil: