Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2)[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[C:10]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH3:2]
Reactant: CCC1CCCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of methyl 3-(2-ethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (45 mg, 0.11 mmol) in methanol (15 mL) was added sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL), adjusted to pH 5 with hydrochloric acid (3M), and collected by filtration to afford 3-(2-ethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (23.3 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH:11]O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:11])=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: OO
Reactant: Cc1cnc(C)c(C)c1Cl
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Temperature: 60 °C
Yield: 83 %

Procedure:
11.3 g (72.8 mmol) 4-chloro-2,3,5-trimethylpyridine was dissolved in 50 ml acetic acid and heated to 60° C. and 6.2 ml (50% H2O2) was added slowly and the temperature maintained for several hours and finally increased to 90° for two hours. The solvent was evaporated and extracted from alkaline water with diethyl ether to remove unreacted starting material. The water phase was saturated with sodium chloride and extracted several times with methylene chloride. The methylene chloride was dried and evaporated to give 10.1 g of product. Yield 83%. M.p. 147°-148° C.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:35][CH3:36])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=4[C:28]([NH2:30])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:38]N.[OH-].[K+]>CCOC(C)=O>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:35][CH3:36])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=4[C:28]([NH:30][CH3:38])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccccc3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Reactant: CN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C

Procedure:
The remaining reaction mixture from the preparation of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was diluted with a solution of methylamine (2M in THF 15 mL, 30 mmol). The resulting mixture maintained at rt for 2 days and was diluted with EtOAc (200 mL), washed with a saturated NaHCO3 solution (200 mL) and a saturated NaCl solution (125 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2, followed by trituration using a mixture of CH2Cl2 and Et2O. The crude product was dissolved in dioxane (13 mL) and was treated with a 1M aqueous KOH solution (1.121 mL, 1.121 mmol). The resulting mixture was heated at 90° C. for 6 h and was allowed to cool to rt and diluted with EtOAc (100 mL), washed with a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methylbenzamide as a beige solid (70 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 6H), 2.83 (d, J=4.40 Hz, 3H), 3.04-3.28 (m, 4H), 3.78 (s, 3H), 4.18 (t, J=8.33 Hz, 2H), 6.23-6.38 (m, 1H), 6.87-7.07 (m, 3H), 7.60 Hz, 1H), 7.60 (s, 1H), 7.72 (d, 7.33 Hz, 1H), 8.64 (s, 1H), 8.67-8.81 (m, 1H), 8.90 (d, J=8.24 Hz, 1H), 11.26 (s, 1H), 11.73 (s, 1H); ESIMS (M+H)+=515.33.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].[Br:18]C1C=C([N+]([O-])=O)C(F)=CC=1>>[Br:18][C:9]1[CH:12]=[CH:13][C:6]([NH:5][CH2:4][CH2:3][CH:2]([CH3:17])[CH3:1])=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Product: CC(C)CCNc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
(4-Bromo-2-nitro-phenyl)-(3-methyl-butyl)-amine was prepared by the same procedure as 4-(3-methyl-butylamino)-3-nitro-benzonitrile, except using 3-bromo-6-fluoro-nitrobenzene.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>CN(C)C(=O)C>[S:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:14]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Clc1nsc2ccccc12
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCN(c2nsc3ccccc23)CC1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of 32 parts of ethyl 1-piperazinecarboxylate, 17 parts of 3-chloro-1,2-benzisothiazole and 45 parts of N,N-dimethylacetamide was stirred for 0.5 hours at 150° C. After cooling to 50° C., the reaction mixture was poured into ice water. The aqueous layer was decanted and the oily layer was stirred in water. The product from the oil layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13 parts (44%) of ethyl 4-(1,2-benzisothiazol-3-yl)-1-piperazinecarboxylate as a residue (int. 3).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:24]1[C:29](=[O:30])[CH:28]=[CH:27][NH:26][C:25]1=[O:31])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([N:24]1[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:25]1=[O:31])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCCCCCO)c1ccccc1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Product: O=C(OCCCCCn1ccc(=O)n(C(=O)c2ccccc2)c1=O)c1ccccc1
Yield: 50 %

Procedure:
The title compound (50%) was prepared as described in example 15 but using the alcohol 20 instead of 14 in the coupling reaction with N3-benzoyluracil.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH:5]=[O:6])[CH3:2].B.C1COCC1.Cl.CCOCC>C1COCC1>[CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH2:5][OH:6])[CH3:2]
Reactant: CCc1cccc(CC)c1C=O
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1CO
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To a solution of 2,6-diethyl-benzaldehyde (0.68 g; 4.19 mmol) in THF (15 mL) was added dropwise a solution of BH3.THF in THF (8.38 ml; 1.00 mol/l; 8.38 mmol), at 0° C. After complete addition the mixture was heated under reflux for 3 hours. Subsequently, the resulting mixture was cooled to 0° C. and 1M aqueous HCl (10 ml) was added dropwise. The mixture was allowed to warm to room temperature (˜10 min.), and treated with Et2O. The layers were separated, the organic layer washed with 1M aqueous HCl (2×), 5% aqueous NaHCO3 (2×), and brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford (2,6-diethyl-phenyl)-methanol (0.67 g), which was used as such.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:23])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc(Sc2ccccc2)cn1
Product: O=S(c1ccccc1)c1ccc(Br)nc1

Procedure:
Following the procedure of Example 7 2-bromo-5phenylthiopyridine is converted to 2-bromo-5-(phenylsulfinlyl) pyridine with m-chloroperbenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=1[F:14])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2,4-difluorobenzyl bromide (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 309 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCNc1ccc(CC(=O)[O-])cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNc1ccc(CC(=O)OC(C)C(=O)OCC)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1oc(-c2ccc(O)cc2)cc1C=O
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 4-hydroxyphenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound (1.6 g, 35%) as a yellow crystal.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-pyrrolidine-2,5-dione was prepared as for Example 10 from pyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:30]=[C:31]=[O:32])[CH2:28][CH3:29]>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[O:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: CCCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: CCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and n-propyl isocyanate (0.011 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in, the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.0 (dd), 158.3, 157.9 (dd), 151.1, 141.0, 138.9, 136.1, 135.0, 132.7, 132.1, 128.9, 127.4 (dd), 126.0 (dd), 122.5, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 42.6, 24.4, 19.7, 11.6
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br>C(=S)=S>[Br:12][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: S=C=S
Product: Oc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
To a stirred solution of 61.65 gm (0.38 mole) 3-trifluoromethylphenol in 240 mL carbon disulfide were added 19.6 mL (0.38 mole) bromine dropwise. The reaction mixture was stirred at room temperature for about 18 hours and was then partitioned between 200 mL dichloromethane and 100 mL water. The organic phase was washed with 20 mL saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing 40% hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 48.8 gm (53%) of the desired compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[NH2:19]>C(O)CO>[CH3:24][O:23][C:21]1[CH:20]=[C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:17]=[C:16]([O:15][CH3:14])[CH:22]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cc(OC)cc(OC)c1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 3,5-dimethoxyaniline (91,153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10i as pure product. To a solution of 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (101,150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1i (201 mg, 78%); mp: 123-125° C.; 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 8.27 (dd, J=2.2, 1.5 Hz, 1H), 7.82 (dd, J=2.2, 1.5 Hz, 1H), 7.72 (t, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.33-7.28 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.97-6.90 (m, 7H), 6.62-6.58 (m, 1H), 6.08 (t, J=2.2 Hz 1H), 5.46 (s, 2H), 4.61 (d, J=5.2 Hz, 2H), 3.80 ppm (s, 6H); MS (ESI m/z): 537 [M+H]+ Yield: 78%
Reaction SMILES: [CH:1]1([C:7](=[O:19])[C:8]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>C(Cl)Cl.CC(OC)(C)C.O.CC(O)=O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:10][CH2:9][C:8]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:18])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)C2CCCCC2)c2ccccc2)CC1
Reaction time: 96 h
Yield: 103.4 %

Procedure:
To a slurry of 13.72 g (0.05310 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde and 11.57 g (0.05058 mol) of 1-(2′-methoxyphenyl)piperazine hydrochloride in 391 mL of CH2Cl2 was added 9.7 mL of AcOH to make the reaction mixture homogeneous. To the reaction solution was added slowly 14.63 g (0.06904 mol) of NaBH(OAc)3. After stirring over 4 days (reaction should be complete within 2-5 h), 200 mL of 1N HCl (aq) was added to quench reaction mixture (pH=1). The mixture was extracted with 200 mL of CH2Cl2. The CH2Cl2 extract was washed again with 200 mL of 1N HCl (aq) (pH=1). Both HCl (aq) washes were combined and saved. The organic extract was washed with 200 mL of 1N NaOH (aq) (pH=14). An emulsion formed and was broken up by addition of 100 mL of water and 100 mL of MTBE. The organic phase was washed again with 200 mL of 1N NaOH (aq) (pH=14) and washed with 200 mL of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated to afford 22.74 g of crude title compound as an amber oil. HPLC analysis against pure standard showed that crude product oil has 13.66 g (61.71%) of title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[K].[SH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.SC1C=CN=CC=1.[OH-].[K+]>CO>[N+:10]([C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: Sc1ccncc1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Sc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-nitroanisole (9.38 g) was added to a solution of 4-mercaptopyridine potassium salt prepared by adding 4-mercaptopyridine (6.67 g) to a solution of potassium hydroxide (3.37 g) in methanol (30 ml) followed by evaporation of the methanol) and DMF (40 ml). After stirring for 1 hour, the mixture was heated at 110° C. for 4 hours and allowed to stand overnight. The reaction mixture was poured into ice-water (1 liter), stirred for 15 minutes, and the yellow solid was filtered off. The solid was stirred with 3M hydrochloric acid (800 ml) for 1 hour, filtered, and the filter cake was washed with 3M hydrochloric acid then water. The filtrate was cooled in an ice-bath and made basic with 28% aqueous ammonium hydroxide to yield approximately 2 g of the title compound. The filter cake was suspended in water (100 ml) with stirring and the mixture was made basic with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organics were combined, dried, filtered and evaporated to give a yellow solid that was triturated with hexane and filtered to give additional title compound (total yield 6.49 g). M.p. 97-100° C.; MS: 263 (M+H); NMR: 3.94 (s, 3H), 7.17 (dd, 1H, J=1.8, 8.4), 7.27-7.7.29 (m, 2H), 7.51 (d, 1H, J=1.8), 7.97 (d, 1H, J=8.4), 8.48-8.50 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40]>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:40])[CH3:41]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1ccccc1C(C)(C)N
Product: COc1ccccc1C(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 96 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(2-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10c) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 96%.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[C:24]([O:34][CH3:35])[CH:23]=1>>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:27]=[CH:26][C:25]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COC(=O)CCc1ccc(O)cc1OC
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC)c2)cc1)c1ccccc1
Yield: 89 %

Procedure:
Compound 37 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.4 g, 1.197 mmol) and methyl 3-(4-hydroxy-2-methoxyphenyl)propanoate (0.268 g, 1.197 mmol) by following the procedure described in scheme 13 (0.2 g, yield: 89%); Purity: 99.31%.