Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[N:9](OC)=[O:10].B(F)(F)F.C[CH2:18][O:19]CC.[S:22](=[O:24])=[O:23]>>[CH3:1][O:2][C:3]1([O:19][CH3:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]=[O:10].[S:22](=[O:24])=[O:23]
Reactant: CCOCC
Reactant: COC1=CCCCC1
Reactant: CON=O
Agent: FB(F)F
Agent: O=S=O
Product: COC1(OC)CCCCC1N=O

Procedure:
1,1-Dimethoxy-2-nitrosocyclohexane dimer was prepared as described in Example 1 from 1-methoxycyclohexene (46.8 g., 0.417 mole), methyl nitrite (30.6 g., 0.501 mole) and boron trifluoride-etherate (0.25 ml., 0.28 g., 2.0 × 10-3 mole) in 250 ml. of sulfur dioxide. The crude nitroso dimer, 76.0 g. of a gummy yellow-green solid still containing traces of sulfur dioxide, was obtained by the method described earlier. Without purification, the dimer was subjected to isomerizing conditions in methanol/sodium methoxide solution. Filtration through celite (to remove colloidal solids that had formed) and evaporation afforded 66.0 g. of an off-white slightly moist solid. Recrystallization from 180 ml. of ether at -70° C. gave 26.8 g. (37.2%) of 1,1-dimethoxy-2-oximinocyclohexane as colorless fine needles, m.p. 112°-116° C. An additional 2.9 g. (4.0%) of slightly impure oxime was obtained from the mother liquor as a white powder, m.p. 105°-112° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([NH2:23])[NH:21][N:22]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(N(C(C)C)CC)(C)C.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[Na+].[I-]>CC(N(C)C)=O>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([NH:23][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[NH:21][N:22]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Nc1cc(-c2ccc3[nH]ccc3c2)n[nH]1
Reactant: O=C(Cl)CCCCBr
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCN1CCCCC1)Nc1cc(-c2ccc3[nH]ccc3c2)n[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromovaleryl chloride (80 μL, 0.60 mmol) in DMA (1 mL) cooled at 0° C. a solution of 5-(1H-Indol-5-yl)-2H-pyrazol-3-ylamine (120 mg, 0.60 mmol) and diisopropylethylamine (104 μL, 1.20 mmol) in DMA (2 mL) was added. The reaction was left stirring for 1 hour at 0° C. and then piperidine (119 μL, 1.20 mmol) and NaI (90 mg, 0.60 mmol) were added and the mixture heated at 60° C. for 5 hours, when LC-MS showed complete conversion of the bromo-intermediate and the solvent was removed under reduced pressure.
Reaction SMILES: [S:1]([C:21]1[CH:26]=C(C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)C=C[C:22]=1C)[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[CH:5]=[CH:4][C:3]=1[CH3:20].C(S([O-])=O)O.[Na+].C(I)(C)C.O>CN(C)C=O>[CH:21]([S:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([Cl:19])=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[CH:12][C:13]=2[Cl:14])[CH:5]=[CH:4][C:3]=1[CH3:20])([CH3:26])[CH3:22]
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: CC(C)I
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(C)C
Yield: 75.3 %

Procedure:
3.3 g (4.9 mmol) of 1,1′-thiodi-[5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzene], 3.0 g (19.5 mmol) of Rongalite and 3.0 g (17.6 mmol) of isopropyl iodide were stirred in 30 ml of N,N-dimethylformamide at room temperature for 3 hours. The resulting reaction mixture was poured into 300 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dtied over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.4 g of [5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylphenyl] isopropyl sulfide (yield 38.0%) as a yellow dough (nD20 1.5462).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O-:26])=[O:25])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]([C:20]([F:23])([F:21])[F:22])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]3)=[CH:13][CH:14]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(-n2ncc(C(=O)[O-])c2C(F)(F)F)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(-n2ncc(C(=O)O)c2C(F)(F)F)cc1)c1ccc(Cl)cc1
Yield: 60.5 %

Procedure:
1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), 1 N sodium hydroxide aqueous solution (1 ml) and ethanol (2 ml) was stirred at 45° C. for 4 hours. After spontaneous cooling, 1 N hydrochloric acid aqueous solution (2 ml) was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethanol to give 1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (91 mg) as colorless powder crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 75 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Solvent: CC(=O)Cl
Solvent: CCO
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To 1.73 g (0.00498 n) of 1-[(p-aminophenyl)sulfonyl]-4-(o-methoxyphenyl)piperazine in absolute ethanol is added 0.35 ml acetyl chloride in 5 ml ethanol (source of hydrogen chloride). After stirring for 5 minutes, 1.15 g (0.00498 m) of 4-chloro-7-trifluoromethylquinoline is added. The reaction mixture is stirred at reflux for 3 hours and at room temperature overnight. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate. The organic layer is filtered through anhydrous sodium sulfate and taken to dryness and the product mixture is chromatographed on silica gel, once with 4% methanol: 96% methylene chloride as eluant, and a second time with methylene chloride as the eluant. Crystallization from methylene chloride/Skelly-solve® B hexanes gives 1.61 g (61%) of 1-(2-methoxyphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine of melting point 146°-148° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:18][C:17]([Cl:33])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Cl:33][C:17]1[CH:18]=[C:19]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.9 %

Procedure:
To a solution of 4-[5-chloro-3-(3-trifluoromethyl-benzoylamino)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.40 g, 2.89 mmol) in methylene chloride (100 mL) is added hydrogen chloride (3.00 mL, 12 mmol) as a 4.0 M solution in 1,4-dioxane. The mixture is stirred at room temperature for 2 days during which time a solid precipitates from solution. The off-white solid is collected by filtration, washed with methylene chloride and dried on the filter pad to afford 1.20 g of N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-3-trifluoromethyl-benzamide in 100% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[CH:22]=1.[Br:23]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[C:22]=1[Br:23]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 75 g (0.239 mol) of (S)-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 1500 ml of glacial acetic acid is cooled to 0°, treated rapidly with a solution of 12.5 ml of bromine in 350 ml of glacial acetic acid and then the mixture is stirred at 0° for a further 30 minutes. The mixture is treated with ice/water and extracted with methylene chloride. The organic extract is dried over sodium sulphate and evaporated. The residue obtained is recrystallized from methylene chloride/ether and there is obtained (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 243°; [α]25D =41.7° (1 percent solution in methylene chloride).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.[N:19]([C:22]1[C:31]([CH2:32]Cl)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1)=[N+:20]=[N-:21].[Li+].[OH-]>C1COCC1>[N:19]([C:22]1[C:31]([CH2:32][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1)=[N+:20]=[N-:21]
Reactant: COc1ccc2nc(N=[N+]=[N-])c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2N=[N+]=[N-])c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (161 mg, 0.69 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2-azido-3-(chloromethyl)-6-methoxyquinoline hydrochloride SLA 41152 (197 mg, 0.69 mmol) followed by a 2 N aq. LiOH solution (0.69 mL, 1.38 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 4-((2-azido-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol (10 mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-((2-azido-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 68 as a yellow solid (11 mg, 3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 90.9 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) in methanol (4 mL) was added a solution of NaOH (40 mg, 1 mmol) in water (2 mL). The mixture was heated at 70° C. for 2 h, evaporated to remove methanol, cooled to room temperature, and acidified to “pH” 1 with HCl aq. The precipitate was collected, washed with water and dried to give the title compound as a white solid (175 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd].O>[C:1]([CH:3]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C#N)C(C)c1ccccc1

Procedure:
A mixture of methyl cyanoacetate (198 g, 2.0 moles), acetophenone (240 g, 2.0 moles), ammonium acetate (30.8 g, 0.4 moles) and acetic acid (96 g, 1.60 moles) in toluene was refluxed with a Dean and Stark trap until water separation ceased (about 4 hours). The resulting Knoevenagel adduct was cooled and stirred under hydrogen (60 psig) with 5% palladium on carbon (8 g) for 2 days. The solution was then depressurized, degassed, filtered and evaporated. The liquid residue was distilled and the fraction with bp 110°-140° C. (about 0.03 mm) collected as mixed stereoisomers of methyl 2-cyano-3-phenylbutyrate as identified by the nmr spectrum.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:31][S:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C[Si](Cl)(C)C.O>C(O)CCC.C(OCC)(=O)C>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([S:32][CH3:31])=[CH:34][CH:35]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CSc1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CSc1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 116 °C
Yield: 45.5 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.912 mmol), 4-(methylthio)aniline (0.227 mL, 1.83 mmol) and trimethylsilyl chloride (TMSCl) (0.231 mL, 1.83 mmol) in n-butyl alcohol (8 mL) was heated at 116° C. for 72 h. Water and ethyl acetate were then added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in CH3CN (20 mL), and water was added to induced precipitation. The solid was collected by filtration to give N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (225 mg). The filtrate was also purified by HPLC to give another portion of the desired product (127 mg).
Reaction SMILES: N1C=CN=C1[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27].Cl>CN(C)C=O>[CH2:24]([NH:28][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: O=C(c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2)c1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-(Imidazolylcarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (1 g.) is suspended in dry dimethylformamide (60 ml.) and n-butylamine (1.1 g.) is added. The mixture is stirred at room temperature overnight then at 70° C. for 11/2 hours. The product is added to dilute HCl and the solid is collected, washed with water, ethanol and ether and dried to yield the desired 7-(n-butylaminocarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[CH3:29][N:30]([CH3:39])[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32]>O1CCOCC1>[CH:25]([C:24]1[CH:27]=[CH:28][C:21]([C:12]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:8]3[CH:7]=[N:6][C:5]([N:36]4[CH2:35][CH2:34][N:33]([C:31]([N:30]([CH3:39])[CH3:29])=[O:32])[CH2:38][CH2:37]4)=[N:10][C:9]=3[N:11]=2)=[CH:22][CH:23]=1)=[O:26]
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: CN(C)C(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (6-4; 100 mg, 0.258 mmole) in dioxane (1 mL) was added N,N-dimethylpiperazine-1-carboxamide (48 mg, 0.309 mmole) and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 467.2, found 467.1.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[C-]#[N:38].[Na+].N>CO>[CH3:26][S:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([N:9]3[CH:10]=[C:6]([C:4]([NH2:38])=[O:5])[N:7]=[C:8]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:36])[F:35])=[CH:16][CH:15]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Agent: N
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(N)=O)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 60 °C
Yield: 316.4 %

Procedure:
Ethyl-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H imidazole-4-carboxylate (500 mg, 0.971 mmol), NaCN (10 mg, 0.194 mmol) and 6 mL 2M NH3 in MeOH were added to a 15 mL sealed tube and heated at 60° C. for 72 h. The reaction was cooled and the compound was absorbed on to silica purified by column chromatography using hexanes:ethyl acetate as eluents to afford 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide (298 mgs, 63%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 8.14-8.13 (m, 2H), 8.04-8.01 (m, 1H), 7.92-7.89 (m 1H), 7.85-7.80 (m, 3H), 7.74-7.65 (m, 4H), 7.45 (s, 1H), 7.37-7.35 (m, 2H), 7.27 (s, 1H), 3.28 (s, 3H); MS (ES): 486.1 [M+H]+ and 508.3 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[CH:3]1.S(Cl)([Cl:37])(=O)=O>C(#N)C>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[C:3]1[Cl:37]
Reactant: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1c(Cl)n(C)c3cccc2c13

Procedure:
To a stirred solution of 2 g of 1,6-dimethyl-8β-methyl[3-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-10α-methoxy-ergoline in ml 50 of acetonitrile and ml 0.5 of BF3-2 Et2O was added dropwise a solution of 0.6 g of sulphuryichloride (SO2Cl2) in ml 15 of acetonitrile at -5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[Cl:9][C:10]1[C:15]([C:16]#N)=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.CC[O:21]CC>>[C:16]([C:15]1[C:10]([Cl:9])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: N#Cc1cccnc1Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Mg]
Product: O=C(c1ccccc1)c1cccnc1Cl
Temperature: 25 °C

Procedure:
A solution of 3.14 g (0.02 mols) bromobenzene in anhydrous ether is added dropwise to a suspension of 0.02 mols magnesium in anhydrous ether. The mixture is refluxed 1.5 hr. and is then cooled until room temperature. Now a solution of 1.38 g 2-chloro-3-cyanopyridine in 25 ml anhydrous ether is added slowly while stirring. The reaction mixture is refluxed 24 hrs. and there is added, after standing, 10% aqueous HCl. The aqueous layer is separated and the ethereal layer is washed with 25% aqueous HCl. The combined washings and the first aqueous layer are basified with 40% NaOH and extracted with ether. The combined extracts are dried (MgSO4) and solvent evaporated. The crude is distilled in vacuo. Yield: 0.8 g of title product, identical with that described in Ex. 1b.
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:27])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:26])=[C:16]([O:24]C)[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[CH:28]#[CH:29].Cl>CO.O>[C:28]([C@:7]1([OH:27])[CH:6]=[CH:5][C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]12[CH3:9])[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:26])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)#[CH:29]
Reactant: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: C#C
Agent: Cl
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=C(C)C(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
3.5 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one is reacted with acetylene analogously to Example 5. The resultant 17α-ethynyl-3-methoxy-4-methylandrosta-3,5,15-trien-17β-ol is allowed to react, as described in Example 5, with concentrated hydrochloric acid in a mixture of methanol/water. After the crude product has been chromatographed on silica gel with a hexane-ethyl acetate gradient, 1.3 g of 17α-ethynyl-17β-hydroxy-4-methylandrosta-4,15-dien-3-one is obtained as a foam.