Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15](=[O:17])[NH2:16])[CH2:11][C@@H:10]1[O:18]C(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:18][C@@H:10]1[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13][C@@H:12]([C:15]([NH2:16])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1O
Reaction time: 2 h
Yield: 70.8 %

Procedure:
4-Nitrobenzoic acid (1S,2R,5R)-2-tert-butoxycarbonylamino-5-carbamoyl-cyclohexyl ester (i) (3.62 g, 8.9 mmol) in dry MeOH (250 mL) was treated with potassium carbonate (1.84 g, 13.3 mmol). After 2 hours at room temperature, the mixture was concentrated and the residue purified by flash column chromatography (silica gel, DCM/MeOH, 5-15%) to give a white solid (1.62 g, 6.3 mmol, 71%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH:30][CH3:31]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
A solution of ethyl 5{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.00 g, 2.53 mmol) in ethanol (8 ml) was cooled to 0° C. and treated dropwise with dimethylamine (5.6M in ethanol, 4.50 ml, 25.3 mmol). The solution was stirred for 17 hours being allowed to warm up to room temperature over this time. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1) to afford the title compound as a yellow oil (0.93 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)[CH3:12].C(O)C>ClCCl>[CH2:11]([O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromopyridine-5-carboxylic acid (J.Org.Chem., 12, 456 (1947)) (2.32 g, 11.49 mmol) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (3.12 g, 12.64 mmol) in dichloromethane (30 ml) was stired at room temperature for 1 hour under nitrogen. Absolute ethanol (5 ml) was added and the mixture stirred for 30 minutes and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (40 ml) and 10% w/w aqueous potassium carbonate solution (40 ml). The aqueous layer was extracted with dichloromethane (25 ml) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel, eluting with dichloromethane gave 2-bromopyridine-5-carboxylic acid ethyl ester (2.18 g, 83%) as a colourless oil.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N1([C:29](=O)[C:28]2N(C)C=N[C:23]=2N(C)C1=O)C>O>[CH:28]([O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2])([CH3:29])[CH3:23]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Br
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
HBr (120 g) and tryptophan (5 g) were dissolved in water (1 L). Caffeine (100 g) was added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:13]([F:14])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[F:14][C@@H:13]1[CH2:12][NH:11][CH2:10][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of (3R,4R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (3.0 g, 8.8 mmol) in MeOH (50 mL) was added wet Pd/C (0.3 g, 10%) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred at rt under hydrogen balloon for 3 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (1.6 g, 88% yield) as light yellow oil that solidified on standing.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>>[NH2:14][C:13]1[CH:15]=[CH:16][C:17]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:11]([F:10])[CH:12]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)c1ccccc1
Product: Nc1ccc(C(=O)c2ccccc2)c(F)c1
Temperature: 220 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To stirred 900° C. polyphosphoric acid (150 g) was added 18.32 g (15.0 mmol) of benzoic acid and 8.33 g (7.5 mmol) of 3-fluoroaniline and the bath temperature raised to 220° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid collected. The 1.88 g of solid was chromatographed on silica gel (methylene chloride) to yield 1.15 g (7%) of white fluffy 4-amino-2-fluorobenzophenone, mp 133°-5° C. 1H NMR (250 MHz, CDCl3): 4.20 (s, 2H, NH2) 6.33-6.50 (m, 2H, aromatic) 7.27-7.55 (m, 4H, aromatic) 7.76-7.79 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([NH:16][C:17]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: NC1CCC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A 13 g sample of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine is dissolved in 100 ml of dichloromethane and stirred under nitrogen atmosphere. A solution of 6.86 g of isopropyl isocyanate in 45 ml of CH2Cl2 is then added over a 48 minute period at 20° C to 28° C. The mixture is stirred for 16 hours at room temperature and filtered to give the title compound, melting point 185° C to 188° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N+:13]([O-])=O)[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[CH:17]([CH3:22])[C:18](OC)=[O:19]>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH:17]([CH3:22])[C:18](=[O:19])[NH:13][C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: COC(=O)C(C)Br
Reactant: CCS(=O)(=O)c1ccc(O)c([N+](=O)[O-])c1
Product: CCS(=O)(=O)c1ccc2c(c1)NC(=O)C(C)O2

Procedure:
Using 4-(ethylsulfonyl)-2-nitrophenol and methyl 2-bromopropanoate in the general procedure for alkylation of substituted-2-nitrophenols followed by reaction of the product in the general procedure for reduction of nitro group and subsequent ring closure gives a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.96 (s, 1H), 7.43 (dd, J=8.3, 2.0 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.85 (q, J=6.8 Hz, 1H), 3.23 (q, J=7.3 Hz, 2H), 1.46 (d, J=6.8 Hz, 3H), 1.10 ppm (t, J=7.5 Hz, 3H). ESI-MS: m/z 256.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:15](=[S:18])([OH:17])=[O:16])[C:12]([F:14])=[CH:13][C:8]=3[C:7](=[O:19])[NH:6][C:5]2=[O:20])[CH2:3][CH2:2]1.[H-].[Na+].[N+:23](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:23][N:6]1[C:7](=[O:19])[C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15](=[S:18])([OH:17])=[O:16])=[N:10][C:9]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(S(=O)(O)=S)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 0.47 g (1.57 mmol) of 1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Example 35) in 20 mL of dimethylformamide/dioxane (1:1) is treated portionwise with 0.08 g (2.0 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred at room temperature for 1 hour and 0.32 g (1.6 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 100 mL with ice and water and stirred at 5° C. for 1 hour. The aqueous solution is extracted with ethyl acetate (3×50 mL) with the combined organic layers being washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.4 g of the title compound, mp 167–169° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([C:14]1[N:15]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32]C)=[O:30])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:13].ClC(Cl)(Cl)C([N:40]=C=O)=O>ClCCl>[NH2:40][C:18]1[C:17]2[N:26]=[C:14]([CH2:12][CH3:13])[N:15]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:16]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)(C)Cn1c(CC)nc2cnc3ccccc3c21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
mCPBA (4.8 g of 75%, 22 mmol) was added over a period of several minutes to a solution of ethyl 3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (3.6 g, 11 mmol) in dichloromethane (100 mL), which had been cooled to approximately 0° C. The reaction mixture was stirred cold for ten minutes and then for three hours at ambient temperature. The reaction mixture was then washed twice with a mixture of saturated aqueous sodium bicarbonate (34 mL) and 25% aqueous sodium hydroxide (1 mL), dried over potassium carbonate, filtered, and then cooled to 0° C. Trichloroacetyl isocyanate (1.7 mL, 14 mmol) was added, and the reaction was stirred cold for 15 minutes, warmed to ambient temperature, and stirred for one hour. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (50 mL). Sodium methoxide (6.5 mL of a 25% solution in methanol, 30 mmol) was added to the resulting solution, and the reaction was stirred at ambient temperature overnight and cooled to approximately 0° C. for 30 minutes. A precipitate formed and was isolated by filtration to provide 1.2 g of methyl 3-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[N:9][CH:10]=1.[CH2:26]([O:28][C:29](=[O:42])[CH2:30][C:31]1[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][NH:34][CH:35]=1)[CH3:27].O>CN(C)C=O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:34]2[CH:35]=[C:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:42])[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (575 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (575 mg, yield: 63%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1
Yield: 90 %

Procedure:
The title compound was prepared in 90% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-ethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H16N4, 289. Found, 289.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:23])[C:11]2[C:16]([CH2:17][CH2:18]/1)=[CH:15][C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2>[Pt]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Cl)CC2
Agent: [Pt]
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1Cl)CC2

Procedure:
The title compound 101 is prepared according to the procedure reported in Example 36.1 with compound 85 (93 mg, 2.83 mmol) and Pt/C (5 wt/o loading, 93 mg) as reactants. White solid. (Yield 0.47 g, 51%).
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][N:4]=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[F:13][C:2]([F:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][NH2:4]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccn1

Procedure:
A stirred solution of 100 mg of 2,2-difluoro-2-(2-pyridyl)ethyl azide was hydrogenated in 10 ml of ethyl acetate over 100 mg of 10% palladium on carbon under a balloon of hydrogen for 1 h. The catalyst was removed by filtration and the solvents removed at reduced pressure to give 1-10 as a yellow oil: 1H NMR (CDCl3) δ6 8.66 (d, 1H, 4.2 Hz), 7.82 (td,1H, 7.7, 1.7 Hz), 7.68 (d, 1H, 8.1 Hz), 7.37-7.40 (m, 1H), 3.44 (t, 2 H, 14.3 Hz), 1.41 (br s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH2:25][CH2:24][C:23]4[CH:32]=[CH:33][CH:34]=[CH:35][C:22]3=4)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].[Cl:38]CCl.Cl>C(O)C>[ClH:38].[CH:32]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:21](=[CH:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:7]4[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:17][CH2:16]3)[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of the above ester (2.1 g, 4.5 mmol) and 20% sodium hydroxide (3.0 ml) in ethanol (21 ml) was stirred at room temperature for 16 h. The solution was poured into dichloromethane (250 ml) and acidified with 2 N hydrochloric acid. The organic phase was washed with water (10 ml), dried (MgSO4) and the solvent evaporated in vacuo. The foamy residue was stripped with acetone and crystallized from acetone, affording 1.5 g (70%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CC=CC=1>CN(C)C=O>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
19-Hydroxy-4-androstene-3,17-dione, t-butyldimethylsilylchloride and pyridine are mixed in dry dimethylformamide and heated on a steam bath overnight. The reaction mixture is poured onto water and stirred well for 15 minutes. The resulting solid is filtered and dissolved in methylenechloride, dried over magnesium sulfate and the solvent removed. The residue is crystallized from an acetone-hexane solution to yield 19-t-butyldimethylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[C:27]([NH:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: COc1ccc(-c2nc(CNC(C)(C)C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 39.4 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.78 g), tert-butylamine (17.4 g) and dichloromethane (40 ml) was stirred at room temperature for 13 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with dichloromethane-ethanol (30:1, v/v) gave 2-(tert-butylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.77 g, 40%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18](=[O:25])[CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:25])[CH:19]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1cccc(OC)c1)C(=O)OC
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-methoxyphenol (115 g) in acetone (1000 ml) was added K2CO3 (115 g). The suspension was stirred at 40° C. for 15 min. A solution of dimethylchloromalonate (133 ml) in acetone was added over a period of 45 min. The resulting brown suspension was stirred overnight at 70° C. Finally, the solvent was removed under reduced pressure and the residue was taken up in water (1000 ml) and extracted twice with DCM (500 ml). The combined organic layers were washed with water (500 ml), dried over Na2SO4, and evaporated to give crude dimethyl-(3-methoxyphenoxy)malonate (230 g) as an orange oil. The product was not purified any further.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]=O>C(O)=O>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][CH3:35])=[CH:15][CH:16]=2)[C:11]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:22]2)=[C:10]1[CH3:34])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Cc1c(CCN2CCCC(CC3CCCCC3)C2)c2cc(N)ccc2n1C(=O)c1ccccc1
Solvent: O=CO
Product: CNc1ccc2c(c1)c(CCN1CCCC(CC3CCCCC3)C1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of the 1-benzoyl-3-[2-(3-cyclohexylmethylpiperidino)ethyl]-5-amino-2-methylindole described above in Example 95 with formaldehyde and formic acid affords 1-benzoyl-3-[2-(3-cyclohexylmethylpiperidino)ethyl]-5-methylamino-2-methylindole.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6](OCC)(OCC)([O:8][CH2:9]C)[CH3:7]>C(O)C>[CH3:9][O:8][C:6](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:7]
Reactant: N#CCC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: COC(C)=C(C#N)C#N
Temperature: 45 °C
Yield: 65.9 %

Procedure:
To a 100 mL flask equipped with air stirrer and thermometer and distillation condensor were added malononitrile (9.1 g, 0.138 mol, triethyl orthoacetate (26.8 g, 0.165 mol) and glacial acidic acid (0.4 mL) sequentially, and the mixture was stirred and gently heated (90° C.) until the ethanol formed in the reaction began to distill off. When all the ethanol had distilled off, the reaction temperature was raised slowly from 90° C. to 140° C. for 30 min to ensure completion of the reaction. The reaction mixture was allowed to cool to 45° C. to solidify. The resulting solid mass was broken up under hexane (20 mL) and hexane was decanted off. The solid was washed with ethanol (50 mL) to afford a colorless crystal. The ethanol solution was concentrated and allowed to cool to room temperature. Then the crystal was filtered, washed with ethanol dried under vacuum (12.3 g, 65.9% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 4'-fluoroacetophenone (13.8 g, 100 mmol), 4-methylimidazole (8.2 g, 100 ml) and potassium carbonate (20.7 g, 150 mmol) in dry dimethylformamide (190 ml) was heated at 150° C. for 23 hours. Most of the solvent was evaporated at reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was washed (3×) with brine, dried (magnesium sulphate) and evaporated to leave a sticky solid which was purified by flash chromatography (eluting 5% diethylamine in ethylacetate). Recrystallization from ethyl acetate/hexane afforded the title compound (yield 4 g, 20%), m.p. 100° C.