Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2N(C)C=CN=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:17]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc3ncccc3c1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.59 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain the title compound as a white solid (61 mg, yield 25%). LC-MS (ESI) m/z: 409 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.52-4.55 (d, J=9.6 Hz, 1H), 4.98-5.01 (d, J=9.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H), 7.41-7.43 (d, J=7.6 Hz, 1H), 7.46-7.50 (m, 1H), 7.54 (s, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (m, 1H), 7.84 (s, 1H), 7.91-7.93 (m, 1H), 8.24-8.26 (d, J=7.6 Hz, 1H), 8.85-8.86 (m, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:3][CH2:2]1.[N+:17]([O-])([OH:19])=[O:18]>CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Nc1ccccc1OCC1CC1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
N-(2-(cyclopropylmethoxy)phenyl)methanesulfonamide (1.3 g, 5.39 mmol) was cooled to 0° C., and nitric acid (0.746 ml, 10.77 mmol) was added. The mixture was stirred at RT for 1 hour. The mixture was diluted with EtOAc and washed with NaHCO3 5% and brine. The organic phase was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 60:40). 0.390 g of title product were obtained by collection and evaporation of clean fractions. Product obtained from mixed fractions was triturated with EtOAc affording 0.285 g of title compound. The mother liquor from trituration was evaporated and purified by flash chromatography on silica gel (DCM:petroleum ether=80:20) to give 0.155 g of title compound. Title product N-(2-(cyclopropylmethoxy)-4-nitrophenyl)-methanesulfonamide was obtained (0.830 g, 2.90 mmol, 53.8% yield, MS/ESI+ 286.9 [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH:10]([C:13]#[N:14])[C:11]#[N:12].[CH3:25]I>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:10]([CH3:25])([C:13]#[N:14])[C:11]#[N:12]
Reactant: CI
Reactant: COc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Solvent: C1CCOC1
Product: COc1ccccc1C(c1cccc2ccccc12)C(C)(C#N)C#N
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
2-[(2-Methoxyphenyl)(1-naphthyl)methyl]malononitrile of Example 1 (196 mg, 0.63 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to −35° C. Potassium hexamethyldisilyl amide (1.14 mL, 0.75 mmol, 0.66 M in toluene) was added. The cooling bath was removed, and the reaction allowed to warm to room temperature, after which methyl iodide (0.078 mL, 125 mmol) was added. The reaction mixture was stirred 30 minutes, then quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over mgnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) and recrystallization from methanol, 104 mg product was isolated as a crystalline solid, mp 175-177° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4C3CCCCO3)=[CH:16][CH:15]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>O1CCOCC1>[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)=[CH:18][CH:19]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]cnc23)cc1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To 2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)-amino]carbonothioyl}acetamide (190 mg, 0.38 mmol) in 30 mL of dioxane was added 3 mL of 4N HCl in dioxane and let to stir for 1 h. On concentration of the reaction mixture and trituration with ether yielded 2-phenyl-N-({[4-(9H-purin-6-yloxy)phenyl]amino}carbonothioyl)acetamide (102 mg, 65% yield) as a colorless solid. 1H NMR (400 MHz, DMSO d6): δ 12.40 (s, 1H), 11.80 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.70 (m, 2H), 7.35 (m, 7H), 3.8 (s, 2H). MS (ESI) for C20H16N6O2S: 433 (MH+).
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[Rh].[Pd]>[NH2:2][CH2:1][C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CC1(CC(=O)O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
One gram of 10% rhodium on carbon, containing 1% palladium, (Pearlman, W. M., Tetrahedron Letters, pages 1663-1664 (1967) is slurried in 30 ml methanol and reduced under hydrogen in a Parr shaker. 1-Cyanocyclohexaneacetic acid (16.7 g, 0.1 mol) is dissolved in 40 ml methanol and combined with the reduced catalyst. The mixture is placed under 50 pounds per square inch gauge (psig) hydrogen and shaken for two hours at room temperature. The catalyst is removed by filtration, and the filtrate is condensed to a volume of 25 ml by vacuum distillation. Isopropanol, 100 ml, is added and an additional 25 to 50 ml of solvent is removed by vacuum distillation. The resultant slurry is cooled at 0° to 5° C. for 24 hours and filtered and dried to give 13.65 g (79% of theory) of 1-(aminomethyl)-cyclohexaneacetic acid; mp 162°-163° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=O>C(O)(=O)C>[C:8]([C:7]1[C:2]2[N:1]=[C:12]([CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]3[C:24]([O:26][C:7]([CH3:8])([CH3:2])[CH3:6])=[O:25])[NH:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)c1cccc(NC(=O)C2CCc3ccccc3N2C(=O)OCc2ccccc2)c1N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1c2ccccc2CCC1c1nc2c(C(N)=O)cccc2[nH]1
Reaction time: 2 h

Procedure:
Step-2: A solution of benzyl 2-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroquinoline-1(2H)-carboxylate (50 mg, 0.122 mmol) in acetic acid (2 ml) was heated to 80° C. and stirred for 2 h. The reaction mixture was concentrated, neutralized with aq. NaHCO3 and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification of the crude product over preparative TLC using ethyl acetate/hexane mixture (2:1) as eluent afforded tert-butyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate. MS (ES+): m/z 393.23 [M+H]+
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(O[C:25]([CH3:28])([CH3:27])[CH3:26])(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[C:1]([NH:11][C@H:12]([C:18]([O:20][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(=O)OC(C)(C)C
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 25 g of Nα-CBZ-L-lysine from Sigma, where CBZ is benzyloxycarbonyl, 250 mL of t-butyl acetate and 14 mL of 70% perchloric acid was vigorously mixed until all solids were dissolved. After stirring overnight, 375 mL of ethyl acetate was added followed by 250 mL of water. The pH of the aqueous layer was raised to 5.5 with 20% NaOH whereupon the organic phase was separated. The aqueous phase was extracted with the ethyl acetate solution and the pH again raised to 10.5 whereupon it was again extracted with 200 mL of fresh ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over Na2SO4 and concentrated. The residue was dried overnight under high vacuum to yield 23.2 g of a colorless, viscous material.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]([Br:18])([Br:17])[C:14](Cl)=[O:15]>C(#N)C>[C:1]([N:4]([C:14](=[O:15])[C:13]([Br:18])([Br:17])[Br:12])[NH2:5])(=[O:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: O=C(Cl)C(Br)(Br)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N(N)C(=O)C(Br)(Br)Br
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
4.68 g (0.063 mol) of acetohydrazide (2-a) and 5 g (0.063 mol) of pyridine were dissolved in 50 ml of acetonitrile, and stirred with cooling in an ice-bath. Thereto, a solution of 20 g (0.064 mol) of tribromoacetic acid chloride (which was prepared from tribromoacetic acid and thionyl chloride, and had b.p. of 800°-81° C./17 mm Hg) dissolved in 20 ml of acetonitrile was added dropwise. After the conclusion of the dropwise addition, the stirring ring was further continued for 30 min. Thereupon, a white precipitate was deposited. It was filtered off, and washed with successive, acetonitrile and water. Thus, 10.7 g (0.030 mol) of N-acetyl-N-tribromoacetylhydrazine (3-a) was obtained. Yield 48%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2([O:15][C:14](=[O:16])[NH:13][C:12]2(O)[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2([O:15][C:14](=[O:16])[NH:13][C:12]2=[CH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)NC(=O)OC12CCN(Cc1ccccc1)CC2
Solvent: C1COCCO1
Product: C=C1NC(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 62 %

Procedure:
A solution containing 14.0 g of 8-benzyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 210 ml of dioxane is boiled under nitrogen while azeotropically distilling out the water formed in the reaction. After termination of the reaction dioxane is evaporated under reduced pressure. The residue is recrystallized from ethanol under clarifying by activated carbon to give the title compound in 62% yield, m.p.: 169°-170° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(C(=O)CCl)C1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.8 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[N:24][N:23]([CH3:26])[C:22]=2[CH:27]=1>>[CH3:26][N:23]1[C:22]2[CH:27]=[C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)[CH:19]=[CH:20][C:21]=2[N:25]=[N:24]1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: Cn1nnc2ccc(CCl)cc21
Product: Cn1nnc2ccc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)cc21

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 6-chloromethyl-1-methyl-1H-benzotriazole
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]([CH3:19])=[CH2:18])=[CH:12][CH:11]=1.C(O)(=O)CC>CO>[CH3:19]/[C:17](=[CH:16]\[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)/[CH2:18][CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: C=C(C)C(O)c1ccc(C)cc1
Solvent: CCC(=O)O
Solvent: CO
Product: COC(=O)CC/C(C)=C/c1ccc(C)cc1
Yield: 40.1 %

Procedure:
Trimethyl orthoacetate (273 g, 2.24 mol) and 1-(4-methylphenyl)-2-methyl-2-propen-1-ol (91.4% pure, 39.92 g, 0.224 mol) were heated in the presence of propionic acid (0.5 ml) in an oil bath at 120°-150° C. The methanol formed during the reaction was distilled first, followed by the excess orthoacetate. The product was then freed from residual orthoacetate under vacuum and purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 5:1), followed by bulb-to-bulb distillation (100° C./0.001 mbar). 19.62 g (yield=40%) of the desired product were obtained.
Reaction SMILES: C(=O)(OC)[O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([NH2:20])=[N:13][C:14]=3[Cl:19])[CH2:5][CH2:4]1.Cl>[OH-].[K+]>[NH2:20][C:12]1[N:11]=[C:10]2[C:15]([NH:16][C:17](=[O:18])[N:9]2[C@H:6]2[CH2:5][CH2:4][C@H:3]([OH:2])[CH2:8][CH2:7]2)=[C:14]([Cl:19])[N:13]=1
Reactant: COC(=O)O[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(N)nc32)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](O)CC3)c2n1

Procedure:
Trans-4-(2-Amino-6-chloro-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl methyl carbonate (1.43 g) was dissolved in 80 mL of an aqueous solution 0.5 N KOH and the reaction mixture heated at reflux for 30 min (LC-MS analysis indicated reaction to be complete). The reaction mixture was then cooled in an ice bath, and its pH was brought to 7 by drop wise addition of a concentrated aqueous solution of HCl. A light pink solid precipitated. It was filtered under vacuum, thoroughly dried in vacuum oven at 60° C., to give the desired product in 86% yield. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 8.48 (br s, 1H), 7.73 (s, 2H), 4.26-4.18 (m, 1H), 3.70-3.61 (m, 1H), 2.53-2.40 (m, 2H), 2.10-2.06 (m, 2H), 1.81-1.76 (m, 2H), 1.48-1.37 (m, 2H); MS (EI) m/z 284.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](=[O:18])[N:10]([C@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:17])[C:4]=2[C:3]=1[NH2:19].[CH3:20][N:21]=[C:22]=S.O>C1(C)C(CCO)=CC=CC=1>[CH3:20][NH:21][C:22]1[NH:1][C:2]2=[N:7][CH:6]=[C:5]3[NH:8][C:9](=[O:18])[N:10]([C@H:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]4[CH3:17])[C:4]3=[C:3]2[N:19]=1
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc(N)c(N)c21
Reactant: CN=C=S
Agent: Cc1ccccc1CCO
Solvent: O
Product: CNc1nc2c(ncc3[nH]c(=O)n([C@H]4CCCC[C@H]4C)c32)[nH]1
Temperature: 80 °C

Procedure:
To a mixture of 6,7-diamino-1-[(1S,2R)-2-methylcyclohexyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (147 mg) in toluene-ethanol (1 mL-0.5 mL) was added methyl isothiocyanate (43 μL). The resulting solution was heated for 80° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was added drop wise water. The mixture was extracted with EtOAc (2×15 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4. Removal of the solvent preceded the crude thiocarbamate which was used in the next step with out purification. To a solution of above carbamate in toluene (1 mL) was added WSCD HCl (162 mg) at ambient temperature. The mixture was heated at 110° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (20 mL), and washed with saturated aqueous sodium hydrogencarbonate (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel chloroform:methanol=90:10) to give 2-(methylamino)-8-[(1S,2R)-2-methylcyclohexyl]-6,8-dihydrodiimidazo[4,5-b:4′,5′-d]pyridin-7(3H)-one (10 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Reactant: O=S(Cl)Cl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 87 %

Procedure:
A mixture of 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (638 mg, 2 mmol) and thionyl chloride (8 ml) was heated at reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The residue was suspended in methylene chloride and 10% aqueous solution of sodium hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (590 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C@@H:9]([CH3:40])[C:10]([NH:12][C@@H:13]([CH:37]([CH3:39])[CH3:38])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:41])[C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:15])[CH:37]([CH3:39])[CH3:38])[CH3:40])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccccc1
Yield: 69.3 %

Procedure:
To the stirred solution of toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (Intermediate 2) (50 mg, 0.085 mmol) in 1,4-dioxane (0.5 mL), K2CO3 (29.3 mg, 0.127 mmol), was added aniline (0.012 mL, 0.127 mmol) and the reaction mixture irradiated in a microwave at 125° C. for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water and brine and the separated organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC (X Bridge Prep C18 (250×19.0 mm) 5μ, acetonitrile and 0.05% formic acid) to give methyl-{(S)-1-[(S)-2-methyl-1-((S)-2-phenylaminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (30 mg), m/z=510.6 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C)cc(N)c1N
Yield: 96 %

Procedure:
A solution of 2-amino-5-methyl-3-nitro-benzoic acid methyl ester (5.5 g, 26 mmol) in methanol (200 mL) was hydrogenated with hydrogen balloon in presence of 10% Palladium on charcoal (1.5 g) for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get the required product as a brown coloured solid 4.5 g (95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][C@@H:22]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:8]1)=[O:5])[CH3:2].CCCCCC.BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)N=C(C)C=1>C1(C)C(C)=CC=CC=1.C(OC(=O)C)C>[CH2:1]([O:3][C:4]([O:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][C@@H:22]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](OC(=O)OCC)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](OC(=O)OCC)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Reaction time: 0.33 h
Yield: 105.8 %

Procedure:
A solution of 1α,3β,24(R)-triethoxycarbonyloxycholest-5-ene (3.49 g, 5.5 m moles), dry hexane (58 ml) and 1,3-dibromo-5,5-dimethylhydantoin (998 mg, 3.3 m moles) was boiled under the irradiation of infrared rays for 15 minutes. The reaction mixture was cooled, and the resulting 5,5-dimethylhydantoin and the excessive 1,3-dibromo-5,5-dimethylhydantoin were removed by filtration. The filtrate was concentrated at reduced pressure to afford a residual product. Xylene was added to this substance to form a solution. The resulting solution was added dropwise to a solution held 170° C. of s-collidine (14.5 ml) in dry xylene (19 ml), and the reaction was carried out for additional 20 minutes. After the reaction, the hydrobromide of s-collidine was removed by filtration and the filtrate was concentrated under reduced pressure at 40° C. to give residual product. The residue was dissolved in ethylacetate (200 ml). The organic phase was washed with 1 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 3.68 g of residual product.