Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=[CH:9][C:8]=1[S:7]2.Cl[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]1[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=[CH:9][C:8]=1[S:7]2
Reactant: CCOC(=O)C(C)Cl
Reactant: N#Cc1ccc2c(c1)Nc1ccc(Cl)cc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 2 h

Procedure:
Sodium hydride (1.85 g; in 50% strength dispersion in vaseline) is added slowly in the course of 10 minutes to a solution of 7-chloro-2-phenothiazinecarbonitrile (10 g) in N,N-dimethylformamide (250 cc). The mixture is then brought to 120° C. and treated in the course of 30 minutes with a solution of ethyl (2RS)-2-chloropropionate (18.5 cc) in N,N-dimethylformamide (100 cc). Heating is continued for 2 hours. After cooling, the mixture is diluted in ethyl acetate (1 liter) and washed with distilled water (1.5 liters). The organic phase is dried over magnesium sulphate, treated with charcoal 3S, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is purified by chromatography on a column (height: 25 cm; diameter: 4.0 cm) of silica (0.2-0.06 mm), eluting with a 90:10 (by volume) mixture (1.5 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give ethyl (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propionate (5.3 g) in the form of a pale yellow product of meringue-like consistency.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>O>[CH:34]1([N:33]([CH2:2][C:3]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=2)[CH3:32])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CNC1CCCCC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CN(C)C2CCCCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-(N-cyclohexyl-N-methylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%) which was then recrystallized from ethanol. Colorless prisms. mp. 172°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[C:14]([CH:23]=[CH2:24])=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:26])([CH3:25])[C:9]2=[O:27])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:23]([C:14]1[C:13]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[O:11][C:12]=2[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=1)[CH3:24]
Reactant: C=Cc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Yield: 104 %

Procedure:
To a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro -2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 156, 200 mg) in ethanol (20 mL) was added 10% palladium-carbon (water content: ca. 50%, 200 mg), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; chloroform→chloroform/ethyl acetate=10/1) to give N-[5-ethyl-4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (209 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=O)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH2:15][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C=O)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(CN3CCN(C)CC3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1H-indazole-4-carboxamide (0.1 g, 0.255 mmol) in methanol (2 mL) was added acetic acid (0.015 g, 0.255 mmol) and 1-methylpiperazine (0.077 g, 0.765 mmol) and stirred it at room temperature for 3 h. NaBH3CN (0.016 g, 0.255 mmol) was then added. The resulting reaction mixture was stirred at room temperature overnight. After completion of reaction, the solvent was removed under reduced pressure and water was added. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-indazole-4-carboxamide (0.027 g, 28.8%). LCMS: 477.25 (M+1)+; HPLC: 99.71% (@ 254 nm) (Rt; 4.649); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.39 (t, 1H, J=4.8 Hz), 8.27 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 5.89 (s, 1H), 5.19-5.14 (m, 1H), 4.35 (d, 2H, J=5.2 Hz), 3.58 (s, 2H), 2.39-2.33 (m, 8H), 2.21 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.00 (m, 2H), 1.99-1.96 (m, 2H), 1.91-1.86 (m, 2H), 1.69-1.68 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:10]([C:12]2[CH:16]=[C:15]([Si](C)(C)C)[O:14][N:13]=2)[N:11]=1)=[O:5].[F-].[Cs+]>C(O)C.C(Cl)Cl>[F:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:10]([C:12]2[CH:16]=[CH:15][O:14][N:13]=2)[N:11]=1)=[O:5]
Reactant: C[Si](C)(C)c1cc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)no1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(Nc1nc(-c2ccon2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Into a solution of Compound 105 (55.0 mg, 0.10 mmol) in ethanol (2.0 mL) at room temperature was added cesium fluoride (152 mg, 1.0 mmol). The mixture was stirred at room temperature for 1 hour, diluted with CH2Cl2, washed with water (2×), dried (Na2SO4), filtered and concentrated. The residue was purified on silica to give Compound 106 (39 mg).
Reaction SMILES: [Si]([C@@:8]1([OH:42])[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:11][C@@H:10]([N:22]2[CH:29]=[C:28]([CH2:30][O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[C:26]([NH2:27])=[N:25][C:23]2=[O:24])[CH2:9]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N+:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:31][CH2:30][C:28]1[C:26]([NH2:27])=[N:25][C:23](=[O:24])[N:22]([CH:29]=1)[C@@H:10]1[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:42])[CH2:9]1)([O-:41])=[O:40]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(COCc3ccccc3[N+](=O)[O-])c(N)nc2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of compound 42 (55 mg, 0.09 mmol) in THF (10 mL), n-Bu4NF (63 mg, 0.20 mmol) was added. The mixture was stirred at room temperature for four hours and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 5-(2-nitrobenzyloxyl)methyl-2′-deoxycytidine 43 (34 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=8.0 Hz, 1H, Ph-H), 7.89 (s, 1H, H-6), 7.74 (m, 2H, Ph-H), 7.55 (m, 1H, Ph-H), 7.39 (br s, 1H, D2O exchangeable, NH2), 6.74 (br s, 1H, D2O exchangeable, NH2), 6.12 (t, 1H, J=6.4 Hz, H-1′), 5.21 (br s, 1H, D2O exchangeable, 3′-OH), 4.99 (br s, 1H, D2O exchangeable, 5′-OH), 4.81 (s, 2H, Ph-CH2), 4.30 (dd, 2H, J=11.6 Hz, 5-CH2), 4.20 (m, 1H, H-3′), 3.76 (m, 1H, H-4′), 3.55 (m, 2H, H-5′), 2.11 (m, 1H, H-2′a), 1.95 (m, 1H, H-2′b).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].ClCCC(C)C(Cl)=O.[Cl:16][C:17]1[CH:26]=[C:21]([C:22]([NH:24]O)=[O:23])[C:20](O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:4][CH:3]3[CH:2]([CH3:1])[CH2:7][CH2:6][O:5][N:24]3[C:22](=[O:23])[C:21]=2[CH:26]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: CC1CCOC1=O
Agent: CC(CCCl)C(=O)Cl
Product: CC1CCON2C(=O)c3cc(Cl)ccc3OC12

Procedure:
40 g. of 2-methylbutyrolactone was converted to 45 g. of 4-chloro-2-methylbutryl chloride (b.p. 70°-72° C at 15 mm.) by the method detailed in Example 4. The acid chloride (15.5 g.) was reduced to the corresponding aldehyde, condensed with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][CH2:23][CH2:22][C:20]([C:19]2[S:18][CH:17]=[N:16][C:15]=2[CH3:14])=[O:21])=[N:5][N:4]=[N:3]1
Reactant: Cc1ncsc1C(=O)CCCCl
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ncsc1C(=O)CCCSc1nnnn1C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 4-methyl-5-thiazolyl ketone (3.1 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrated is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(4-methyl-5-thiazolylcarbonyl)propyl]thio-1,2,3,4-tetrazole (2.6 g) as colorless needles, m.p. 64°-65° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([OH:21])=O)[N:11]=[C:12]([C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:5]=12.Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][C:33]([CH3:38])([CH3:37])[CH2:32]2)=[CH:27][C:26]=1[O:39][CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:39][CH3:40])[CH:27]=4)[CH2:32][C:33]3([CH3:38])[CH3:37])=[O:21])[N:11]=[C:12]([C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C:5]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: COc1cc(N2CCNC(C)(C)C2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)C(C)(C)C2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
[4-Amino-3-(1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid dihydrochloride (100 mg, 0.2 mmol) and 1-(4-chloro-3-methoxyphenyl)-3,3-dimethylpiperazine dihydrochloride (100 mg, 0.3 mmol) were suspended in anhydrous DMF (2.5 mL). N,N-Diisopropylethylamine (0.32 mL, 1 mmol) was added at 0° C. and the mixture was stirred at room temperature until all solids dissolved to give a brown solution. HBTU (114 mg, 0.3 mmol) was added. After 2 h, the reaction mixture was poured slowly into a flask of vigorously stirred ice-water (100 mL). The resulting suspension was extracted with dichloromethane (100 mL) and washed with saturated NaHCO3 (100 mL), brine (100 mL) and evaporated. The residue was purified by flash column chromatography to afford 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)-2,2-dimethylpiperazin-1-yl]ethanone as a light tan solid (45 mg) after evaporation and drying in vacuo. 1H NMR (400 MHz, d6-DMSO) δ 10.14 (d, 1H, J=3.6 Hz), 8.16 (s, 1H), 7.95 (d, 1H, d, J=3.6 Hz), 7.24 (s, 1H), 7.15 (s, 1H), 7.14 (d, 1H, J=8.8 Hz), 6.40 (d, 1H, J=2.4 Hz), 6.31 (dd, 1H, J=2.4 and 8.8 Hz), 5.29 (s, 2H), 3.90 (t, 2H, J=5.4 Hz), 3.84 (s, 3H), 3.46 (t, 2H, J=5.4 Hz), 3.30 (s, 2H), 1.38 (s, 6H). MS (ES) m/z 496.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl>CO.O1CCOCC1>[NH:21]1[CH2:22][CH2:23][C@H:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:17]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2cc(-c3ccccc3O)nc3ccccc23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccccc1-c1cc(N[C@H]2CCNC2)c2ccccc2n1
Reaction time: 12 h
Yield: 53.2 %

Procedure:
(S)-tert-butyl 3-(2-(2-hydroxyphenyl)quinolin-4-ylamino)pyrrolidine-1-carboxylate (0.050 g, 0.123 mmol) was dissolved in methanol (2 mL) and 4 M HCl in dioxane (5 mL) was added. After stirring for 12 hours, the solution was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by preparative thin layer chromatography, eluting with 20% methanol in dichloromethane, gave the title compound as a solid (0.020 g, 53%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=O.[NH3:38]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:2])[NH2:38])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: N
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(N)=O)cn4c3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg) and a solution of ammonia in methanol (7M, 1.4 mL) was heated at 130° C. for 90 minutes under microwave irradiation. On cooling, the reaction mixture was concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>[N+](C1C=CC=CC=1)([O-])=O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([C:7]3[NH:19][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:18]=3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Nc1ccccc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc2[nH]c(-c3ccc4c(c3)OCO4)nc2c1
Yield: 48.9 %

Procedure:
A solution of 50 g (0.34 mol) of piperonal and 37 g (0.34 mol) of phenylenediamine in 0.3 L of nitrobenzene was stirred under reflux for 12 hours. The resulting mixture was concentrated in vacuo. The solid residue was collected via filtration, and rinsed with ether to give 39.6 g (49%) of desired material as an off-white solid: 1H NMR (CDCl3) δ 5.96 (s, 2H), 6.79 (d, J=8.5 Hz, 1H), 7.17-7.30 (m, 2H), 7.50-7.65 (m, 4H), 8.80-9.40 (br s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([Cl:21])[C:17]=3[O:19][CH3:20])[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:22][Br:23])[CH:15]=[C:16]([Cl:21])[C:17]=3[O:19][CH3:20])[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)cc(CBr)c2cnn(S(=O)(=O)c3ccccc3)c12

Procedure:
1-Benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole (2.45 g, 7.3 mmol), recrystallized N-bromosuccinimide (1.36 g, 7.6 mmol) and benzoyl peroxide (90 mg, 0.37 mmol) are dissolved in carbon tetrachloride (25 mL). The reaction is degassed and then placed in a 80° C. bath. The reaction is heated (about 2 h) until no starting material remains by TLC analysis (PhMe). The reaction is cooled, diluted with EtOAc, and washed with water. The solution is dried with MgSO4, concentrated and purified by column chromatography (silica, PhMe) to provide 1-benzenesulfonyl-4-bromomethyl-6-chloro-7-methoxy-1H-indazole.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:28][C:29]1[C:33]([C:34]2[CH:35]=[C:36](C3C(C)=CC=C4C=3C=CC=N4)[C:37]3[NH:41][C:40](=[O:42])[NH:39][C:38]=3[CH:43]=2)=[C:32]([CH3:55])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([C:34]2[CH:35]=[C:36]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C:3](=[O:21])[N:2]4[CH3:1])[C:37]3[NH:41][C:40](=[O:42])[NH:39][C:38]=3[CH:43]=2)=[C:32]([CH3:55])[O:31][N:30]=1
Reactant: CN1C(=O)CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2cccc3c2CCC(=O)N3C)c2[nH]c(=O)[nH]c2c1

Procedure:
5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one was synthesized using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:19][N:18]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CNCC34CCCC4)n2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CN(C(=O)CC#N)CC34CCCC4)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.4]nonan-4-yl)pyrimidine-2,4-diamine (393 mg, 1.13 mmol), 2-cyanoacetic acid (240.83 mg, 2.83 mmol), HATU (429.63 g, 1.13 mmol) in a mixture of DCM and DMF (4/1 (v/v), 25 mL) was added Et3N (456.52 mg, 4.52 mmol) and the reaction mixture was stirred at rt for 3 hours. The resulting mixture was diluted with H2O (20 mL) and extracted with a mixture of DCM and MeOH (10/1 (v/v), 20 mL×3). The combined organic phases were washed with brine (50 mL), and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=100/1 to 20/1) to give the product as a white solid (290 mg, 61.8%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=C)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CC[O+:35]([O-])CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:35])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Reactant: CN1CC[O+]([O-])CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (Preparation 48B, 26.2 mg, 0.064 mmol) in 0.5 mL of THF were added 0.113 mL of 10% N-methyl-morpholine-1-oxide in water and 0.04 mL of 4% OsO4 in water, and 0.2 mL of water. The heterogeneous mixture was stirred at room temperature for 18 hrs. To the homogenous reaction mixture was added 0.14 mL of 10% sodium periodate in water, and the mixture was stirred for 3 hrs. The reaction mixture was extracted with EtOAc, washed with water, brine dried over Na2SO4 and evaporated to give a solid residue which was purified by Combiflash (24 g silica gel) eluting with 1:9 followed by 3:7 EtOAc-hexane to give 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazole-7-carbaldehyde (20.2 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (1H, s), 7.51-7.61 (2H, m), 7.44 (1H, d, J=7.70 Hz), 7.36 (2H, d, J=7.70 Hz), 7.22-7.30 (3H, m), 2.99-3.05 (2H, m), 2.83 (2H, t, J=8.03 Hz).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][NH2:17])[N:10]=[CH:9]2)C=CC=CC=1.[ClH:30]>CO>[ClH:30].[ClH:30].[NH2:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: NC[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CO
Product: NC[C@@H]1C[C@H]1c1c[nH]cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of N-triphenylmethyl-4-(trans-2-aminomethyl-cyclopropyl)imidazole (100 mg, 0.26 mmol) in methanol (15 mL) was added 2N HCl solution (2.5 mL). The mixture was stirred at 60° C. for 2 hours and then concentrated. The resulting residue was extracted with ether (3×20 ml). The aqueous layer was lyophilized to give the product (47 mg, 83% yield).