Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[C].[Pd].[H][H]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CC(c2ccccc2)c2ccccc21
Yield: 97.3 %

Procedure:
A mixture of 3.0 g of 1-benzoyl-3-phenylindole, 0.33 g of 10% palladium-carbon catalyst, and 60 ml of acetic acid was stirred in hydrogen for six hours under the conditions of 60° C. and normal pressure, cooled, then filtered to remove the catalyst, and distilled to expel the acetic acid. The residue was alkalinized by addition of an aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then distilled to expel the ethyl acetate and obtain 2.94 g of 1-benzoyl-3-phenylindoline (97.4%) having a melting point of 127-129° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:19][C:20](=[O:43])[C@H:21]([NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH2:17]([O:19][C:20](=[O:43])[C@@H:21]([NH:26][C:27](=[O:42])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:38][CH2:39]2)=[CH:32][CH:33]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:18]
Reactant: CCOC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(N2CCC(C=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.098 g, 0.4 mmol), (2R)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]amino}4-methylpentanoic acid ethyl ester (0.4 mmol) and glacial acetic acid (0.023 g, 0.4 mmol) in 5 mL of methanol-THF (4:1, v/v) was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.026 g, 0.4 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 20:1). to give the product (0.072 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([NH2:13])=[CH:5]2.[C:14](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:15]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([N:13]=[C:14]=[S:15])=[CH:5]2
Reactant: Nc1cc2cc(Cl)cc(Cl)c2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc2cc(Cl)cc(Cl)c2cn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To 6,8-dichloroisoquinolin-3-amine (0.27 g, 1.28 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.30 g, 1.29 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 6,8-dichloro-3-isothiocyanatoisoquinoline (0.2 g, 0.78 mmol, 61.9% yield) as a powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.42 (s, 1H), 8.16 (d, J=1.83 Hz, 1H), 8.02 (d, J=2.14 Hz, 1H), 7.92 (s, 1H). MS (LC/MS) R.T.=3.63; [M+H]+=255.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>O1CCCC1>[CH2:6]1[O:5][CH:4]([CH2:3][CH2:2][CH:28]([OH:29])[CH:25]2[CH2:24][CH2:23][CH:22]([CH:19]3[CH2:20][CH2:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]3)[CH2:27][CH2:26]2)[O:9][CH:8]1[CH3:7]
Reactant: CCCCCC1CCC(C2CCC(C=O)CC2)CC1
Reactant: BrCCC1OCCCO1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(C(O)CCC3OCC(C)O3)CC2)CC1
Yield: 82.8 %

Procedure:
To Grignard reagent prepared from 33.7 g (173 mmol) of 2-(2-bromoethyl)-1,3-dioxane and magnesium in 300 ml of tetrahydrofuran (THF), a solution of 40.0 g (151 mmol) of 4-(4-pentylcyclohexyl) cyclohexane carbaldehyde (10) in 200 ml of THF was added dropwise, and the resultant solution was stirred for 3 hours. The reaction solution was added into 500 ml of 1N-hydrochloric acid, and the reaction product was extracted with 300 ml of toluene. The formed organic layer was sequentially washed with a saturated aqueous solution of hydrogen sodium carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane) to obtain 47.5 g (125 mmol) of 4-hydroxy-4-(4-(4-pentylcyclohexyl) cyclohexyl)butanal propylene acetal (11) at a yield of 82.8 percent.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(OC(=O)C)=O.[CH3:14][NH:15][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(O)=O>[C@@H:16]1([N:15]([CH3:14])[CH:5]=[O:7])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@H]1CCCc2ccccc21
Agent: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C=O)[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Acetic anhydride (73.5 g) was chilled and stirred as 98% formic acid (44.2 g) was added over 30 minutes keeping the temperature below 10° C. The resulting solution of acetic-formic anhydride was stirred for a further 15 minutes at 5° C. and added over 5 minutes to a stirred, chilled solution of (S)(+)-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine (26 g) in 98% formic acid (26 ml). The reaction solution was stirred at ambient temperature for 1 hour, poured into an ice-water mixture (200 g) and basified with 10N aqueous sodium hydroxide solution (about 250 ml) to pH 10; the mixture was then extracted with dichloromethane (3×200 ml). The combined extracts were back-washed with 1N aqueous hydrochloric acid (100 ml ), then water (100 ml), and evaporated under vacuum to give the title compound (28.69 g, 94%) as a solid, m.p. 52°-54° C.; Rf 0.80 (silica; chloroform, methanol; 95:5). A chiral HPLC assay on an acetylated β-cyclodextrin column showed this material to be a 94:6 mixture of the (S)- and (R)-enantiomers, respectively.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:7]2
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
The title compound, MS: m/e=371.0 (M+H+), was prepared in accordance with the general method of example 63 from 5-iodo-2-chloroquinoline, (R)-1-aminoindane and 2-chlorophenyl-boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH:20]([S:23]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:24])=[O:25])=[CH:27]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1c[nH]c2ccccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CC(C)S(=O)(=O)c1cn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(isopropylsulfonyl)-1H-indole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10].[OH-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccccn1
Yield: 89.2 %

Procedure:
A mixture of 3.0 g of methyl 2-(2-pyridinyl)benzoate and 600 mg of sodium hydroxide in 50 ml of 9:1 methanol:water is refluxed for 4 hours. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution is neutralized with glacial acetic acid and the resulting product filtered, washed with water, and dried to give 2.5 g of the desired product:M=200.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)[CH:7]=2.ClC1C=CC=C(C(OO)=[O:45])C=1>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][C:6]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:7][C:8]=2[S:9](=[O:45])(=[O:26])[C:10]2[C:15]1=[CH:14][CH:13]=[C:12]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=1)[CH:11]=2
Reactant: CN1c2ccc(-c3ccc4ccccc4c3)cc2S(=O)c2cc(-c3ccc4ccccc4c3)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CN1c2ccc(-c3ccc4ccccc4c3)cc2S(=O)(=O)c2cc(-c3ccc4ccccc4c3)ccc21

Procedure:
For the preparation as a by-product in the synthesis of 10-methyl-3,7-bis(2-naphthyl)phenothiazine 5-oxide, see under Example 8. For a selective preparation of the sulfone, at least two molar equivalents of m-chloroperbenzoic acid are used. Yellowish microcrystals having a melting point of 328-332° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8]C>B(Br)(Br)Br.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(N2CC(NC(=O)c3ccccc3)CC2=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NC1CC(=O)N(c2ccc(O)c(F)c2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-(1-(3-fluoro-4-methoxyphenyl)-5-oxopyrrolidin-3-yl)benzamide (Step 3, 0.9 g, 2.74 mmol) in 14 mL of 1 M BBr3/CH2Cl2 was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was diluted with 50 mL of MeOH and concentrated in vacuo again. The resulting yellow solid was washed with 50% EtOAc/hexane to give a yellow solid. MS (ESI pos. ion) m/z: 315.3 (M+H). Calc'd Exact Mass for C17H15FN2O3: 314.31.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=O)=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:12].C(OC(C1C(C=O)(C)C=CN1)=O)C>>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:29]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: O=C1Cc2ccccc2N1
Agent: CCOC(=O)C1NC=CC1(C)C=O
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)cc1C
Yield: 21 %

Procedure:
Oxindole (66.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl) amide (prepared from 3-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give 39 mg (21%) of the title compound.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.Cl>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:2]([Cl:1])=[O:4]
Reactant: C[C@H]1CCCCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 184.4 %

Procedure:
To a pale yellow solution of triphosgene (742 mg, 2.50 mmol) and pyridine (0.404 mL, 5.00 mmol) in dry DCM (10 mL) at 10° C. under N2 was added (S)-2-methyl piperidine (Aldrich, 0.603 mL, 5.00 mmol) cautiously over 2 min. The vivid orange solution was stirred at RT for 18 h, then pyridine (0.404 mL, 5.00 mmol) and triphosgene (742 mg, 2.50 mmol) were added sequentially (CARE: exotherm on addition of triphosgene) and the orange solution stirred at RT for 4 h. Aqueous HCl solution (1M, 10 mL) was added and the mixture stirred vigorously until gas evolution ceased (30 min). The aqueous layer was extracted with DCM (10 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave the title compound as a dark red oil (745 mg, 92%). 1H NMR (300 MHz, CDCl3): 1.25 (3H, d, J 7.0), 1.42-1.77 (6H, m), 3.07 (1H, br s), 4.17 (1H, dd, J 13.8, 4.0), 4.62 (1H, apparent quin, J 6.3).
Reaction SMILES: BrC1C=C(C(F)(C(F)(F)F)C(F)(F)F)C=C(Br)C=1[NH2:4].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1.[OH-].[Na+]>N1C=CC=CC=1.O.O1CCCC1>[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH2:4])=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Reactant: O=C(Cl)c1ccc(-n2cncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
2,6-Dibromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)aniline (0.45 g) was dissolved in pyridine (5 ml). To the solution, the crude product of 4-(1H-1,2,4-triazol-1-yl)benzoyl chloride (0.45 g) was added and the mixture was refluxed under heating for 1.5 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a residue, which were then dissolved in tetrahydrofuran (20 ml), added with a 2N sodium hydroxide solution (5 ml) and stirred under heating at 50° C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain N-[2,6-d]bromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.18 g, yield 28%).
Reaction SMILES: C(O)CC(C)C.[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10](Cl)[N:9]=1.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>C(OCC)C>[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:10]2[N:9]=[C:8]([NH2:7])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([Cl:18])[CH:16]=3)[N:11]=2)[CH2:35][CH2:36]1)=[O:30]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Solvent: CC(C)CCO
Solvent: CCOCC
Product: COc1c(Cl)cc2c(N)nc(N3CCN(C(=O)C4CCCO4)CC3)nc2c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 35 ml. of isoamyl alcohol were added 1.50 g. (5.47 mmole) of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g. (6.02 mmole) of 1-(2-tetrahydrofuroyl)piperazine and the mixture was heated at reflux under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, 20 ml. of ethyl ether was added and the resulting mixture stirred at room temperature overnight. It was then cooled in ice and the precipitated solid collected by filtration. The crude material was recrystallized once from a mixture of isopropanol, methanol and ethyl ether. The recrystallized material was dissolved in water made strongly alkaline with sodium hydroxide solution while stirring, the precipitated brownish solid collected by filtration, dried, decolorized with activated carbon and recrystallized from isopropanol/ethyl ether to obtain 0.38 g. of yellow solid, M.P. 192°-193° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:9]1)C1C=CC=CC=1.[H][H]>Cl.[OH-].[OH-].[Pd+2].CO>[C:25]1([NH:24][C:22]([NH:21][C@@H:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]2[NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a PARR shaker was added 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol), Pd(OH)2 (0.484 g, 3.44 mmol), MeOH (20 mL) and 3 drops of 1N HCl. The reaction vessel charged with hydrogen and the pressure was maintained at 30 psi with shaking overnight. After this time, the reaction was filtered through CELITE® and the filtrate was concentrated to give the product, 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (1.05 g, 3.32 mmol, 96% yield), as an off white solid. It was used in the next step without further purification. Anal. Calcd. for C18H28N4O m/z 316, found: 317.3 (M+H)+; 1H NMR (500 MHz, methanol-d3) δ ppm 7.35 (d, J=7.70 Hz, 2H), 7.24 (t, J=7.42 Hz, 2H), 6.97 (t, J=7.42 Hz, 1H), 3.49-3.37 (m, 1H), 3.16-3.03 (m, 1H), 2.94-2.83 (m, 1H), 2.70 (td, J=9.35, 4.95 Hz, 1H), 2.57-2.47 (m, 1H), 2.47-2.39 (m, 1H), 2.39-2.25 (m, 1H), 2.10-1.90 (m, 3H), 1.79-1.68 (m, 3H), 1.58-1.43 (m, 1H), 1.39-1.16 (m, 5H).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:35][N:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)N>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:36]([CH3:35])[C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 562.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[CH:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1cc(CCl)n(C)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1cc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light-yellow gum. MS(m/e): 391.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[NH:4][CH:3]=1.CC1C(=O)C2C(=CC([N+]([O-])=O)=CC=2)NC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:4]1[C:5]2[C:10](=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][CH:6]=2)[C:11](=[O:12])[C:2]([CH3:1])=[CH:3]1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: Cc1c[nH]c2cccc([N+](=O)[O-])c2c1=O
Agent: Cc1c[nH]c2cc([N+](=O)[O-])ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1cc(C)c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 3-methyl-5-nitroquinolin-4(1H)-one and 3-methyl-7-nitroquinolin-4(1H)-one (Eur. J. Med. Chem. 1997, 32, 547, 500 mg, 2.45 mmol,) and cesium carbonate (800 mg (2.45 mmol) in toluene (50 mL) was treated with ethyl bromoacetate (0.3 mL, 2.45 mmol) and stirred at RT for 3 days. The solid (Cesium salt of starting materials) was filtered and washed with dichloromethane. The filtrate was concentrated to give 400 mg of the crude material which was purified using flash column chromatography (DCM:MeOH, 99:1) to isolate the desired region-isomer: 100 mg 1H NMR (CDCl3, 300 MHz): δ 1.3 (m, 3H, J=7.2 Hz), 2.08 (s, 3H), 4.25 (q, 2H, J=7.2 Hz), 4.8 (s, 2H), 7.3 (m, 2H), 7.4 (s, 1H), 7.65 (t, J=8 Hz, 1H). The other isomer was also recovered: 70 mg.
Reaction SMILES: [CH3:1]I.[OH-].[K+].[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1>C(O)C.O>[CH3:1][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: CI
Reactant: c1ccc2[nH]cnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc2ccccc21

Procedure:
14.1 g of methyl iodide and 6.15 g of potassium hydroxide were added to a suspension of 11.8 g of benzimidazole in 50 ml of ethanol and 30 ml of water and the mixture was refluxed for 6 hours and was then cooled. The mixture was extracted three times with chloroform and the combined chloroform extracts were dried and filtered. The filtrate was evaporated to dryness and the oily residue was chromatographed over neutral alumina. Elution with chloroform yielded 1-methyl-benzimidazole as a crude oil which was used as is for the next step.