Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]=2)=[CH:5][CH:4]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: ClCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2ccc(Cc3ncc[nH]3)cc2)co1)\c1ccccc1

Procedure:
In substantially the same manner as in Working Example 25, 4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole was allowed to react with imidazole to give 4-[4-(1-imidazolylmethyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 149-150° C.
Reaction SMILES: [CH:1]1([C:7]2([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:11]3[CH2:12][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:14][CH2:15][N:10]3[C:9](=[O:35])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>O1CCCC1>[CH:36]1([C:7]2([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:35])[O:8]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.7 %

Procedure:
To a solution of hexahydro-1,1-dicyclohexyl-7-(triphenylmethyl)-3H-oxazolo[3,4-a]pyrazin-3-one (0.92 g, 1.7 mmol) in tetrahydrofuran (5 mL) was added a 4 M hydrogen chloride/ethyl acetate solution (5 mL) with ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, water was then added thereto and washed with diethyl ether. To the aqueous layer was added sodium hydrogen carbonate, and the mixture was adjusted to pH 7 and then extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The precipitated crystals were washed with hexane and dried to obtain the title compound (0.41 g, yield 80%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:8][CH:9]=2)=[N:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (2.98 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, which was 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 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (2.40 g, yield 76%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from tetrahydrofuran-hexane. Melting point: 117–118° C.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[NH2:12].O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:20])([F:21])[F:19]
Reactant: Nc1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: CC1(C(=O)O)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C(=O)Nc2ccc(OCC(F)(F)F)c(Cl)c2)CC1
Yield: 82.9 %

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (1.8 g) in pyridine (50 ml), a solution of 3-chloro-4-(2,2,2-trifluoroethoxy)aniline (2.3 g) in pyridine (10 ml) cooled with ice was dropwise added while stirring. After stirring at room temperature for 10 hours, the reaction mixture was admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.8 g) were recrystallized from ethanol to give N-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-1-methylcyclopropanecarboxamide (2.6 g). M.P., 95°-96° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1>C(O)(C)C>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(C(=O)O)c([N+](=O)[O-])c2)c1=O
Temperature: 90 °C
Yield: 85 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyrazin-2-one (1.0 g, 3.73 mmol) and 4-amino-2-nitrobenzoic acid (0.68 g, 3.73 mmol) are dissolved in isopropanol (20 mL) and heated at 90° C. for 4 hours. The reaction is cooled to room temperature and the resulting suspension is filtered. The filter cake is then washed with ethyl ether (3×100 mL) and air dried to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoic acid (3) as a tan solid (1.17 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[NH:20][CH2:19][CH2:18][CH:17]4[OH:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1O>CO.C(Cl)Cl>[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1[O:24][CH:17]1[C:16]2[C:21](=[N:22][CH:23]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)[CH:15]=2)[NH:20][CH2:19][CH2:18]1
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Oc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 54 %

Procedure:
6-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (85 mg) was reacted with 2-chloro-3,6-difluorophenol (50 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-10% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (54% yield). LCMS: m/z=472 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.89 (m, 1H), 2.21 (s, 3H), 2.24 (m, 1H), 2.39 (t, J=4.8 Hz, 4H), 3.40 (m, 1H), 3.47 (t, J=4.8 Hz, 4H), 3.63 (m, 1H), 6.82 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H) 7.25 (m, 1H), 7.39 (m, 1H), 7.52 (dd, J=2.5, 8.8 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:17][CH:16]2[C:18]([O:20][CH3:21])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Br:22][CH2:23][CH2:24][OH:25].B(F)(F)F.CCOCC>C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH:16]([NH:15][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH2:17][O:25][CH2:24][CH2:23][Br:22]
Reactant: OCCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CC2C(=O)OC)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)NC(COCCBr)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
To a 0° solution of 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-2-aziridinecarboxylic acid, methyl ester (0.55 g, 1.78 mmol) in 2-bromoethanol (1.26 mL,17.8 mmol) was dropwise added boron trifluoride etherate (0.18 mL). The mixture was stirred at 0° C. for 30 minutes and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate. The organic layer was washed with 1N NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (7:3) to obtain 0.2 g of 3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonylamino)-propionic acid methyl ester. Yield: 26%. mp 45-46° C. Electrospray Mass Spec 434.1.436.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:13]([CH3:30])[C@@H:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1)[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])([O-])=O.O.NN.Cl>[Ni].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:13]([CH3:30])[C@@H:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12]
Reactant: CN(C(=O)Cc1ccccc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C(=O)Cc1ccccc1N)[C@H](CN1CCCC1)c1cccc(N)c1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
With stirring at 55° C., Raney nickel was added in small quantities to a mixture of 10 (0.9857 g, 2.3899 mmol) and hydrazine hydrate (55%, 2 mL) in EtOH (30 mL) until gas evolution stopped in about 10 min. The mixture was then filtered through celite, and the Raney nickel was washed with hot MeOH (100 mL). The filtrate was evaporated and dried in vacuo before the residue was partitioned between sat'd NaHCO3 and CH2Cl2, which was dried (Na2SO4), filtered through celite, and evaporated. The product was gravity column chromatographed eluting with CHCl3:2% NH3:2% MeOH before it was converted to the HCl salt with Et2O—HCl to yield 9 3HCl.(0.3159 g, 29%, unoptimized): m.p. (HCl salt) 219-222° C.; 1H NMR (HCl salt, DMSO-d6) δ1.98 (br s, 4H, —CH2CH2—), 2.87 (s, 3H, —NCH3), 3.2-4.3 (complex, 8H, 4 —CH2—), 6.1 (m, 1H, —CH—), 7.11-7.45 (complex, 8H, aromatic). MS(FAB) m/z 353. Anal. (C, H, N) C21H28N4O. 3HCl0.25H2O.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9](F)[CH:10]=2)[N:5]=1)[CH3:2].Cl.[OH:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([N:29]3[CH:30]=[C:26]([CH2:25][OH:24])[N:27]=[CH:28]3)[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 120 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of ethyl 2-ethoxy-6-fluoro-7-nitroquinoline-3-carboxylate (1.00 g, 3.24 mmol) in acetonitrile (10 ml) were added 4-(hydroxymethyl)imidazole hydrochloride (2.18 g, 16.2 mmol) and successively triethylamine (3 ml), and the mixture was stirred for 16 hours at 120° C. in a sealed tube under shading. After cooling, solvent was distilled off and the residue was submitted to silica gel column chromatography [dichloromethane-methanol(50:1→20:1)] under shading to obtain 583 mg of title compound as light brown powder. Yield 47%. 1H-NMR(DMSO-d6, δ): 1.35(3H,t,J=7.3 Hz), 1.42(3H,t,J=7.3 Hz), 4.38 (2H,q,J=7.3 Hz), 4.42(2H,d,J=6.8 Hz), 4.58(2H,d,J=7.3 Hz), 5.05(1H, t,J=5.4 Hz), 7.27(1H,s), 7.88(1H,s), 8.39(1H,s), 8.50(1H,s), 8.87 (1H,s).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1[O:10][C:11](=O)[C@H:12]([CH3:21])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:23]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([O:30][C:31](=[O:34])[CH2:32][NH:33][C:11](=[O:10])[C@H:12]([CH3:21])[NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.3 Parts N-t-butoxycarbonyl-L-alanine 2,4,5-trichlorophenyl ester and 9.7 parts glycine benzyl ester are dissolved in 200 parts methylene chloride and the resulting solution is stirred overnight at room temperature. Removal of the solvents under reduced pressure affords crude N-t-butoxycarbonyl-L-alanylglycine benzyl ester which is purified by low pressure column chromatography. The purified blocked dipeptide is then dissolved in 50 parts dioxane and stirred with a 10 fold excess of 2 N HCl in dioxane for 15 minutes. The solvent is removed by evaporation under reduced pressure to give, after trituration with ethyl ether, L-alanylglycine benzyl ester hydrochloride. This compound is represented by the following formula
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[N:50]1([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH2:51][CH2:52][O:53][CH2:54][CH2:55]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(N4CCOCC4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-morpholin-4-yl-phenylamine (0.040 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.066 g of 1541I in a 76% yield: LCMS (ESI) m/z 381 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41]>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]5[OH:41])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (202 mg, 0.5 mmol) from Step 4 of this Example in DMA (4 mL) were added DIEA (129 mg, 1.0 mmol) and (1R,2R)-2-aminocyclohexanol (69 mg, 0.6 mmol) at rt. The mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a white solid (127 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.04-7.34 (m, 4H), 5.40 (s, 2H), 4.77 (br s, 1H), 3.76 (s, 6H), 3.51 (br s, 1H), 1.77-2.14 (m, 3H), 1.61 (br, 2H), 1.04-1.38 (m, 4H). LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH:14]C(=O)C(Cl)(Cl)Cl)[C:5]=2[N:21]=1.C[O-].[Na+].C>CO>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:21]=1
Reactant: Cc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2s1

Procedure:
Trichloroacetyl isocyanate (2.0 mL, 16.8 mmol) was added to a suspension of 2-methylthiazolo[4,5-c]quinoline-5N-oxide (3.03 g, 14.0 mmol) in dichloromethane (150 mL). The reaction mixture was stirred at ambient temperature for about 50 minutes. The dichloromethane was concentrated under vacuum to provide crude N-(2-methylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was dissolved in methanol and then sodium methoxide (1 mL of 25% sodium methoxide in methanol) was added. The reaction was heated at reflux for 40 minutes then the methanol was evaporated under vacuum. The resulting brown solid was washed with water and dried to provide 2.85 g of crude product. This material was treated with charcoal and then recrystallized from ethyl acetate to provide 2-methylthiazolo[4,5-c]quinolin-4-amine as a solid, m.p. 184-186° C. Analysis: Calculated for C11H9N3S: % C, 61.37; % H, 4.21; % N, 19.52; Found % C, 61.48; % H, 4.17; % N, 19.60.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].FC1C=CC(C2C=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)=CC=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1
Reactant: CC(=O)c1cccc(F)c1F
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Product: O=C(O)c1ccc(-c2cccc(F)c2F)nc1

Procedure:
The title compound was prepared from 2′,3′-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:12]=2)=[CH:7][C:4]=1[CH:5]=O.[OH-].[NH4+:31].II>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:31]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C=O
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The aldehyde 36 (98 mg, 241 μmol) was dissolved in tetrahydrofuran (5 ml). To this was added 30% aqueous ammonium hydroxide (3 ml) and iodine (79 mg, 313 μmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ether and ethyl acetate. The organics were washed with aqueous sodium sulfite (50 mg) in water (10 ml). The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 37 (95.8 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([I:9])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(I)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1I
Temperature: 25 °C
Yield: 51.1 %

Procedure:
4-Fluoro-3-iodotoluene (50 g, 210 mMol), N-bromosuccinimide (37.7 g, 212 mMol) and 2,2'-azobis-(2-methylpropionitrile) (348 mg, 2.12 mMol) were dissolved in carbon tetrachloride (300 mL) under an atmosphere of dry N2. The mixture was heated to reflux for 4 hours and then cooled to ambient temperature. The mixture was concentrated under vacuum and triturated with Et2O. The filtrate was successively washed with water, aqueous saturated NaHCO3 and brine. The ether layer was dried over MgSO4, filtered and concentrated under vacuum to give a red oil. The oil was chromatographed on flash silica gel eluting with hexanes to give 33.8 g of the titled compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11]CN1CC.C(=O)C>>[N:1]1([CH2:11][CH2:12][CH2:8][CH2:7][NH2:6])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: NCCCCn1ccnc1

Procedure:
By using imidazole (2.00 g) as a starting material, the title compound (0.37 g) was obtained in the same manners as those of Reference Example 63, (1) and Reference Example 9, (2).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][C:25]=1[Cl:26]>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][C:25]=1[Cl:26])[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.42 g, 39%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4,5-dichlorophthalic anhydride (0.80 g, 3.64 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:30]C(=O)C(F)(F)F)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[C:22]([N:7]2[C:8]([NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cccc(CCNC(=O)C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cccc(CCN)c2)n1
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a stirring solution of 1-(3-t-butyl-1-(3-(2-(2,2,2-trifluoro-acetamido)ethyl)phenyl)-1 H-pyrazol-5-yl)-3-(2,3-dichloro-phenyl)urea (0.134 g, 0.264 mmol) in MeOH (10 mL) and H2O (0.6 mL) at RT was added K2CO3 (0.182 g, 1.32 mmol). The resulting suspension was stirred at 60-65° C. for 2 h, then cooled to RT and the volatiles evaporated. The residue was carefully dissolved in 1N HCl to pH 1-2 and extracted with Et2O (2×). The aqueous was then basified (pH 13-14) with 3M NaOH and extracted with CH2Cl2 (4×). The combined CH2Cl2 extracts were washed with brine (1×), dried (Na2SO4), filtered, and concentrated to provided 1-{1-[3-(2-aminoethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl}-3-(2,3-dichlorophenyl)urea as a foam (25.6 mg, 97% yield). 1H NMR (400 MHz, CDCl3): δ 8.17 (dd, J=1.2, and 8.0 Hz, 1H), 7.31-7.28 (m, 4H), 7.14-7.06 (m, 4H), 6.45 (s, 1H), 3.48 (brt, J=4.4 Hz, 2H), 3.46-3.39 (m, 2H), 2.86 (t, J=7.0 Hz, 2H), 1.3 (s, 9H); MS (ESI) m/z: 446.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(C#N)c(-c3ccc(OCC)cc3)n(CC)c2c1

Procedure:
6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B was treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).