Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([CH2:27][NH2:28])[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[N:29]1([C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([CH2:27][NH:28][S:40]([C:37]3[CH:38]=[CH:39][C:34]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)=[CH:35][CH:36]=3)(=[O:41])=[O:42])[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(-n2ccnc2)cc1
Reactant: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(CN)C2)c1
Product: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(CNS(=O)(=O)c3ccc(-n4ccnc4)cc3)C2)c1

Procedure:
In a manner similar to Preparation 3, react 4-(3-bromo-5-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanamine with 4-(1H-imidazol-1-yl)benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCCCCl)cc1N

Procedure:
6 G. of 2-nitro-4-(3-chloropropylthio)aniline is treated in 120 ml. of methanol and 120 ml. of water with 30 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for about 5 minutes. The reaction mixture is concentrated under vacuum and extracted well with chloroform. Evaporation of the dried extract affords 1,2-diamino-4-(3-chloropropylthio)benzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:19]2=[C:20]3[C:12]([C:13]4[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:11][CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=1)=O.[Li+].[BH4-].C1COCC1.Cl>O>[OH:2][CH2:3][C:5]1[C:19]2=[C:20]3[C:12]([C:13]4[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:11][CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2cccc3c2c1-c1ccccc1-3
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2cccc3c2c1-c1ccccc1-3
Yield: 85.7 %

Procedure:
To a RB flask equipped with magnetic stirrer, condenser, and N2 inlet line with bubbler was added methyl-1-fluoranthenecarboxylate (3A, 71.54 g, 0.275 mol), LiBH4 (Aldrich, 100 g, 0.459 mol) and dry THF (1 L). The mixture was refluxed overnight, cooled and poured into H2O (2 L). The mixture was cautiously acidified with 1N HCl, filtered and the resulting solid washed with H2O (2×300 mL). After recrystallization (CH2Cl2 /hexane) and drying, 54.75 g (86%) of 1-hydroxymethylfluoranthene was obtained, mp 147°-185°, (C,H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH2:58])[CH3:57])=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH:58][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:57])=[N:55][C:51]=2[CH:50]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: COc1cc(C(=O)O)ccc1N1CCCCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequent purification by preparative HPLC.
Reaction SMILES: [O:1]([C:8]([NH:10][C:11](=[S:24])[C:12](=[CH:18]N(CC)CC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32](=[O:35])[CH2:33]Br)(=[O:28])=[O:27].C(O)(C)C>O>[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([C:33]1[S:24][C:11]([NH:10][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1)=[O:35])(=[O:28])=[O:27]
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)Oc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 130 g of ethyl 2-[[(phenoxycarbonyl)-amino]thioxomethyl]-3-(diethylamino)propenoate (0.37 mole), 104 g of m-fluorosulfonylphenacyl bromide (0.37 mole), and 350 ml of isopropanol was heated to reflux and held one hour. During this time, the reactants dissolved and the product precipitated. The mixture was cooled to 20°-25°, filtered, washed with isopropanol and then water to yield 133 g of white solid, ethyl 5-[3-(fluorosulfonyl)benzoyl]-2-[(phenoxycarbonyl)-amino]-3-thiophenecarboxylate, (75% yield), melting point 161°-163°. Ir: 2.88, 5.72, 5.98, 6.18, 7.12, 8.10, 8.40μ; NMR (CDCl3) δ10.75 (s,1,N-H); 8.4 (m,1); 8.2 (m,2); 7.8 (m,1); 7.7 (s,1, thiophene-proton); 4.4 (q,2); 1.4 (t,3).
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3[C@H]2C)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Nc4ccccc4)ncc3[C@H]2C)cc1

Procedure:
A solution of 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-(R)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.32 g; 0.51 mmol) (from Example 14e supra) and aniline (0.12 mL; 1.32 mmol) (Aldrich) in toluene (0.25 mL, dried over molecular sieves) was heated in an oil bath at 110° C. for 1.75 hours. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (Biotage 40L; 40:60 ethyl acetate-hexanes) to give 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-3-(4-methoxy-phenyl)-4-(R)-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.30 g; 81.6%). This material showed an e.e. of ≧95%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1CCCC1=O>>[C:12]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)#[N:13]
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CN1CCCC1=O
Product: Cn1ccc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
Cuprous cyanide (12.8 g, 143 mmol) was added to a stirred solution of 6-bromo-1-methylindole (10 g, 47 mmol) in N-methylpyrrolidinone (60 ml) under a nitrogen atmosphere. The reaction mixture was heated at 150° C. for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate (200 ml) and aqueous ammonia (200 ml of 0.88 M). The organic layer was washed with brine (3×200 ml), dried (MgSO4) and concentrated. Flash column chromatography (elution with 70% hexane/30% ethyl acetate) gave the product as a crystalline white solid (5.3 g).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:16]
Reactant: CCO
Reactant: Nc1cccc2c(Cl)ccnc12
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccnc2c(N)cccc12
Temperature: 110 °C

Procedure:
To a solution of ethanol (5 mL) was added NaH (141 mg, 5.6 mmol, 95%) at 0° C. and the reaction mixture was stirred at rt for 30 min. before 4-chloroquinolin-8-amine (200 mg, 1.12 mmol) was added to the reaction mixture. Then the reaction mixture was heated in a sealed tube at 110° C. for 12 h before it was quenched with 1N HCl. Then the reaction mixture was extracted with chloroform and the organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 140 mg of the title product. MS [M+H]+: 189.15.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([S:15][C:16]([F:19])([F:18])[F:17])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7].ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[NH:3][C:4]([S:15]([C:16]([F:19])([F:18])[F:17])=[O:25])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: FC(F)(F)Sc1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(c1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 38.5 %

Procedure:
A solution of 2,3-dibromo-4-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (1.0 g, 0.0023 mol) in chloroform (10 mL) is treated with 3-chloroperoxybenzoic acid (0.4 g, 60%, 0.0023 mol) with stirring at 0° C., warmed to room temperature with stirring for two hours, washed with saturated sodium metabisulfite solution, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.4 g, mp 165.50°-167.5° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][O:28][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:25][CH3:26])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:29])[CH2:35][CH2:34][CH2:33]1
Reactant: BrCC1CCC1
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC3CCC3)c2)n1

Procedure:
Using the compound obtained in Example 347 and (bromomethyl)cyclobutane, white powdery N-[2-(3-Cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].S(OC)(O[CH3:16])(=O)=O>C(O)=O>[CH3:16][N:5]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][N:8]=[C:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc([N+](=O)[O-])[nH]1
Reactant: COS(=O)(=O)OC
Solvent: O=CO
Product: CC(C)c1ncc([N+](=O)[O-])n1C
Temperature: 5 °C
Yield: 72 %

Procedure:
155 parts of 2-isopropyl-5-nitroimidazole, 350 parts of formic acid and 126 parts of dimethyl sulfate are heated under reflux for 2 hours. The formic acid is distilled off in vacuo and the residue which remains is dissolved in 500 parts of water. A pH of 1.8 is set up with dilute aqueous ammonia solution and the solution is cooled for 2 hours at +5° C. The unreacted 2-isopropyl-5-nitroimidazole (15 parts) is suction filtered and the filtrate is adjusted to pH 10 by adding aqueous ammonia solution. After cooling for 2 hours at 5° C. the mixture is suction filtered and the end product is dried. 110 parts of 1-methyl-2-isopropyl-5-nitroimidazole having a melting point of 56° C. is obtained and this is equivalent to a yield of 72% of theory based on reacted 2-isopropyl-5-nitroimidazole.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](Cl)(=O)[CH3:15]>C(O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hyroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1 h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269°-270° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:9]=[CH:10][C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[CH:10]=[N:9]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1cnn2C1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.1 %

Procedure:
To the solution of tert-butyl 3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (700 mg, 2.2 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The resulting mixture was stirred at rt for 1 h, and concentrated in vacuo to afford the title compound (620 mg, 100%) which was used without further purification. ESI-MS (M+H′): 219.0.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH:1]1([NH:12][C:11]2[CH:13]=[CH:14][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cc(NC2CCCC2)ccc1F
Reaction time: 0.5 h

Procedure:
6.7 g (0.08 mol) of cyclopentanone, 12.5 g (0.08 mol) of 4-fluoro-3-nitro-aniline and 30 ml (0.1 mol) of titanium-IV-isopropoxide are stirred for 30 minutes at 40° C. and one hour at ambient temperature. After the addition of 150 ml of ethanol the reaction mixture is stirred for 30 minutes and subsequently combined batchwise with 2.4 g (0.066 mol) of sodium borohydride. After 4 hours the reaction mixture is poured onto ice water and combined with ethyl acetate. After filtration the organic phase is separated off, dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1). The desired fractions are combined and evaporated down.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[C:24]([C:21](=[O:23])[CH3:22])[CH:25]=[CH:26][CH:27]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: COc1ccc2c(-c3cccc(C(C)=O)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 373(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][CH2:40][Cl:41]>O>[Cl:41][CH2:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 79.4 %

Procedure:
A mixture of 0.370 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 3 mL of dimethylformamide, 1.6 g (5 mmole) of cesium carbonate and 0.297 mL (3 mmole) of 1-bromo-3-chloro-propane was heated at 100 degrees for 1 hour. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.355 g of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a) as a brown solid.
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH:1]1([NH:6][C:7]([NH:9][C:10]2[N:15]=[N:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NC1CCCC1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CCCC1

Procedure:
Following the procedure of Example 5, making variations only as required to use cyclopentylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (91% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.02, 7.82, 7.75, 7.65, 7.58, 7.51, 7.34, 3.91-3.98, 3.67-3.80, 3.46-3.58, 3.36-3.44, 3.11-3.35, 1.80-1.88, 1.46-1.67, 1.30-1.40. MS (ES+) m/z 451 (M+1).
Reaction SMILES: [H][H].Cl[C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([CH3:13])[N:5]=1.C(N(CC)CC)C>[Pd].C(O)C>[CH3:13][C:6]1[N:5]=[CH:4][CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A hydrogen filled balloon was attached to a flask containing 2-chloro-6-methylpyridine-4-carboxylic acid (2 g, 12.0 mmol), palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) and ethanol (24 ml) and then stirred overnight at room temperature. The is reaction mixture was filtered through celite, washed with methanol and concentrated. The residue was titurated with dichloromethane and then filtered to afford 6-methylpyridine-4-carboxylic acid as a white solid; 1.05 g (66%). 1H NMR (MeOD) δ (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH:8]3[CH2:13][CH2:12][CH:11]([O:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]5[C:26]=4[C:25]4[C@@H:24]([CH2:27][OH:28])[CH2:23][CH2:22][C:21]=4[S:20]5)[CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:28][CH2:27][C@H:24]1[CH2:23][CH2:22][C:21]2[S:20][C:19]3[C:26](=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][CH:8]([N:6]5[CH2:7][C:4]6([CH2:3][O:2][CH2:1]6)[CH2:5]5)[CH2:9][CH2:10]4)[N:16]=[CH:17][N:18]=3)[C:25]1=2)(=[O:32])=[O:31]
Reactant: OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol (250 mg, 0.62 mmol, 1.00 equiv) and TEA (188 mg, 1.86 mmol, 2.99 equiv) in dichloromethane (10 mL) was added MsCl (142 mg, 1.25 mmol, 2.00 equiv) and the resulting mixture was stirred for 1 h at 25° C. under nitrogen. After completion, the reaction was quenched with water and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvents were concentrated under reduced pressure vacuum to afford [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methyl methanesulfonate (250 mg, crude) as a yellow oil.
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].[Br:11][C:12]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2>>[Br:11][C:12]1[CH:20]=[C:19]([CH:21]=[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:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc(Br)c2cn[nH]c2c1
Product: O=C1Nc2ccccc2C1=Cc1cc(Br)c2cn[nH]c2c1

Procedure:
According to the method described for Example A1, oxindole (15 mg, 0.11 mmol) was reacted with 4-bromo-1H-indazole-6-carbaldehyde (25 mg, 0.11 mmol) to give the title compound as an orange solid. The E and Z stereoisomers were separated by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ncccc2C#N)c1
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
3-Methoxyphenol (124 g) and anhydrous potassium carbonate (69 g) were heated together with stirring in dry DMF (500 ml) at 80° C. under an atmosphere of nitrogen. After 45 minutes, the greyish solution was cooled and 2-chloronicotinonitrile (138.5 g) and copper bronze (10 g) were added (washed in with 100 ml DMF). The resulting brown reaction mixture was heated to 125°-130° C. After 21/2 hours, the reaction mixture was cooled and filtered to remove excess copper bronze and undissolved solid material. The resulting solution was added to water (3 liters) and left to stand overnight. The resulting precipitate was filtered, washed with water then dissolved in ether. The ether solution was dried, filtered and evaporated to afford 2-(3-methoxyphenoxy)-3-cyanopyridine as an off-white solid (203.5 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-fluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 63%).