Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: COc1ccc(CNc2nc(CCC(N)=O)nc3sc4ccccc4c23)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CNc2nc(CCC#N)nc3sc4ccccc4c23)cc1Cl
Reaction time: 1 h

Procedure:
At 0°, 1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-benzothieno[2,3-d]pyrimidin-2-yl]propionamide is then added. The mixture is stirred for one hour. Customary work-up gives 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]propionitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][OH:22])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COc1cccnc1)COc1noc2ccccc12
Yield: 51.3 %

Procedure:
To a solution of 0.5 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 5 ml of tetrahydrofuran are added 0.154 g of 3-hydroxypyridine, 0.553 g of triphenylphosphine and 0.33 ml of diethyl azodicarboxylate at room temperature with ice-cooling, and they are subjected to reaction at room temperature for eight hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is purified by a silica gel column chromatography [eluant:n-hexane:ethyl acetate=4:1], to obtain 0.32 g of oily 3-[2-tert-butoxycarbonylamino-3-(3-pyridyloxy)propoxy]-1,2-benzoisoxazole.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:25]2[NH:36][C:28]3=[N:29][CH:30]=[C:31]([C:33]([OH:35])=[O:34])[CH:32]=[C:27]3[CH:26]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:23])([O:16]C3CCCCO3)[CH3:15])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C>[CH:1]1([CH2:6][CH:7]([C:25]2[NH:36][C:28]3=[N:29][CH:30]=[C:31]([C:33]([OH:35])=[O:34])[CH:32]=[C:27]3[CH:26]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])([CH3:23])[CH3:15])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(OC1CCCCO1)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1F
Solvent: CCO
Product: CC(C)(O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1F
Temperature: 25 °C
Yield: 28 %

Procedure:
To a stirred solution of 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-ethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.5 g, 3.04 mmol) in 95% ethanol (50 mL) was added cupric chloride dihydrate (52 mg, 0.3 mmol) at room temperature. The mixture was refluxed for 3 h and then cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (350 mg, 28.1%) as a light yellow solid: LC/MS m/e calcd for C24H27FN2O3 [M+H]+ 411.49, observed 410.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.79 (br. s., 1H), 8.56 (br. s., 1H), 7.53-7.60 (m, 1H), 7.13 (br. s., 1H), 7.02 (d, J=12.1 Hz, 1H), 6.51 (br. s., 1H), 4.19 (br. s., 1H), 2.22 (br. s., 1H), 2.12 (br. s., 1H), 1.61-1.88 (m, 5H), 1.56 (br. s., 6H), 1.51 (br. s., 2H), 1.23 (br. s., 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:9]1[CH2:10][C:11]2[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2cccc(O)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CC(=O)CC3)nc1
Yield: 24.2 %

Procedure:
Using a method similar to Intermediate 1, using 8-hydroxy-2-tetralone (J. Med. Chem. (1978), 21(9), 913-22) (1.55 g, 9.55 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K2CO3 (1.98 g, 14.3 mmol) gives the title compound (652 mg), after purification on silica gel (50% THF/DCM), as an yellow foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (CDCl3): 8.52 (s, 1H), 8.18 (d, 1H), 7.30 (t, 1H), 7.17 (d, 1H), 7.02 (m, 2H), 5.92 (broad, 2H), 3.42 (s, 2H), 3.15 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C(OC1C=CC2C(=C(OCC(=O)C)C=CC=2)N=1)(=O)C>>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:17][C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Agent: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Product: CC(=O)Oc1ccc2cccc(OCC(=O)c3ccccc3)c2n1
Yield: 74 %

Procedure:
2-Acetoxy-8-(2-oxo-2-phenylethoxy)quinoline (6a) was prepared from 2-acetoxy-8-hydroxyquinoline (5b) and 2-bromoacetophenone by the same procedure as 5c in 74% yield. mp: 141°-142° C.; 1H-NMR (CDCl3): δ1.92 (s, 3H, CH3), 5.66 (s, 2H, OCH2), 7.11 (d, 3-H), 7.25-8.04 (m, 8H, Ar--H), 8.05 (d, 4-H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1[nH]nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (Intermediate 1A, 2.01 g, 10.7 mmol) in MeOH (8.2 mL) and THF (8.2 mL) was added 2N aq. NaOH solution (27 mL, 53.3 mmol). The reaction mixture was stirred at room temperature overnight, then cooled to 0° C. and neutralized with 1N aq. HCl solution (pH=3-4). The resulting solid was collected by filtration and washed with water to give the title compound (1.50 g, 87%) as a white solid. 1H NMR (DMSO-d6) δ 2.19 (br s, 3H); MS (ESI+) m/z 160.9 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: ClCc1ccccn1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccn1
Yield: 39.5 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (376 mg) was reacted with 2-(chloromethyl)pyridine hydrochloride (328 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline (170 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH3:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:22][CH:21]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Yield: 51.5 %

Procedure:
A degassed mixture of 5,8-dibromo-imidazo[1,2-a]pyrazine (2.19 g, 7.916 mmol), 4-methylsulfonylaniline (1.49 g, 8.708 mmol), Pd2dba3 (145 mg, 0.15 mmol) and Xantphos (183 mg, 0.317 mmol), in dry toluene (50 mL) is stirred at 110° C. for 16 hours. After evaporation of the solvent, the residue is purified by silica gel column chromatography eluting with 95:5 DCM:NH3 (7M in MeOH). The title compound (1.496 g, 51%) is isolated containing some starting material (20%) and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:14][C:12](=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12](=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCC(c2ccc(Cl)cc2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Yield: 22.1 %

Procedure:
A mixture of 200 mg of 5-(4-chlorophenyl)-δ-valerolactone, 0.5 g of aniline, 20 mg of p-toluenesulfonic acid and 10 ml of xylene was refluxed for 6 hours. After removal of solvent, the residue was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution and dried. After removal of the solvent, the residue was purified, by silica gel thin layer chromatography (solvent; chloroform:methanol=10:1) to give 60 mg of 6-(4-chlorophenyl)-1-phenyl-2-piperidone.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH2:24]([O:23][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:34])=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(OCC)OCC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCC(OCC)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-(3,3-diethoxyproyl)-2-propyl-1H-imidazo[4,5-c]quinoline (4.50 g, 13.2 mmol) by reaction with m-CPBA (5.3 g) to provide 1-(3,3-diethoxypropyl)-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (4.89 g, 25.7 mmol) and ammonium hydroxide solution (40 mL) to provide 1-(3,3-diethoxypropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as grey needles after recrystallization from methanol, mp 148-150° C.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([O:9]C(=O)C)[C@@H:7]([CH2:13][O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:6][CH:5]1Cl)=[N+:2]=[N-:3].C[Si]([N:28]([Si](C)(C)C)[C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[N:30]=1)(C)C>ClCCCl>[N:1]([C@H:4]1[C@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]1[N:32]1[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][C:31]1=[O:35])=[N+:2]=[N-:3]
Reactant: CC(=O)O[C@H]1[C@H](N=[N+]=[N-])C(Cl)O[C@@H]1COC(=O)c1ccccc1
Reactant: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Solvent: ClCCCl
Product: [N-]=[N+]=N[C@H]1[C@H](OC(=O)c2ccccc2)[C@@H](CO)O[C@@H]1n1ccc(N)nc1=O
Temperature: 62.5 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a stirred solution of 7.8 g. of 2-azido-2-deoxy-3-O-acetyl-5-O-benzoyl-D-arabinofuranosyl chloride in 300 ml, of 1,2-dichloroethane is added 6 g. of bis(trimethylsilyl) cytosine dissolved in 200 ml. of 1-2-dichloroethane. The solution is stirred at 60-65 degrees C. for 3 days, cooled to room temperature and washed successively with 100 ml. of a saturated NaHCO3 solution and 100 ml. of water. It is then dried and evaporated at reduced pressure at 45 degrees C., and the residue is dissolved in 50 ml. of chloroform. The chloroform solution is applied to a silica-gel column and the β and α anomers are eluted with an acetyl mixture of chloroform and 2-propanol (10:1). The β-anomer, 1-(2-azido-2-deoxy-3-O-acetyl-5-O-benzoyl-β-D-arabinofuranosyl) cytosine, is eluted from the column first, and is obtained after evaporation of the solvent in 37% yield. The α-anomer, 1-(2-azido-2-deoxy-3-O-benzoyl-α-D-arabinofuranosyl) cytosine, is obtained in 10% yield.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH3:31]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][CH3:31])[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCBr
Product: CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of bromoethane are treated as described in Example 5. The title compound is crystallized in the form of hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([N:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[N:19]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3ccnc(N4CCC(N)CC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 {1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl]piperidin-4-yl}carbamic acid tert-butyl ester. The product is in the form of the hydrochloride.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.I[CH:13]([CH3:15])[CH3:14].[OH:16][C@@H:17]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][C@@H:20]([O:29][CH2:30][CH:31]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1)[C:21]1[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=1>CC(C)=O>[CH:13]([O:28][C:26]([C:24]1[S:25][C:21]([C@H:20]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32]2)[CH2:19][CH2:18][C@@H:17]([OH:16])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:23]=1)=[O:27])([CH3:15])[CH3:14]
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Reactant: CC(C)I
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)OC(C)C)s1
Reaction time: 120 h
Yield: 85.7 %

Procedure:
DBU (9 μL, 0.06 mmol) and 2-iodopropane (62 μL, 0.62 mmol) were added to a solution of acid 6 (12 mg, 0.031 mmol) in acetone (0.3 mL) at room temperature under nitrogen. After 5 days at room temperature, the solvent was removed under a stream of nitrogen. The residue was acidified with 1 N HCl (2 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica (CH2Cl2→10% MeOH/CH2Cl2) afforded 11.3 mg (85%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.Cl.[F:19][C:20]1([F:24])[CH2:23][NH:22][CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14]([N:22]3[CH2:23][C:20]([F:24])([F:19])[CH2:21]3)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1
Reactant: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)Cl
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)N1CC(F)(F)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
7-Bromo-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (500 mg, 1.481 mmol) obtained in step 1 was dissolved in acetonitrile (5.0 mL), and the solution was stirred at 50° C. for 30 minutes after adding 3,3-difluoroazetidine hydrochloride (230 mg, 1.78 mmol) and triethylamine (0.413 ml, 2.96 mmol). The reaction mixture was allowed to cool to room temperature, and a sodium hydrogen carbonate aqueous solution was added. The precipitated solid was collected by filteration to give 7-bromo-3-(3,3-difluoroazetidin-1-ylsulfonyl)-2-isopropylimidazo[1,2-a]pyridine (546 mg, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (370 mg, 1.2 mmol) according to general procedure II. Obtained as a yellow solid (244 mg, 44%). MS (ISP) 549.3 [(M+H)+]; mp 226-229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:20]=3)[CH:25]=2)=[CH:5][CH:4]=1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: COc1ccc(CN)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CNc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
4-Methoxy-benzylamine (3.40 mL, 3.59 g, 26.20 mmol) and anhydrous DMSO (5.20 mL) were added to a high-pressure flask charged with 36 (3.00 g, 9.58 mmol), K3PO4 (4.19 g, 19.73 mmol), CuII (290 mg, 1.52 mmol), and L-(−)-proline (255 mg, 2.21 mmol); the sealed flask was heated to 80° C. for 44 hours. After cooling to room temperature, reaction contents were partitioned between water (100 mL) and EtOAc (200 mL), then were extracted with EtOAc (2×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution (500 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 7:1:1 Hexanes:CH2Cl2:EtOAc) to give 37 as a light orange amorphous solid (952 mg, 27%): 1H NMR (CDCl3, 500 MHz) δ 7.55 (d, J=8.7 Hz, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.37-7.32 (m, 3H), 7.15 (dd, J=8.8, 2.6 Hz, 1H), 7.13 (m, 1H), 6.92 (dd, J=8.8, 2.3 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.87 (m, 1H), 5.14 (s, 2H), 4.35 (s, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.1, 154.6, 137.4, 130.7, 129.3 (2C), 128.8 (2C), 128.1, 128.0, 127.8 (2C), 119.4 (2C), 118.6, 114.3 (2C), 107.9, 70.3, 55.5; IR (film) νmax 3734, 1558, 1456, 1259, 1167, 847, 746, 702, 660 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C25H23NO2, 370.1807. found, 370.1786.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:10]1.C(N(CC)CC)C.[CH:44]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45]1>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:26][S:47]([CH:44]4[CH2:46][CH2:45]4)(=[O:49])=[O:48])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:27]([C:33]([F:36])([F:34])[F:35])([C:29]([F:31])([F:30])[F:32])[OH:28])=[N:10]1
Reactant: NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
1-(2-Chloro-phenyl)-5-{4-[4-amino-piperidin-1-yl]-phenyl}-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 331, triethylamine (37.3 uL, 0.27 mmol) and cyclopropanesulfonyl chloride (10.4 mg, 0.08 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([OH:12])[C:9]([OH:11])=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1)=[O:11]
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
Example 158 was prepared from bis(2-chlorophenyl)(hydroxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.43–7.18 (m, 11 H), 7.05 (d, 1 H, J=8.0 Hz), 5.03 (s, 1 H), 3.60–3.49 (m, 2 H), 3.03–2.91 (m, 2 H), 2.71–2.54 (m, 1 H), 2.54–2.37 (m, 3 H), 2.25 (s, 3 H), 2.08–1.91 (m, 2 H), 1.84–1.63 (m, 4 H), 1.63–1.50 (m, 2 H), 1.17 (d, 6 H, J=6.8 Hz); ESMS m/e: 596.3 (M+H)+.