Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: COC(=O)C(C)Br
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)n1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C
Yield: 27.8 %

Procedure:
2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (4.6 g, 15 mmol) was dissolved in DMF (16 mL), treated with cesium carbonate (10 g, 31 mmol) and methyl 2-bromopropanoate (7.6 g, 46 mmol), and heated at 50° C. for 3 hr. Partial conversion prompted addition of cesium carbonate (10 g, 31 mmol) and methyl 2-bromopropanoate (7.6 g, 46 mmol) and the reaction mixture was heated at 50° C. for 20 hr. The reaction mixture was cooled to ambient temperature and diluted with water and ethyl acetate and the layers separated. The aqueous phase was extracted into ethyl acetate (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford methyl 2-(2-chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)propanoate as a yellow foam (1.6 g, 26%). LC/MS (ESI+): m/z 384 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=[O:17])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>N1C=CC=CC=1>[C:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=[O:17])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[S:9]2)=[CH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)CN1C(=O)C(c2ccc(O)cc2)Sc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(=O)O)C2=O)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of [3,4-dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]acetic acid (compound No. 17, 49.2 g) in pyridine (150 ml), acetic anhydride (22 ml) is added and the mixture is standed overnight. The reaction mixture is poured into a mixture of 6N HCl and ice, and the separated oil is extracted with ethyl acetate. The organic layer is washed with N HCl, dried over anhydrous sodium sulfate and concentrated in vacuo. Benzene and ether are added to the residue and separated crystals are collected by filtration to give 34.9 g (63%) of the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:12]([CH3:16])([CH3:15])[CH2:13][F:14])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Na+]>CO>[Cl:11][C:10]1[C:9]([C:12]([CH3:16])([CH3:15])[CH2:13][F:14])=[N:8][N:7]([CH3:17])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)c(C(C)(C)CF)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)CF)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloro-5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (738 mg, 2.81 mmol, prepared as described in the previous step) was dissolved in MeOH (3 mL) and 2 M NaOH (1.83 mL, 3.65 mmol) was added. The resulting mixture was stirred at room temperature for 18 h and then the solvent was removed under reduced pressure. The resulting residue was dissolved in H2O (10 mL) and then acidified to pH ˜2 with concentrated HCl. The product oiled out of solution and solidified on standing. The solid was isolated by filtration, washed with H2O (2×20 mL), and dried under high vacuum to yield 4-Chloro-5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 13.89 (br. s., 1H), 4.56 (d, J=48 Hz, 2H), 4.00 (s, 3H), 1.35 (d, J=1.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C.ClCCl>[CH3:1][C:2]1([CH3:17])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:19]([CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1)[CH3:18]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC1(C)[C@H]2CC[C@@H](CCOCCCCCl)[C@@H]1C2
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCCOCC[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1OC
Yield: 42.5 %

Procedure:
7 g 4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]-butyl chloride, 5.8 g N-methyl-homoveratrylamine, 4 ml triethylamine and a catalytic quantity of potassium iodide were refluxed in 10 ml acetonitrile for 8 hours. Then the reaction was stopped and 150 ml dichloromethane were added to the reaction mixture after it had become cold. The resulting solution was washed with 70 ml aqueous 2N sodium hydroxide solution and then twice with water, dried over sodium sulfate, and the solvent was distilled off. The crude title compound which remained as a residue was purified by chromatography on silica gel using ethyl acetate/methanol (8:2) as eluent. 4.8 g N-(4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]butyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine were obtained. Rf value=0.2. In addition, it was possible to isolate 2.3 g of unreacted 4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[ 3,1,1]hept-2-yl)ethoxy]-butyl chloride. Rf value=0.6.
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl>C1COCC1.O>[C:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1csc(C(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(C(=O)O)cs1
Reaction time: 16 h

Procedure:
Lithium hydroxide (2.8 g, 120.25 mmol) was added to a stirred mixture of ethyl 2-tert-butylthiazole-4-carboxylate (6.56 g, 30.76 mmol) in THF (100 mL) and water (40 mL). After 16 h, HCl (62.5 mL, 125 mmol) was added and the solution concentrated to ˜40 mL. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over magnesium sulphate, filtered and evaporated in vacuo to give the sub-title compound as an off white/yellow solid. Yield: 5.41 g
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOS(C)(=O)=O)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOc3ccc(C(=O)C(=O)OC)cc3)cc12
Temperature: 60 °C
Yield: 40.4 %

Procedure:
To a stirred suspension of sodium hydride (55% dispersion in mineral oil, 0.105 g) in dimethylformamide (5 mL) was added dropwise a solution of 4-hydroxy-alpha-oxobenzene acetic acid methyl ester (0.432 g) in dimethylformamide (5 mL) under argon. The mixture was then treated dropwise with a solution of 2-[8-(2,2-dimethyl-1-oxobutoxy)-2naphthalenyloxy]ethyl methanesulfonate (0.76 g) in dimethylformamide (5 mL). The reaction was heated for 18 hours at 60° C., diluted with brine, and extracted with ethyl acetate. After evaporation of volatiles, the residue was purified by chromatography over silica gel (hexane-ethyl acetate; 10: 1) to yield 0.375 g of 4-[[2-[8-(2,2-dimethyl-1-oxobutoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a white solid, mp 119°-120° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[CH2:25](N1CCCCC1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[C:7]=2[O:23][CH3:24])[CH2:8][CH2:7]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Reactant: c1ccc(CN2CCCCC2)cc1
Product: COc1c(SCCCN2CCC(Cc3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
According to the procedure indicated in Example 1), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-benzylpiperidine gives the title compound; beige powder; m.p. 73-75° C. (hydrated).
Reaction SMILES: [C:1]([N:5]([CH3:16])[S:6]([C:9]1[CH:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>>[C:1]([N:5]([CH3:16])[S:6]([C:9]1[CH:10]=[N:11][C:12]([NH:18][NH2:19])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(NN)nc1
Yield: 84 %

Procedure:
According to the process described in Example 4.2, starting with 0.66 g (2.53 mmol) of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide and 0.46 mL of hydrazine monohydrate, 0.55 g of N-tert-butyl-6-hydrazino-N-methylpyridine-3-sulfonamide is obtained in the form of a white solid, which is used without further purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc(Br)cn3)CC2C1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (7.0317 g, 33.2 mmol) in 180 mL toluene was added 2,5-dibromopyridine (22.03 g, 92.9 mmol), tris(dibenzylidenacetone)dipalladium (0) (Pd2(dba)3, Strem, 0.6087 g, 0.664 mmol), 2,2′-bis(diphenyphosphino)-1,1′binaphthyl (BINAP, Aldrich, 1.0506 g, 1.68 mmol), and NaOtBu (Aldrich, 4.778 g, 49.7 mmol. The reaction mixture was heated to 90° C. under dry N2 for 6 hours. The reaction mixture was cooled to room temperature and was filtered through diatomaceous earth and the residue was washed with 250 mL ethyl acetate. The combined organic extracts were concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, gradient 5% to 60% EtOAc-hexanes) to give 7.71 g (20.6 mmol, 62% yield). H NMR (300 MHz) δ 1.45 (s, 9H) 2.94-3.14 (m, 2H) 3.17-3.38 (m, 4H) 3.51-3.76 (m, 4H) 6.46 (d, J=9 Hz, 1H) 7.59 (dd, J=9, 3 Hz, 1H) 8.05 ppm (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([O:24]CC)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>O1CCCC1.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([OH:24])=[O:23])=[CH:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg ethyl 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylate are dissolved in 2 ml of tetrahydrofuran and combined with 2 ml of 1 N sodium hydroxide solution. The mixture is stirred for 48 hours at ambient temperature, the tetrahydrofuran is eliminated in vacuo, the residue is diluted with water, and 1 N hydrochloric acid is added until the pH is 2. The precipitated solid is suction filtered, washed with water and dried in vacuo.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.[C:14]([OH:19])(=[O:18])[CH:15]([CH3:17])[CH3:16].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37]Br)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:15]([CH3:17])([CH3:16])[C:14]([OH:19])=[O:18])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCOc1ccc(OCc2ccccc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 15 g of diisopropylamine in 75 ml of dry tetrahydrofuran was dropwise added 100 ml of n-butyl lithiun (15 w/w, n-hexane solution) at -5° to 0° C. After stirring at the same temperature for 30 minutes, 6.7 g of isobutyric acid was added dropwise to the mixture. After stirring was continued at the same temperature for 1 hour, a solution of 20 g of p-(3-bromopropoxy)phenyl benzyl ether in 60 ml of dry tetrahydrofuran was added dropwise to the solution. Thirty minutes after, the mixture was stirred at room temperature for 16 hours. The mixture was cooled and 250 ml of water was added thereto. After the aqueous layer was washed with ether, the aqueous layer was acidified with 6N hydrochloric acid and extracted twice with 70 ml of methylene chloride. The extract was washed with an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from ethyl acetate to give the desired product, 5-(p-benzyloxyphenoxy)-2,2-dimethylpentanoic acid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([Sn](=O)CCCC)CCC.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.IC>>[CH3:18][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCC[Sn](=O)CCCC
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Solvent: CI
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (8.5 g) was treated with dibutyl tin oxide (8.2 g, 1 eq). The resulting 2',3'-O-dibutylstannylene uridine was treated with iodomethane (16 ml) at 42° C. as per Example 50 to give a mixture of the 2' and 3' alkylated products (3.5 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[CH:12]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[N:10]3)[CH:14]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(Cl)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (470 mg; 1.49 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (WO 02/083628) (488 mg; 1.79 mmol), and 0.87 mL (5.0 mmol) of DIPEA were combined in 15 mL DMF. Then 1.14 g (2.99 mmol) of HATU and 403 mg (2.99 mmol) of HOBt were added and the dark brown solution was stirred overnight at room temperature. The mixture was then partitioned between EtOAc and water. The layers were separated and the organic portion was washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. Chromatography provided 375 mg (0.66 mmol; 44%) of the title compound with 95% purity. ESI MS m/z 569 [C27H29ClN6O4S+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[C:43]([CH3:58])=[CH:42][C:40]=1[NH2:41])[CH3:37].Cl>FC(F)(F)CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[C:43]([CH3:58])[C:44]([N:46]4[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 56.9 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (19.7 g, 39.9 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (13.6 g, 39.9 mmol) in 2,2,2-trifluoroethanol (200 mL) was added HCl (4M in dioxane) (19.97 mL, 80 mmol). The reaction mixture was heated at 85° C. for 2 days. The reaction was determined to be complete by LCMS. The reaction was cooled and quenched with solid NaOMe. The suspension was concentrated. Purification by flash chromatography, followed by trituration with EtOH provided the title compound of Step H (18.1 g, 22.7 mmol, 57% yield). Alternatively, this reaction can be effected using microwave irradiation. Additionally, further purification of the title compound can be effected by recrystallization from equal parts DCM and EtOH. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.37 (d, J=6.0 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.64-7.83 (m, 2H), 7.55 (s, 1H), 7.35-7.52 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.20 (t, J=8.0 Hz, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J=5.0 Hz, 1H), 3.92-4.15 (m, 5H), 3.11-3.27 (m, 2H), 2.91-3.11 (m, 5H), 2.61 (t, 2H), 2.15 (s, 3H), 1.62-1.87 (m, 4H), 1.42-1.57 (m, 1H), 1.21-1.42 (m, 5H). MS (M+H, ES+) 796.
Reaction SMILES: CC1C(C)=CC(C)=CC=1O.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[C:13]=1[CH3:21].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[O:25]>C(OCC)(=O)C.CCCCCC>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[O:25])=[C:14]([CH3:20])[C:13]=1[CH3:21]
Reactant: Cc1cc(O)c(C)c(C)c1Br
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Agent: Cc1cc(C)c(C)c(O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(=O)c2ccc(C(C)C)cc2)c(C)c(C)c1Br
Yield: 51 %

Procedure:
Using 2,3,5-trimethylphenol, 4-bromo-2,3,5-trimethylphenol was synthesized in the same manner as in Reference Example 23. Using this compound and 2-bromo-1-(4-isopropylphenyl)ethanone obtained in Reference Example 164, the title compound was synthesized in the same manner as in Reference Example 159. Yield 51%. Melting point: 71-72° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[NH:16][C:17]3[CH:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[NH:16][C:17]3[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc2ccc(CO)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-3H-benzo[d]imidazole-5-carboxylate (Example 14, 65 mg, 0.156 mmol), in dry THF (6 mL) was added to a cooled (0° C.) solution of LiAlH4 in THF (0.39 mL, 1.0 M solution). After 2 h, the reaction was allowed to warm to rt and stirred for 24 h. The mixture was cooled to 0° C., the excess of LiAlH4 was destroyed very with a saturated solution of NH4Cl. The product was extracted with EtOAc (4×20 mL), dried over MgSO4 and evaporated to yield a white solid. Example 145 was obtained after preparative HPLC purification (continuous gradient from 10% B to 60% B; A=90:10:0.1 H2O:MeOH:TFA; B=90:10:0.1 MeOH:H2O:TFA). tR=4.589 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/inn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H25N4O2 [M+H]+ 389.1978. found 389.1972.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH:26]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[Cl:35])O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([Cl:35])=[C:28]([CH:33]=1)[CH2:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Br)cc1Cc1cc2ccccc2s1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
Then, Et3SiH (9.2 mL, 0.058 mol) and BF3.Et2O (3.6 mL, 0.029 mol) were added sequentially to a chloroform (110 mL) solution of (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.2 g, 0.0288 mol) at −15° C. The reaction mixture was warmed to room temperature and stirred at the temperature for ten hours. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution, the organic phase was separated, washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain a colorless oily title compound (5.5 g, 56%).