Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(C)=CC(O)=CC=1[Cl:10].[Br:11][C:12]1[C:26]([CH3:27])=[CH:25][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:14](OC)[CH:13]=1>>[Br:11][C:12]1[C:26]([CH3:27])=[CH:25][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:14]([Cl:10])[CH:13]=1
Reactant: Cc1cc(O)cc(Cl)c1Br
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Yield: 83 %

Procedure:
[2-(4-Bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane was prepared in 83% yield from 4-bromo-3-chloro-5-methyl-phenol according to the procedure for [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79 (t, 2H, J=8.4 Hz), 2.35 (s, 3H), 0.95 (t, 2H, J=8.4 Hz), 0.02 (s, 9H). Anal. (C13H20ClBrO2Si) C, H. Calculated: C, 44.39; H, 5.73. Found: C, 45.08; H, 5.91.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:19]([O:18][C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2)=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A solution of dicyclohexylcarbodiimide (1500 g, 7.27 moles) in THF (7 L) was added to a reactor containing a mixture of N-carbobenzyloxy-L-valine (3630 g, 14.5 moles) in THF (20 L). The resulting mixture was stirred at 20±5° C. for 1-2 hours. The product of Example 30, step e) (2500 g, 4.81 moles) and 4-dimethylaminopyridine (59 g, 0.48 moles) were charged to a second reactor. To this second reactor was filtered the THF mixture from the first reactor, followed with a rinse of THF (15 L). The resulting mixture was stirred at 20±5° C. for 1-3 hours. Water (600 mL) was added and the solution was concentrated under vacuum at not more than 45° C. The residual oil was taken up in ethyl acetate (14 L) and filtered. The filtrate was washed successively with 10% aqueous sodium bicarbonate (2×14 L) and 10% brine (14 L). The organic phase was concentrated under vacuum and the residue was dissolved in methanol (10 kg) at 50-60° C. The warm solution was added gradually to a mixture of acetonitrile (30 kg) and water (13 kg) at ambient temperature. The mixture was stirred 1 hour at 15° C., then filtered to isolate the crude product, which was dried at 40° C. under vacuum to provide the desired product as a white solid (3.9 kg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:66]=[CH:65][C:50]([CH2:51][NH:52][S:53]([C:56]2[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=2)(=[O:55])=[O:54])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:59]2[CH:58]=[CH:57][C:56]([S:53](=[O:54])(=[O:55])[NH:52][CH2:51][C:50]3[CH:49]=[CH:48][C:47]([O:46][CH3:45])=[CH:66][CH:65]=3)=[CH:61][CH:60]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(B(O)O)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)cc2)c1C
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.10 g, 0.25 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.015 g, 0.055 mmol), palladium (II) acetate (0.006 g, 0.027 mmol), 4-(N-(4-methoxybenzyl)sulfamoyl)phenylboronic acid (0.109 g, 0.33 mmol) and a 2 M aqueous solution of sodium carbonate (0.6 mL, 1.2 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford {6-chloro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.093 g, 70%) as a solid. MS calcd. for C28H25ClNO5S [(M−H)−] 522, obsd. 522.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27]O)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:27]=[C:21]2[C:20]3[C:24](=[CH:25][C:17]([F:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])=[CH:11][CH:12]=1)[CH3:15]
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1
Yield: 38.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Diethylamino-ethoxy)-phenylamine (697 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (399 mg, 39%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.S(Cl)([Cl:39])=O.O.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Cl:39][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 816 mg of 4-hydroxymethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step e) in Example 1 in 25 ml of THF was cooled in ice, and 0.301 ml of triethylamine and 0.157 ml of thionyl chloride were added to the cooled solution under an argon atmosphere. The mixture was stirred at the same temperature for 20 min, brine was then added to the reaction solution, and the mixture was adjusted to pH 8 by the addition of sodium bicarbonate water. The mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give 512 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:10].[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[N:13][CH:12]=1)([OH:10])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reactant: Br[Mg]Cc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C(O)(Cc2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2,3-dimethylphenyl)(I-trityl-1H imidazol-5-yl)methanone (450 mg, 1.01 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (1.51 mmol) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 5 hours. The mixture was quenched with water (10 mL) and a sat. solution of ammonium chloride (10 mL). The residue was isolated in a typical aqueous to give 1-(2,3-dimethylphenyl)-2-phenyl-1-(1-trityl-1H-imidazol-5-yl)ethanol (Intermediate 8) crude, which was taken to the next step without any purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21]C(=O)OC(C)(C)C>CO>[NH2:21][C:3]1[C:2]([F:1])=[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])[C:6]([F:20])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Solvent: CO
Product: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F

Procedure:
A solution of tert-butyl (2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)carbamate (600 mg, 1.56 mmol, 1 eq.) in HO/MeOH (6 N, 50 mL) was stirred at rt for 3 h, then concentrated to provide crude (3-amino-2,6-difluorophenyl) (quinoxalin-6-yl)methanone which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[N:7][C:8](=[S:10])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:14]>C(COC)OC>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:14])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=S)N=N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a stirred solution of 3-t-butylpyrazole-5-thione (2.0 g) in glyme (50 ml) was added sodium hydride (0.6 g) in small quantities, with cooling. After stirring the mixture briefly at room temperature, iodomethane (1.85 g, 0.9 ml) was added. The reaction mixture was stirred at room temperature, then the solvent evaporated in vacuo. The residue was extracted with ether and washed with water to give after evaporation, 3-t-butyl-5-(methylthio)pyrazole (0.8 g, 36% yield), of melting point 135°-6° (after recrystallisation from petrol). The product was identical, by nuclear magnetic resonance spectroscopy, to that of Example 2.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH2:6][N:5]2[N:9]=[CH:10][CH:11]=[C:4]12)=O.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[N+:12]([C:11]1[CH:10]=[N:9][N:5]2[CH2:6][CH2:7][CH2:8][NH:3][C:4]=12)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: O=CN1CCCn2nccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.5 %

Procedure:
To a solution of 4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.51 g) in sulfuric acid (7.5 ml) was added potassium nitrate (111 g) under ice-cooling. The mixture was stirred at room temperature for 17 hours. The reaction mixture was added to ice (100 g). The crystalline residue was collected by filtration and dried in vacuo to give 3-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.63 g) as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[C:12]([N+:20]([O-])=O)[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[NH:10][N:9]=1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[C:12]([NH2:20])[CH:13]=[C:14]([NH2:17])[CH:15]=2)[NH:10][N:9]=1)[CH3:24]
Reactant: CCN(CC)CCCNc1n[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCN(CC)CCCNc1n[nH]c2c(N)cc(N)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
A mixture consisting of 9.0 g of the 3-(3-diethylaminopropylamino)-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After cooling, the mixture was filtered, and the pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution. The filtrate was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Then, ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 1.67 g of 3-(3-diethylaminopropylamino)-5,7-diaminoindazole having the following analytical values in a yield of 22%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:19].C([O-])(=O)C>CO>[Zn:19].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CSCC[C@H](N)C(=O)O
Agent: C[O-]
Solvent: O
Solvent: CO
Product: [Zn]

Procedure:
L-methionine (2.00 g, 13.4 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.30 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.50 g) was then slowly dropwise added thereto at room temperature. After stirring for 3 hours, the precipitated crystal (in suspension) was recovered by filtration, washed with water, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[N:23]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:24](=[O:26])[NH:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[N:23]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:31][CH2:32]3)[C:24](=[O:26])[NH:25][C:21]=2[CH:20]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: ClCCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 7.35 parts of 1-chloro-4,4-diphenylbutane, 6.3 parts of 5-chloro-1-(4-piperidyl)-2-benzimidazolinone, 6.35 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature and water is added. The organic layer is separated, dried, filtered and evaporated. The residue is crystallized twice; first from 2-propanol and then from 4-methyl-2-pentanone, yielding 5-chloro-1,3-dihydro-1-[1-(4,4-diphenylbutyl)-4-piperidinyl]-2-H-benzimidazol-2-one; mp. 164.7° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CC#N.CN(C1C=CN=CC=1)C>[C:22]([O:21][C:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Yield: 100 %

Procedure:
To a stirring solution of 30.3 g (0.23 mol) of 3-methylindazole, prepared as in Part A, in 300 mL of CH3CN is added 35.0 mL (0.25 mol, 1.1 equiv) of Et3N and 5.77 g (47.2 mmol, 0.2 equiv) of DMAP, and the mixture is cooled to 0° C. 60.5 g (0.28 mol, 1.2 equiv) of (BOC)2O in 200 mL CH3CN is added dropwise with stirring at 0° C. and the resultant reaction mixture stirred 3 h at RT. The solvent is removed in vacuo and the crude material partitioned between Et2O (300 mL) and H2O (100 mL). The pH is adjusted to 2.0 with 1N HCl, the organic phase separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil which is purified by filtration through a pad of silica gel using Hexane/EtOAc 4/1 as eluent. The filtrate is concentrated in vacuo to give 53.4 g of 1-tert-butoxycarbonyl-3-methylindazole as a white solid: 1H NMR (CDCl3, 300 MHz) δ8.15 (d, 1H, J=7.8), 7.67 (d, 1H, J=7.8), 7.56 (dd, 1H, J=7.3, 7.3), 7.35 (dd, 1H, J=7.3, 7.3), 2.62 (s, 3H), 1.77 (s, 9H); TLC Rf =0.66 (EtOAc/Hexane 1/2).
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][CH2:8][C:9]1([C:28]#N)[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:45]>COCCOC>[C:1]([Si:5]([CH3:30])([CH3:31])[O:6][CH2:7][CH2:8][C:9]1([CH:28]=[O:45])[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCC1(C#N)CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCC1(C=O)CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 4-[2-(t-butyldimethyl silyloxy)ethyl]-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (600 mg) in 1,2-dimethoxyethane (12 mL) was added diisobutylaluminum hydride (1.0 M toluene solution, 6.39 mL) at 0° C. The mixture was stirred for 4 hours. To the reaction solution was added aqueous citric acid solution and extracted with ethyl acetate. The organic layer was sequentially washed with aqueous citric acid solution, water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (526 mg). Yield: 87%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8]([C:3]1[C:2]([O:1][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1ncccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccnc1C(=O)OCC
Yield: 82.2 %

Procedure:
A mixture of ethyl 3-hydroxy-picolinate (11.0 g, 65.8 mmol), ethyl bromoacetate (12.1 g, 72.4 mmol) and anhydrous potassium carbonate (11.8 g, 85.5 mmol) in acetone (120 mL) was heated under reflux for 15 h. After cooling, the inorganic material separated by filtration. The filtrate was dissolved in chloroform, washed with water, then brine and dried (MgSO4), filtered, and the solvent was evaporated to give a brown oily residue. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give ethyl 2-(2-ethoxycarbonyl-3-pyridyloxy)acetate (13.7 g) as a yellow oil (13.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCO3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=427.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:21])[CH2:7][CH2:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10]2)([O:3][CH3:4])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C(Cl)(Cl)Cl>CCOCC>[C:1]([CH:5]1[CH:14]2[N:9]([CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH2:8][CH2:7][C:6]1=[O:21])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=C2CCC(c3ccccc3)CN2CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(=O)CCN2CC(c3ccccc3)CCC12
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Compound I (15.1 g.) was suspended in ether and LiAlH4 (1.5 g.; 0.75 equiv.) was added portionwise at room temperature. The mixture was stirred for 1 hr. at room temperature. The mixture was treated with wet THF and the mixture filtered. The filtrate was treated with CHCl3 /H2O, the CHCl3 separated, dried and the solvent removed in vacuo. Yield, 9 g. The filter-cake was stirred repeatedly with CHCl3 and an additional 4.1 g. of material was obtained. The 13.1 g. was chromatographed on a silica gel column. Compound II was eluted with CHCl3. Yield, 6.82 g. (44.9% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][S:28]([N:31]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32]1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[C:3]([NH:36][CH:33]2[CH2:34][CH2:35][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: CS(=O)(=O)N1CCC(N)C1
Product: CS(=O)(=O)N1CCC(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)C1
Yield: 19 %

Procedure:
By a procedure similar to that of Example 207 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and 1-(methylsulfonyl)pyrrolidin-3-amine, the title compound was obtained in 19% yield.
Reaction SMILES: C(Cl)Cl.[C:4]([C:7]1[C:8]([CH3:28])=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1)(=[NH:6])[NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([C:39]1([C:42]([F:45])([F:44])[F:43])[CH2:41][CH2:40]1)=O>[Cl-].[Na+].O>[CH3:24][C:19]([CH3:25])([CH2:18][O:17][C:16]1[CH:26]=[CH:27][C:13]([C:10]2[CH:9]=[C:8]([CH3:28])[C:7]([C:4]3[NH:5][C:37]([C:39]4([C:42]([F:45])([F:44])[F:43])[CH2:41][CH2:40]4)=[CH:36][N:6]=3)=[CH:12][N:11]=2)=[CH:14][CH:15]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2cc(C)c(C(=N)N)cn2)cc1
Reactant: O=C(CBr)C1(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)COc1ccc(-c2cc(C)c(-c3ncc(C4(C(F)(F)F)CC4)[nH]3)cn2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To methylene chloride (10 mL) and saturated brine (10 mL) were added methyl 3-[4-(5-carbamimidoyl-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (500 mg) and potassium carbonate (430.3 mg), then, 2-bromo-1-[1-(trifluoromethyl)cyclopropyl]-ethanone (431.6 mg) was added to the mixture, and the resulting mixture was stirred at 50° C. overnight. The organic layer was separated and the residue obtained by concentrating the same under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=75:25 to 25:75) to obtain methyl 2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]propanoate (423 mg).