Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1(C)C=CC=CC=1.[CH3:18][O:19][C:20](=[O:49])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.IC>C1COCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:49])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[CH3:11])=[CH:25][CH:26]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(CC(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(CC(C)(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of LiHMDS in toluene (1.0M, 1.6 mL, 1.6 mmol) was cooled in a dry-ice acetone bath (−78° C.) and diluted with 3 mL of THF. A solution of 4-[2-Benzyloxycarbonyl-2-(4-tert-butyl-phenyl)-ethyl]-benzoic acid methyl ester (675 mg, prepared as described in Bioorg. Med. Chem Lett. 2004, 14, 2047-2050) in 5 mL of THF was added via cannula. The mixture was stirred at the same temperature 30 min. It was then transferred to an acetone/ice bath, where it was warmed to ˜10° C. over a 1.5 h period. The mixture was cooled back to −78° C. and iodomethane (0.11 mL) was added via syringe. The mixture was then stirred for a 2 h period while allowing it to warm up to room temperature (approximately 2 h). The mixture was poured over a mixture of ethyl acetate and ice cold aqueous ammonium chloride. The organic phase was washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The residue obtained after removal of the solven was treated with hexanes/ethyl acetate to cause the formation to precipitate the title compound (307 mg, 44%) HNMR (500 MHz, DMSO-d6, selected signals): 5.12 (2H, ABquartet), 3.82 (3H, s), 3.47 (1H, d, J=13.0 Hz), 3.22 (1H, d, J=13.2 Hz), 1.37 (3H, s), 1.28 (9H, s)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=C(S(N[C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:27][CH:26]=2)(=O)=O)C=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:29][CH:30]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Reactant: NS(=O)(=O)c1ccncc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie, A. M.; et al., J. Chem. Soc., 1958, 3514) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:19]([C:3]1[C:4]([O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31])#[N:20]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: CCCNC(=O)C(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Yield: 85 %

Procedure:
Prepared as in Example 24a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide (Example 197b, Method A) and benzoyl isocyanate in 85% yield as a white solid. MS 423 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Br:8][CH:9]([CH:12]=O)[CH:10]=O>>[Br:8][C:9]1[CH:10]=[C:6]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:7][CH:12]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=CC(Br)C=O
Product: Cc1n[nH]c2ncc(Br)cc12
Yield: 10 %

Procedure:
5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine x153 is synthesized according to the method described in example 20.1 using 3-methyl-1H-pyrazol-5-amine b40 and bromomalonaldehyde a9.
Reaction SMILES: CN1CCOCC1.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20]3([C:23]([N:25]4[CH2:29][CH2:28][C@@:27]5([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=6[C:31](=[O:38])[O:30]5)[CH2:26]4)=[O:24])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:39]1([C:42](O)=[O:43])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(#N)C>>[CH:39]1([C:42]([N:11]2[CH2:12][CH2:13][N:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]4([C:23]([N:25]5[CH2:29][CH2:28][C@@:27]6([C:33]7[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=7[C:31](=[O:38])[O:30]6)[CH2:26]5)=[O:24])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:10]2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C(O)C1CC1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)nc4)CC3)C2)c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylmorpholine (2.0×10−1 μL, 0.00018 mol) was added to a mixture of (1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.000036 mol, this compound was prepared in a way similar to that described in example 163), cyclopropanecarboxylic acid (3.4 μL, 0.000043 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.000043 mol) in acetonitrile (0.7 mL, 0.01 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 487.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:16])([F:15])[C:10]([O:12]CC)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.CO>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:10](=[O:12])[C:9]([F:8])([F:15])[F:16])=[CH:22][CH:23]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 57.5 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
In 50 mL of dimethylformamide, 9.4 g (0.1 mol) of 2-aminopyridine was dissolved. To this solution, 28.8 g (0.2 mol) of ethyl trifluoroacetate, 16.2 g (0.1 mol) of 2-chloro-5-chloromethylpyridine, and 13.8 g (0.1 mol) of potassium carbonate were added, followed by stirring at 55 to 60° C. for 20 hours. To the reaction liquid, 1.38 g (0.1 mol) of potassium carbonate powder, 3.24(0.02 mol) of 2-chloro-5-chloromethylpyridine, and 5.68 g (0.04 mol) of ethyl trifluoroacetate were further added, followed by stirring at 55 to 60° C. for 6 hours. To the reaction liquid, 40 mL of methanol was added, and then the reaction liquid was added to 300 mL of hot water of 50° C. After being cooled to room temperature, the mixture was stirred for 1 hour. The crystals were filtered, and washed with 100 mL of water and 75 mL of toluene. The obtained crystals were dried under reduced pressure at 45° C. Thus, 24.0 g of the target compound was obtained (Percentage Yield: 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9]1
Reactant: O=[N+]([O-])c1ccc(N2CC[C@@H](O)C2)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
3-Fluoro-4-((3R)-3-hydroxy-1-pyrrolidinyl)nitrobenzene (35.8 g, 0.158 M) was dissolved in DMF (200 ml), and treated with imidazole (21.6 g, 0.318 M) and t-butyldimethylsilyl chloride (35.7 g, 0.239 M) and stirred for 18 hours at ambient temperature under nitrogen. Solvent was evaporated, and the residue treated with EtOAc (300 ml) and water (200 ml). The organic layer was washed with water (150 ml) and dried (magnesium sulfate). Evaporation gave the desired product (54 g), of sufficient quality for use without purification.
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([B:28]3[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 79.9 %

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) was dissolved in 20 ml of dry toluene and 3.18 ml of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23 mmol), 20 mg (0.08 mmol) of palladium(II) chloride diacetonitrile complex, 80 mg (0.005 mmol) of S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) and 774 μl (5.7 mmol) of triethylamine were added successively. The reaction mixture was submitted to microwave irradiation in a sealed vial at 90° C. for 30 minutes. The mixture was then filtered through a celite pad and the filtrate evaporated in vacuo. The residue was taken up with dichloromethane and washed with water and the organic layer dried over sodium sulphate and evaporated again. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 1%), affording 800 mg (80%) of the title compound, crystallized from diethylether.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C(=O)([O-])O.[Na+]>O.C(OCC)C>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][OH:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NO)c1ccc(CCl)cc1
Yield: 91.6 %

Procedure:
4-Chloromethyl-benzoyl chloride (18.9 g) (0.1 mol) and 13.8 g (0.2 mol) of hydroxylamine hydrochloride are suspended in 200 ml of water and 150 ml of diethyl ether. 25.2 g (0.3 mol) of sodium hydrogen carbonate are added while stirring. After 30 minutes the product is filtered off under suction and washed with water and diethyl ether. After drying in a high vacuum at room temperature there are obtained 17 g of white α-chloro-N-hydroxy-p-toluamide of m.p. 120°-145° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:34]1(=[O:39])[O:38][CH2:37][CH2:36][CH2:35]1.C[Al](C)C>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][OH:39])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCO1
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCCO)NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl amine 11 (0.05 mmol) in DMSO (1 mL) was mixed with a solution of 4-butyrolactone (0.05 mmol) in CH2Cl2 (1 mL) under N2. To the mixture was added AlMe3 (0.25 mmol) and stirred for 10 min at room temperature and then 6 h at 45° C. The crude product was purified from preparatory HPLC to give II-8 as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[OH-:7].[Na+].[N+]([C:12]1C=CC=C[C:13]=1[C:14]([O-:16])=O)([O-])=O.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:47][SH:48])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>CC(O)(C)C>[CH:30]1[C:31]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:47][S:48][CH2:12][C@H:13]([OH:7])[CH2:14][OH:16])[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[O:37])[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])c1ccccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (2S)-(+)-glycidyl-4-nitrobenzoate (9, 1.1 eq) and 1M NaOH (1.1 eq) in tBuOH (0.1 M) was stirred at room temperature until complete hydrolysis of the nitrobenzoate (30 minutes). To the resulting mixture, a solution of (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1 eq) in tBuOH (1 M) was introduced. The reaction was stirred at room temperature for 15 hours. The reaction mixture was concentrated en vacuo to remove tBuOH and dissolved in EtOAc. The EtOAc solution was washed three times with water, and once with brine. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-90% EtOAc/Hex to give the title product as colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:29][CH:30]1[CH2:33][N:32]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:31]1
Reactant: FC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), 3-fluoroazetidine hydrochloride (74.7 mg, 669 μmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (228 μl, 1.34 mmol) in tetrahydrofurane (7 ml) is stirred for 18 hours room temperature. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (36 mg, 37.3%) as a light brown solid. mp.: 247-9° C. MS: m/z=421.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[CH3:15]>ClCCCl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][O:12][CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:9][CH3:10])[CH3:15]
Reactant: CCC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCCl
Product: CCOC(=O)COCC(CC)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of (1-(hydroxymethyl)propyl)carbamic acid tert-butylester (7.2 g, 39 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (6.0 ml, 57 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 60 min and the mixture was heated at 80° C. for 6 hours. Then another portion of ethyldiazoacetate (2.0 ml, 19 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 7 hours. The mixture was cooled to room temperature and washed with sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with pentane/ethyl acetate 7:3 as eluent to give 4.3 g of (2-(tert-butoxycarbonylamino)butoxy)acetic acid ethylester. The product was dissolved in of 1 M lithium hydroxide in water/methanol 1:3 (40 ml) and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and water (100 mL) was added and the solution was washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 2.46 g of (2-(tert butoxycarbonylamino)butoxy)acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1([CH:27]=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:18]([O:20][C:21]([C:23]1([CH2:27][NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[N:9]([CH3:17])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(C=O)CCC1
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethyl ester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added acetic acid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, the mixture is cooled with an ice-water bath and sodium triacetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, the mixture is heated to reflux for 1.5 h, cooled to room temperature, diluted with dichloromethane, washed with 1M aqueous NaOH, water and brine. The combined aqueous phase is extracted once with dichloromethane and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H), 3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8 Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.C(N(CC)CC)C>O1CCCC1>[CH3:7][Si:8]([CH3:11])([CH3:10])[N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6]
Reactant: S=C1NCCN1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1CCNC1=S

Procedure:
30.6 parts by weight of imidazolidine-2-thione were boiled overnight with 54.4 parts by weight of trimethylchlorosilane and 51.5 parts by weight of triethylamine in absolute tetrahydrofurane. The warm suspension was freed of the precipitated triethylamine hydrochloride by filtration, and the filtrate was evaporated and dried in a vacuum desiccator.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:23]O>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:14][CH3:23])=[O:13])(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Yield: 68.3 %

Procedure:
3-(pyrrolidin-1-ylsulfonyl)benzoic acid (200 mg, 0.783 mmol) was refluxed in the presence of con. Sulfuric acid (5.06 mg, 0.039 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(pyrrolidin-1-ylsulfonyl)benzoate (150 mg, 0.535 mmol, 68.3% yield). 1H NMR (CDCl3, 400 MHz): δ 8.47 (m, 1H), 8.25 (d, 1H, J=7.6 Hz), 8.02 (dt, 1H, J=1.2 & 8.0 Hz), 7.63 (t, 1H, J=7.6 Hz), 3.96 (s, 3H), 3.27 (m, 4H), 1.77 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[C:44]([F:45])[CH:43]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and 3,4-difluorophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene as colorless crystals. APCI-Mass m/Z 648 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 480 (M+NH4).