Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCCc2ccccc21
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCCc2ccccc21
Yield: 119.4 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (720 mg, 2.26 mmol), piperazine (583 mg, 6.77 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.77 mmol) in acetonitrile (10 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 257 mg (30%) of 1,2,3,4-tetrahydro-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.60 (d, 1H), 7.30 (d, 1H), 7.20-7.10 (m, 2H), 6.32-6.26 (m, 2H), 6.23 (br s, 1H), 4.67 (dd, 1H), 3.26 (br t, 4H), 2.98 (br t, 4H), 2.92 (s, 3H), 2.90-2.72 (m, 2H), 2.02-1.80 (m, 4H). MS (ESI) m/z: Calculated: 385.52; Observed: 386.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Brc1ccccn1
Reactant: ClCc1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: Clc1ccccc1Cc1ccccn1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The Grignard reagent, generated from o-chlorobenzyl chloride (52.0 g, 0.32 moles) and magnesium turnings (8.4 g, 0.35 g atoms) in dry diethyl ether (350 ml), was added dropwise to a refluxing solution of 2-bromopyridine (34.2 g, 0.22 moles) and tetrakis(triphenylphosphine)palladium (0) (5.0 g) in dry diethyl ether (200 ml) under a nitrogen atmosphere. A white precipitate was produced and the reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, 1N hydrochloric acid was added carefully to dissolve the white solid and the ether layer separated off. The ethereal extract was washed with 1N hydrochloric acid, neutralised with 2N sodium hydroxide solution, washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with tetrahydrofuran:chloroform 5:95) to give 2-(o-chlorobenzyl)-pyridine (32 g, 73%) as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:30][CH2:29][C:12]2=[C:13]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].ClCCl>[O:22]([CH2:21][CH2:20][C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:30][CH2:29][C:12]=12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN2CCc3c(CCOc4ccccc4)c4ccccc4n3CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc(OCCc2c3n(c4ccccc24)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
(Chart D, Step 4): A dry round bottom flask is charged with 3-benzyl-11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (317 mg, 0.80 mmol), ammonium formate (254 mg, 4.0 mmol), methanol (18 mL) and dichloromethane (3.2 mL). After the addition of 10% Pd/C (64 mg) the reaction is stirred at ambient temperature for two days. The reaction mixture is filtered through a pad of celite, and the catalyst is rinsed with methanol. The filtrates are combined and concentrated to 380 mg of a crude solid. This material is recrystallized from ethyl acetate/methanol/ethyl ether to afford 239 mg of 11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a white solid. IR (drift) 3026, 3015, 2998, 2983, 2948, 2910, 2869, 2806, 2781, 2752, 1468, 1451, 1245, 755, 746 cm−1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24]([Sn](CCCC)(CCCC)CCCC)=[N:23]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:21][N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24]([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)=[N:23]1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c1CCCC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (406 mg, 1.14 mmol) and 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (485 mg, 1.14 mmol) were dissolved in DMF (3.00 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (65.9 mg, 57.0 μmol) and CuI (43.4 mg, 228 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 18 h. The reaction mixture was concentrated under high vacuum and the dark yellow solid residue was purified by chromatography (80 g column, 50 μm from SiliCycle) gradient 0-50% EtOAc in hexanes over 30 min) to give 2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (265 mg, 644 μmol, 56.5%) as a light yellow solid. MS (M+H)+=412; 1H NMR (CDCl3) δ: 10.50 (s, 1H), 9.07 (s, 1H), 8.29 (s, 1H), 5.77 (s, 2H), 3.89 (s, 3H), 3.57-3.72 (m, 2H), 3.05 (t, J=6.0 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 1.80-2.02 (m, 4H), 0.92-1.09 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]1[O:25][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=4)=[N:11][NH:10][C:9](=[O:23])[CH2:8][C:7]=3[CH:24]=[C:3]2[O:2]1.O>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:25][CH2:1][O:2][C:3]4=[CH:24][C:7]=3[CH2:8][C:9](=[O:23])[NH:10][N:11]=2)=[CH:14][C:15]=1[CH3:22]
Reactant: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(3-methyl-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (147 mg, 0.433 mmol) in ethanol (5 mL) was added water (2.5 mL), 5% Pd/C (42 mg), and HCO2NH4 (320 mg, 5.07 mmol). The mixture was stirred at room temperature for 4 h. The catalyst was filtered out. The filtrate was concentrated in vacuo and water (25 mL) was then added to the residue. The resulting solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound as a light yellow solid (65 mg, 0.21 mmol, 49%), mp: 164°-166° C. 1H NMR (CDCl3) 8.23 (s, 1H), 7.35-7.22 (m, 2H), 6.82 (s, 1H), 6.71-6.65 (m, 2H), 6.03 (s, 2H), 3.87 (s, 2H), 3.42 (s, 2H), 2.19 (s, 2H). Anal. calcd. for C17H15N3O3.H2O: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.50; H, 5.19; N, 12.86.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:11]=[C:10]([C:9]2[O:19][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: COc1cc(C(=O)Nc2ccccc2O)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)ccc1C

Procedure:
A mixture of N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide (1.5 g, 5.8 mmol), toluene (30 mL), p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol) and molecular sieves was refluxed overnight. After cooling reaction to rt, filtered washing with warm chloroform and concentrated filtrate in vacuo. The resulting brown oil was purified by flash chromatography on silica gel using 1:4 EtOAc:hexanes to give the desired intermediate, 2-(3-methoxy-4-methylphenyl)-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15](=O)[NH:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:37]2)=CC=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15](=[S:37])[NH:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)CCC2(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2(C)C

Procedure:
(5,5-Dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-carbamic acid tert-butyl ester (1.90 g, 0.00624 mol), THF (100 mL, 1 mol), and 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (2.58 g, 6.4 mmol) were stirred at rt for 16 h. Title compound was obtained as a white solid (1.54 g, 77%), LCMS 321.21 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:25][CH:24]=[CH2:23])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.5 g, 3.6 mmol) and Cs2CO3 (2.26 g, 6.9 mmol) in DMF (20 mL), allyl bromide (0.6 mL, 3.9 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 40 h at RT. DMF was evaporated. The residue was dissolved in EtOAc and washed with aq. HCl 1 N, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:6) to give the title compound. MS (LCMS): 167.9 [MH-Boc]+, 290.0 [M+Na]+.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH:21]([NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:24]([CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:21]([CH3:22])[CH3:23])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCCNC(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCN(C(=O)c2ccccc2C(=O)c2ccccc2)C(C)C)cc1

Procedure:
A solution of 37 grams of ψ-acid chloride of 0-benzoyl benzoic acid in 60 ml. of dichloromethane was added dropwise to a stirred solution of 38.5 grams of N-[2-(isopropylamino) ethyl]-p-toluenesulfonamide, 200 ml. of dichloromethane and 25 ml. of triethylamine. The mixture was refluxed for 3.5 hours. After cooling, the solution was extracted successively with water, 10% hydrochloric acid, and saturated sodium carbonate solution. The dichloromethane solution was dried over magnesium sulfate and the solvent evaporated in vacuo to a solid residue. On recrystallization from ethyl acetate there was obtained 2-benzoyl-N-[2-(p-toluenesulfonamido)ethyl]-N-isopropylbenzamide, m.p. 135°-137°C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:34])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][NH:7][C:14]1[C:17]([CH3:16])=[C:18]([CH:19]=[CH:20][CH:15]=1)[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[O:34]
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCNC(=O)c1cccc(NCc2ncc[nH]2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 127 %

Procedure:
The compound (117 mg) obtained in Example 6-2 was dissolved in methanol (1.2 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (1.2 ml) and the whole was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in water and then purified through solid-phase extraction column (Sep-Pak, tC18, manufactured by Waters Corporation), thereby obtaining a hydrochloride (118 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:9]([CH3:16])=[N:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:23]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:9]([CH3:16])=[N:10][N:11]2[C:15]([Br:23])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn2ccsc2c1NC(=O)OC(C)(C)C
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A tetrahydrofuran (40 mL) solution of tert-butyl(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (1.20 g, 4.74 mmol) was cooled to −78° C., and n-butyllithium (1.57 M, 6.64 mL, 10.4 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes. Then, 1,2-dibromotetrafluoroethane (619 μl, 5.21 mmol) was added to the mixture, and the reaction mixture was warmed to room temperature, and stirred at room temperature for one hour. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, and a substance of interest was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 50% then 66%) to obtain 1.39 g (4.32 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[CH3:16][O:15][C:13](=[O:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(F)ccc1O
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(F)cc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Following the procedure of J. Med. Chem. 1999, 42, 5369, 4-fluoro-2-methylphenol (10.0 g, 79.0 mmol) was dissolved in THF and the mixture was cooled to 0° C. NaH (1 eq, 3.16 g of a 60% dispersion in oil) was added carefully. After gas evolution ceased, methyl chloroformate (1 eq, 6.8 ml) was added. The mixture was allowed to warm to room temperature and stir for 3 hours. The mixture was washed with cold water, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (12.8 g, 88.0%) as an oil.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH:17]([OH:18])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CC1CCC1
Product: CCOC(=O)c1ccc(C(O)C2CCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl 4-iodobenzoate and cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.58 (d, J=8.0 Hz, 1H), 4.29 (q, J=6.8 Hz, 2H), 2.50-2.58 (m, 1H), 1.70-2.02 (m, 6H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][CH2:26][O:27][CH3:28].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:25][CH2:26][O:27][CH3:28])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1ccc(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)ccc(OC)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 563.9 %

Procedure:
To a stirred solution of 500 mg (1.45 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole in 11 ml DMF, NaH (38 mg, 1.6 mmol) is added and stirring is continued for 1 h at RT, and then the reaction mixture is heated to 60° C. 0.152 ml (0.175 mmol) (2-bromoethyl)-methyl ether is added and stirring is continued at this temperature for another 6 h. The reaction mixture is cooled to room temperature, poured into water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 398 mg of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.Cl.Cl.[CH3:24][N:25]1[C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][S:27]/[C:26]/1=[N:37]\[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:29]3[N:25]([CH3:24])/[C:26](=[N:37]/[CH3:38])/[S:27][CH:28]=3)[CH2:32][CH2:33]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C/N=c1\scc(CN2CCNCC2)n1C
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C/N=c1\scc(CN2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1C
Yield: 22.6 %

Procedure:
To a suspension of (2S)-3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoic acid (0.32 g), N-((2Z)-3-methyl-4-(-1-piperazinylmethyl)-1,3-thiazol-2(3H)-ylidene)methanamine trihydrochloride (0.51 g), HOBt (0.20 g) and triethylamine (0.63 mL) in DMF (5 mL), WSC (0.21 g) was added, and the mixture was mixed at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure. The residue was basified with an aqueous potassium carbonate solution, and then the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate, the solvent was then distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.12 g, 23%) as a colorless powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.C([O-])(=O)C.[Na+].[C:18]1([C:24]2[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:12][C:10](=[O:11])/[C:9](=[CH:29]/[C:27]2[O:28][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:25][CH:26]=2)/[N:8]=1
Reactant: O=C(O)CNC(=O)c1ccco1
Reactant: O=Cc1ccc(-c2ccccc2)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccco2)=N/C1=C\c1ccc(-c2ccccc2)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
As illustrated in Scheme 2, N-2-furoylglycine (131 mg, 0.776 mmol) is suspended in acetic anhydride (1 mL) and sodium acetate (76 mg, 0.931 mmol) and 5-phenylfuraldehyde (170 mg, 1 mmol) are added. The reaction mixture is shaken at 60° C. for one hour, and cooled to 0° C. The resulting orange solid is filtered and washed with ice water (75 mL) and heptane (50 mL). The solid is then dried under vacuum at 40° C. to afford 79 mg of (4Z)-2-(2-furyl)-4-[(5-phenyl-2-furyl)methylene]-1,3-oxazol-5(4H)-one which was used without further purification.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CS(O)(=O)=O>C1(C)C=CC=CC=1.CCOCC>[C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1
Reactant: CCCCCCCCCCO
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCOC(=O)c1ccc[n+]([O-])c1
Reaction time: 19 h
Yield: 75 %

Procedure:
Nicotinic acid N-oxide (5.00 g, 36 mmol), decyl alcohol (5.86 g, 37 mmol) and methanesulfonic acid (3.70 g, 38.5 mmol) were stirred and heated to reflux in toluene (50 mL), in a flask equipped with a condenser and a Dean-Stark trap for 19 hours. The reaction mixture was then cooled, diluted with ether and washed successively with water, aqueous sodium bicarbonate and brine. The toluene/ether solution was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ligroine (100 mL) to give 7.50 g (27 mmol) of decyl nicotinate N-oxide, mp 80.5° C.