Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:24])=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 3 h

Procedure:
A 250 mL flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (3.00 g, 13.7 mmol) and CH2Cl2(100 ml) under nitrogen. DMF (cat)(0.100 ml) and oxalyl dichloride (1.49 ml, 17.1 mmol) were added dropwise, and the reaction mixture was stirred for 3 hours, and concentrated in vacuo. The brown solid was redissolved in CH2Cl2(100 ml) and ammonia (gas)(0.233 g, 13.7 mmol) was gently bubbled through the reaction mixture for 5 minutes. The flask was then capped and stirred at room temperature overnight under closed atmosphere. The brown suspension was concentrated in vacuo and the resulting solid was taken up in water (to dissolve the starting material), then collected by filtration to give 7-chlorothieno[3,2-b]pyridine-2-carboxamide. MS m/z=213 [M+H]+. Calc'd for C8H5ClN25OS: 212.66.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:33])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-(4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-one (CB57) (1.0 g, 2.8 mmol) and ammonium acetate (1.7 g, 22 mmol) were combined in dry methanol (22 mL) and stirred at room temperature while sodium cyanoborohydride (0.17 g, 2.7 mmol) was added in 3 equal portions over 30 minutes. The reaction was stirred overnight. The reaction was concentrated and partitioned between aqueous potassium carbonate and diethyl ether. The layers were separated, dried, filtered, and concentrated. Purification by reverse-phase flash column (C18) chromatography using 0-100% acetonitrile/water as eluent provided the title compound as a tan solid (1.0 g, 38%): mp 140-160° C.; 1H NMR (400 MHz, CDOD3) d 9.13 (s, 1H), 8.09 (d, J=8.0 Hz, 2H), 8.00 (d, J=9.0 Hz, 2H), 7.52 7.43 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 3.40-3.33 (m, 1H), 2.86 (t, J=6.7 Hz, 1H), 2.77 (dd, J=13.3, 7.3 Hz, 1H), 1.18 (d, J=6.2 Hz, 3H) (NH2 not observed); ESIMS m/z 363 ([M+H]+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: c1ccoc1
Product: O=C(c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12e and furane
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([SH:20])[N:15]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:16]1[N:15]=[C:14]([CH3:13])[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1ccnc(S)n1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccnc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (1.3 g, 5.0 mmol), 4-methylpyrimidine-2-thiol hydrochloride (543 mg, 3.3 mmol), and triethylamine (1.8 mL, 12.9 mmol) in absolute EtOH (35 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (10 mL), and dried in vacuo. The solid residue was treated with water (75 mL). The mixture was extracted with 50% ethyl acetate/Et2O (75 mL). The organic extract was extracted with brine (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (800 mg, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 (s, 2H), 7.17 (d, 1H, J=5.1 Hz), 8.54 (d, 1H, J=5.1 Hz), 8.67 (s, 2H); M+ 287.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3c(F)cc(F)cc23)CC1

Procedure:
(6.3 mg, 42%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 4-fluorobenzoyl chloride (9.5 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The alcohol from Example 1 (33.1 g) and 20 ml of triethylamine were dissolved in 350 ml of dichloromethane, cooled to 0° C., and treated with 11 ml methanesulfonyl chloride. After being stirred at room temperature for about 20 hours, the reaction mixture was diluted with dichloromethane (100 ml) and the organic layer was washed with three 50-ml portions of water and one of brine. Drying and concentration in vacuo gave the crude product which gradually crystallized upon standing. The solid was washed with diethyl ether, filtered, and dried to yield 12.0 g of 2-[2-(methylsulfonyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a white powder; m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:4]1=[O:19])[CH3:2].CS([C:24]1[N:25](COCC[Si](C)(C)C)[C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:24]3[NH:32][C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:16][CH:17]=2)[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 200 °C
Yield: 14.7 %

Procedure:
The mixture of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF (dry) (3 ml) was heated at 200° C. for 3 h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HCl. The mixture was neutralized with aq. NaHCO2 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[C:38]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1>>[NH2:30][C:4]1[S:3][C:2]([C:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Reactant: OB(O)C1=CCCCC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCC3)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 33 %

Procedure:
Following the procedure for Example 350 starting with (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 338 as a white solid (17.1 mg, 33%). 1H NMR (400 MHz, d4-MeOD) δ 7.58 (s, 1H), 6.31 (t, J=4.1 Hz, 1H), 3.74 (s, 3H), 3.30-3.24 (m, 3H), 3.13-3.07 (m, 1H), 2.64-2.45 (m, 2H), 2.28-2.24 (m, 2H), 2.04-1.88 (m, 3H), 1.83-1.66 (m, 8H). LCMS (ES+) m/z 416 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][CH:2]([CH2:7][CH3:6])[CH2:3][CH2:4][CH2:5][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)[CH:16]=2)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(C)CCCC1=CC(C)(C)Sc2ccc(CCc3ccc(C(=O)O)cn3)cc21
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-nicotinate (Compound 240, 66.0 mg, 0.15 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure to give the title compound as a yellow solid, 50.0 mg (81%). 1H NMR (300 MHz, d6 -acetone) δ: 9.09 (1H, d, J=1.4 Hz), 8.30 (1H, dd, J=2.0, 8.1 Hz), 7.65 (1H, d, J=8.1 Hz), 7.46 (2H, s), 7.24 (5H, m), 5.94 (1H, s), 2.37 (3H, s), 1.48 (6H, s).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3][O:2]1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:18](=[O:22])[C@@H:19]([CH3:21])[NH:20][C:24]4=[O:26])=[CH:15][CH:16]=3)=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1NC(=O)N(c2ccc(Oc3ccc4c(c3)COC4)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
A solution of N1-[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]-D-alaninamide (Intermediate 77, 100 mg, 0.335 mmol) and TEA (0.234 ml, 1.676 mmol) in dichloromethane (10 ml) was stirred under argon at 0° C. Triphosgene (49.7 mg, 0.168 mmol) in dichloromethane (4 ml) was added and the mixture was left stirring at 0° C. for 15 minutes. After 30 min an aqueous saturated solution of NaHCO3 was added. The phases were separated and the aqueous phase was extracted 3 times with dichloromethane. The gathered organic phases were dried over sodium sulphate and concentrated under vacuum. The residue obtained was purified by flash chromatography (Biotage SP1), using as eluents a gradient cyclohexane/ethyl acetate 90:10 to 65:45 to 20:80. This afforded the title compound (20 mg).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[NH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: c1ccc2c(c1)CCCCN2
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.96 g, 5.95 mmol) was reacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.10 g (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:20])[O:19][C:5]=2[CH:4]=1.Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][N:15]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:14][C:13]=3[C:18](=[O:20])[O:19][C:5]=2[CH:4]=1
Reactant: CC(=O)CCl
Reactant: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Product: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CC(C)=O)C3
Yield: 85.8 %

Procedure:
Prepared by the method described for Example 26 from 1,2,3,4-tetrahydro-8-methoxy-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.52 g, 0.02 moles) and 1-chloro-2-propanone (3.5 g, 0.038 moles). Recrystallization from methanol gave the product (5.7 g), mp 222°-225° C.
Reaction SMILES: [C:1]([C:3](=[CH:13]OCC)[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2].Cl.[NH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[NH2:19].CCN(C(C)C)C(C)C>C(O)C>[NH2:2][C:1]1[N:18]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[N:19]=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC=C(C#N)C(=O)NC1CCCCC1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2N)cc1
Temperature: 70 °C

Procedure:
2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg, 2.73 mmol) and methyl 4-hydrazinylbenzoate hydrochloride (Intermediate#123) (552 mg, 2.73 mmol) were suspended in ethanol (20 mL). DIPEA (351 mg, 2.73 mmol) was added and the mixture heated to 70° C. for 1 h. The reaction mixture was cooled to ambient and the resulting precipitate recovered by filtration, washed with ether and dried in vacuo to give the title compound as a white solid. (618 mg 66%)
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]c4)n3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine (60 mg, 0.15 mmol) in DMF (491 μL) was added sodium hydride (11.8 mg, 0.3 mmol). After 5 min, ethyl bromoacetate (25 μL, 0.22 mmol) was added and the mixture was heated at 80° C. for 3 h. The mixture was poured onto ice cold 1N HCl (2 mL) and extracted with EtOAc (3×2 mL). The combined organic fractions were washed with water (2 mL) and then dried over Na2SO4. The solvent was evaporated. Purification by Combiflash chromatography (SiO2-12 g, gradient elution of 30-60% EtOAc/hexanes over 25 min) gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(C#N)cc2)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
4-(Bromomethyl)benzonitrile (318 mg, 1.622 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (160 mg, 0.74 mmol) and potassium carbonate (204 mg, 1.48 mmol) in acetone (40 ml) at 20° C. The reaction mixture was stirred at 55° C. for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 300 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=CC=O)cc(OC)c1OCc1ccccc1
Reactant: O=C1CSC(=O)N1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)cc(OC)c1OCc1ccccc1
Yield: 57 %

Procedure:
According to the same manner as that described in Example 1, 4-benzyloxy-3,5-dimethoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4-thiazolidinedione (yield: 57%). This product was recrystallized from chloroform-ethanol. Yellow prisms, mp: 217-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH:36]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:46][O:45][C:43](=[O:44])[CH2:42][N:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: COC(=O)CNCC(=O)OC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)N(CC(=O)OC)CC(=O)OC)cc([N+](=O)[O-])c1
Yield: 79 %

Procedure:
Conversion of 3-nitro-5-(octadecyloxy)benzoic acid to the acid chloride with thionyl chloride followed by treatment with dimethyl iminodiacetate gave a 79% yield of N-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy)benzoyl]glycine methyl ester as an oil after chromatography on silica gel using 25% ethyl acetate-hexane. The nmr spectrum was consistent with the structure.
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](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:38][N:39]([CH3:49])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1>>[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:44]3[CH:43]=[CH:42][CH:41]=[C:40]([N:39]([CH3:49])[CH3:38])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(N(C)C)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-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 638 (M+H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4](S(OCCCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[CH2:21][CH2:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:30][C:20]([F:19])([F:29])[CH2:21][CH2:22][S:23]([CH:26]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[CH:18])[C:27]#[N:28])(=[O:24])=[O:25]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
To a solution of 1.0 g of 6-heptynyl p-toluenesulfonate and 0.8 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature. The reaction mixture was stirred at room temperature for 1 hour and at 60° C. for 2 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.23 g of 2-(3,3,3-trifluoropropylsulfonyl)-8-nonynenitrile (hereinafter referred to as the present compound (24)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 9 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and dimethylcarbamyl chloride as starting materials, 26 mg (9%) of the desired product was Isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.0 (s, 6 H); ES-MS m/z 503.26 [M+H]+, HPLC RT (min) 2.66.