Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2[nH]cnc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 5-chloro-1H-benzo[d]imidazole (500 mg, 3.28 mmol) in 5 mL DMF, were added TEA (0.502 mL, 3.60 mmol) and TrCl (1.00 g, 3.60 mmol). The mixture was stirred at rt for 3 h, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 75% EtOAc/hexanes gradient) to afford 580 mg of 5-chloro-1-trityl-1H-benzo[d]imidazole, followed by 225 mg of 6-chloro-1-trityl-1H-benzo[d]imidazole (177.1) as a white solid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ncccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (17.3 mg, 0.083 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:40])[CH2:37][O:38][CH3:39]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:40]=[C:36]([CH2:37][O:38][CH3:39])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: COCC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methoxyethanimidamide (J.Med.Chem,; 40; 8; 1997; 1230-1246) (177 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as an oil (350 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(C(=O)O)sc2c1
Temperature: 65 °C
Yield: 98.2 %

Procedure:
To a solution of compound 141-B (6.55 g; 29.4 mmol) in methanol (100 mL) was added 1N NaOH (44.2 mL; 44.2 mmol) and the reaction was heated at 65° C. for 18 h. The reaction was cooled, the solvent evaporated under reduced pressure, the residue dissolved in H2O, cooled to 0° C., acidified with 2N HCl, and the solid filtered, washed with H2O, and dried in vacuo to afford compound 141-C as a white solid (6.01 g, 98%). 1H-NMR (DMSO-d6): δ 3.84 (s, 3H), 7.05-7.08 (m, 1H), 7.60-7.61 (d, 1H), 7.87-7.89 (d, 1H), 8.01 (s, 1H), 13.24 (s, 1H); MS: m/z 208.9 (MH+).
Reaction SMILES: CS[C:3]([N:7]([CH3:16])[N:8]=CC1C=CC=CC=1)=[N:4][C:5]#[N:6].[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.CC(C)=O.Cl>O>[CH3:16][N:7]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)=[N:4][C:5]([NH2:6])=[N:8]1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Yield: 57.2 %

Procedure:
A mixture of N-cyano-1-methyl-2-(phenylmethylene)hydrazine-carboximidothioic acid methyl ester (166 mg) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (104 mg) was heated at 45° under a reduced pressure of 20 mm of mercury for 3 hr. Acetone was added, and the resulting solution treated with dilute hydrochloric acid for 1 hour at room temperature. The mixture was diluted with water, washed with ether, basified with excess sodium carbonate and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave an oil which crystallised from ethyl acetate/light petroleum b.p. 60°-80° to give the title compound as colourless crystals m.p. 95°-96.5° (87 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH3:11])[CH3:10])[N:3]=1.[CH3:12][NH2:13]>C(O)C>[CH3:10][N:9]([CH2:8][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[CH:7]=[CH:6][CH:5]=1)[CH3:11]
Reactant: CN
Reactant: CN(C)Cc1cccc(Cl)n1
Solvent: CCO
Product: CNc1cccc(CN(C)C)n1

Procedure:
2-Chloro-6-dimethylaminomethylpyridine (6.8 g, 0.04 mol), methylamine (12.0 g, 0.32 mole) and ethanol (25 ml) are heated at 180°-200° C. for 36 hours in a sealed reaction vessel. The solvent is removed in vacuo and the residue is made basic with excess sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gives 5.8 g of amber oil. The oil is distilled at 90°-100° C. at 1.8 mm and is further purified by chromatography. This gives 2.7 g of 6-dimethylaminomethyl-2-methylaminopyridine as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.C([BH-](CC)CC)C.[Li+].O>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(CO)ccc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 4-chloro-3-(methylsulfonyl)benzoic acid methyl ester (2.4 g) in tetrahydrofuran (50 mL) was added lithium triethylborohydride (1 M in tetrahydrofuran, 24 mL) at 0-5° C. under nitrogen. The mixture was stirred for 30 min and then more of lithium triethylborohydride (1M in tetrahydrofuran, 5 mL) was added and the mixture was further stirred for 60 min. Water (2 mL) was added and the tetrahydrofuran was evaporated under vacuum. Toluene (100 mL) and water (30 mL) were added and then hydrogen peroxide (30% in water, 20 mL) was added at 10-20° C. After 30 min the organic phase was separated and washed with potassium bicarbonate solution (1 M) and then dried with sodium sulphate and evaporated to dryness (yield 1.2 g). 1H-NMR (400 MHz, DMSO-d6) d=3.36 (s, 3H), 4.59 (d, J=5.7 Hz, 2H), 5.52 (t, J=5.7 Hz, 1 H), 7.66 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:14]1[CH:34]=[CH:35][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(C)=O)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and acetyl chloride (purification by flash chromatography on SiO2, chloroform/MeOH 99:1 to 90:10) as a colorless oil (72%). M+ (ESI): 521.9. HPLC, Rt: 5.4 min (purity: 100%). 1H NMR (CDCl3) δ: 7.62 (m, 1H), 7.41-7.05 (m, 5H), 6.85 (m, 1H), 4.75 (s, 1H), 4.73 (s, 1H), 4.55 (s, 1H), 4.53 (s, 1H), 4.41 (s, 1H), 4.38 (s, 1H), 3.92 (s, 1.5H), 3.90 (s, 1.5H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 2.41 (m, 2H), 2.21 (s, 1.5H), 2.20 (s, 1.5H), 1.62 (m, 2H), 1.45 (m, 2H), 1.31 (brs, 8H), 0.90 (t, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]([OH:15])=O)=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:13]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][CH3:12])[CH:7]=1)=[O:15]
Reactant: CCn1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)Nc2nccs2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
A solution of 6-chloro-1-ethyl-1H-indole-3-carboxylic acid (240 mg, 1.07 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (0.14 mL, 1.61 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 1 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride (1 mL), and this mixture was then added to a solution of 2-aminothiazole (214 mg, 2.14 mmol) and triethylamine (0.30 mL, 2.14 mmol) in N,N-dimethylformamide (2 mL). This mixture was stirred at 25° C. for 16 h. At this time, the reaction was partitioned between water (40 mL) and ethyl acetate (40 mL). This mixture was then treated with a 1N aqueous hydrochloric acid solution (15 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×30 mL), water (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded 6-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (27 mg, 8%) as a pale yellow solid: mp 234-236° C.; EI-HRMS m/e calcd for C14H12ClN3OS (M+) 305.0390, found 305.0383.
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:37])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:29])(=[O:27])=[O:26])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([S:25]([C:28]([CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH3:37])(=[O:27])=[O:26])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C(C)(C)S(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To 0.075 g (0.146 mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanol was added 0.10 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 2 h at room temperature, the catalyst was removed via filtration and the filtrate concentrated to give 0.056 g (91%) of the title compound as a white solid. MS Calcd.: 423. Found: 424 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[CH3:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(C)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-methylbenzenesulfonyl chloride according to METHOD A, giving 0.51 g (75%) of a pink powder: MS (electrospray, [M−H]−) m/z 339.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:11]I>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1Br
Temperature: 0 °C
Yield: 68.2 %

Procedure:
To a stirred mixture of 2-bromo-3-pyridinol (71.0 g) and pulverized KOH (77.8 g) in DMSO (500 mL) at 55°-60° C. and under N2 atmosphere was added dropwise a solution of CH3I (72.4 g) in DMSO (100 mL). After the addition was complete, the reaction was maintained at 55°-60° C. for 1/2 h. The mixture was then poured into ice water (800 g) and the precipitate filtered. The precipitate was triturated with Et2O (3×500 mL) and the combined extracts treated in turn with 1 N NaOH (500 mL), water (500 mL), 1 N HCl (3×250 mL), and sat. NaCl solution (500 mL). The organic phase was dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford 2-bromo-3-methoxypyridine (52.3 g; 68%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[O:5]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCCl>[O:22]=[C:14]1[C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]([CH2:3][CH2:2][O:1][S:31]([CH3:30])(=[O:33])=[O:32])[O:5]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2ccccc2C1=C1OC(CCO)c2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 3-[3-(2-hydroxy-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (0.50 g, 1.71 mmol) and triethylamine (356 μμl, 2.557 mmol) in 1,2-dichloroethane (23 ml) cooled to 0° C. was added methanesulfonyl chloride (145 μl, 1.88 mmol). After 20 minutes at 0° C. the reaction was partitioned between 0.5% HCl aqueous solution and EtOAc. The organic layer was then washed with water, brine, dried with anhydrous Na2SO4 Removal of the solvent led to methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester as a yellow solid (0.502 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH:11]([C:13]1[O:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[N+:8]([C:4]1[CH:3]=[C:2]([C:16]2[O:17][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Temperature: 25 °C

Procedure:
To a mixture of 1.5 g of 1-bromo-3-nitrobenzene (7.42 mmol), 1 g of 5-formyl-2-furanboronic acid (7.42 mmol), and 35 mL of a solution of saturated sodium carbonate (Na2CO3) in 0.2 M tetrahydrofuran was added 0.2 g of tetrakis triphenylphosphine palladium [Pd(PPh3)4] (0.2 mmol) at room temperature with stirring. After completion of the addition, the resulting mixture was heated for an additional 12 hrs, cooled to room temperature, and concentrated in vacuo. The concentrate was extracted with methylene chloride, and the organic layer thus formed was added, washed with saturated brine, dried over magnesium sulfate, and concentrated in a vacuum. Purification by silica gel column chromatography afforded the title compound.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.N1CCOCC1.Cl>O.CS(C)=O>[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[CH:2][C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:3]
Reactant: COc1cccc(C=O)c1O
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: COc1cccc(C=CC(=O)C2C(=O)CCC2=O)c1O
Yield: 49 %

Procedure:
2-Acetyl-1,3-cyclopentanedione (4.26 g.) was treated with 4.94 g. of 2-hydroxy-3-methoxybenzaldehyde in 100 ml. of dimethylsulfoxide in the presence of 6 ml. of morpholine at 85° C for 40 minutes. After cooling, the reaction mixture was poured into 300 ml. of water containing 12 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration and washed with water, and dried. 2-(2-Hydroxy-3-methoxycinnamoyl)-1,3-cyclopentanedione (4.40 g., 49%) was obtained in yellow crystalline state, which showed mp. 198° - 200° C. after recrystallization from a mixed solvent of dioxane and ethanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]>>[CH3:50][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:43]1[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:48][CH:49]=1)[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COc1ccccc1C(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccccc2OC)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C35H34N4O5
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4][CH2:3]1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(F)cc1
Reactant: OC1CCCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 71.2 %

Procedure:
To a mixture of azepan-4-ol hydrochloride (300 mg, 1.98 mmol) and 4-fluorobenzonitrile (311 mg, 2.57 mmol) in dimethyl sulfoxide (3.00 ml) was added potassium carbonate (821 mg, 5.94 mmol). The mixture was stirred at 120° C. for 6 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/4) to afford 4-(4-hydroxyazepan-1-yl)benzonitrile as a yellow solid (306 mg, 1.41 mmol, 71%).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:34])=[CH:25][N:26]=[C:27]2[NH:30][C:31]([NH2:33])=[NH:32])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])(C)(C)C.CCOCC.[C:41]([C:45]([OH:47])=[O:46])([F:44])([F:43])[F:42]>C1(C)C=CC=CC=1>[F:42][C:41]([F:44])([F:43])[C:45]([OH:47])=[O:46].[Cl:34][C:24]1[C:23]2[C:28](=[CH:29][C:20]([S:17]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[CH2:7][C:6]([OH:35])=[O:5])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[N:26][CH:25]=1
Reactant: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (30 mg, 0.058 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was azeotroped with PhMe and then Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine trifluoroacetate (29 mg, 0.05 mmol) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.C[O:20][B:21](OC)[O:22]C.Cl>>[B:21]([OH:22])([OH:20])[C:6]1[CH:7]=[CH:2][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(-c2ccccc2)cc1
Temperature: -95 °C
Reaction time: 0.08 h

Procedure:
5 g of bromobiphenyl was dissolved in 100 mL of tetrahydrofuran(THF), and the solution was cooled to −95° C. Then, 20.2 mL of 1.6M butyllithium was added thereto and stirred for 5 minutes. 24.31 mL of trimethylborate was added thereto at −95° C., and the solution was stirred for 2 hours at −78° C., and for 12 hours at room temperature. Then, 10% HCl solution was added thereto at 0° C. to adjust the pH of the solution to be less than 6, and the solvent was distilled. The reaction product was extracted with ether to obtain biphenylboronic acid. Thereafter, as shown in the following reaction 4, 0.08 g of bromospiro-dimer, 0.034 g of biphenyl boric acid, 0.003 g of Pd(TPP)4 catalyst, 0.11 ml of 2M Na2CO3 were refluxed in 1,2-dimethoxyethane solvent while stirring for 24 hours (Suzuki coupling reaction) to obtain the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([O-])(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[K+].O=P(Cl)(Cl)[Cl:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([Cl:20])(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: COc1ccc2sc(S(=O)(=O)[O-])c(C)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Product: COc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of potassium 5-methoxy-3-methylbenzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the remaining crude product was purified on a small amount of silica using CH2Cl2 as eluent to give 80 mg of the title compound (90%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Na+]>O1CCCC1.CO>[N:1]1[N:2]([C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([OH:14])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccnc1-n1cc2ccccc2n1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of ethyl 2-(2H-indazol-2-yl)nicotinate (3.44 g, 12.87 mmol; prepared according to procedures of WO 2008/080969) in a mixture of tetrahydrofurane (THF) (50 ml) and methanol (100 ml) a 2 M aqueous solution of sodium hydroxide (20 ml) was added and stirred over night at room temperature. The mixture then was concentrated. Water (200 ml) and then a 2 N aqueous solution of hydrochloric acid (HCl) (40 ml) were added, and the immediately formed solid was filtered off under suction. Treatment of the solids with ethylacetate (50 ml) gave 2.95 g of the title compound as a white solid.