Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7]([CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[H][H].[CH3:29]O>[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:29])=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CO
Reactant: CCCCc1ncc(CC=CCCC(=O)O)n1Cc1ccccc1Cl
Agent: O=[Pt]
Agent: Cl
Product: CCCCc1ncc(CCCCCC(=O)OC)n1Cc1ccccc1Cl

Procedure:
6-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-4-hexenoic acid was converted to the methyl ester with methanol and ethereal hydrochloric acid. This methyl ester (302 mg) in methanol was hydrogenated with platinum oxide (25 mg) at one atmosphere of hydrogen for 2 hours. The isolated crude reduced ester was chromatographed over silica gel with 3:1 ethyl acetate/hexane to provide 0.125 g of methyl 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]hexanoate. Basic hydrolysis of this ester with potassium hydroxide as described in Example 11(ii) provided 6-[2-n- butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-hexanoic acid hydrochloride; mp 144°-145° C. (from acetone).
Reaction SMILES: C(OC([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O: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][CH3:30])=[O:15])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[NH:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O: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][CH3:30])=[O:15])=[O:11]
Reactant: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1
Reaction time: 2 h
Yield: 97 %

Procedure:
A suspension of the compound (9) (1.47 g, 3.02 mmol) in trifluoroacetic acid (14 ml) was stirred for 2 h under ice-cooling. The reaction mixture was diluted with toluene and the resulting mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate aq. The organic layer was washed with water and concentrated in vacuo to give 1.08 g of tetradecyl L-prolyl-glycinate (10) as powder.
Reaction SMILES: [CH:1]([O:4][N:5]=[C:6]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](O)[CH:8]=1)([CH3:3])[CH3:2].[CH3:19][C:20]([CH3:24])(C)[CH2:21]O.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([O:4][N:5]=[C:6]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:25][CH2:21][CH:20]([CH3:24])[CH3:19])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)CO
Reactant: CC(C)ON=C(c1cccc(O)c1)n1cncn1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
2.5 g (0. 010M) of 1-(O-isopropyl-3-hydroxybenzohydroximoyl)-1H-1,2,4-triazole of, 0.9 g (10.0 mmol) of 2,2-dimethyl-1-propanol, and 2.6 g (10.0 mmol) of triphenylphosphine were dissolved in 40 ml of tetrahydrofuran. The solution was cooled to not more than 10° C. in a water bath. To the solution was added 1.7 g (10.0 mmol) of diethyl azodicarboxylate drop by drop so that the temperature of the solution was not over 20° C. The mixture was stirred overnight, and then heated to 60° C. The reaction mixture was then concentrated. The residue was purified by column chromatography, thus obtaining 0.8 g (yield: 25%) of the desired product having a refractive index of [nD20 ] 1.5202 at 20° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CS(C)=O>C1COCC1.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:18]=[N+:19]=[N-:20])=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-(benzoxazol-2-yl)benzyl bromide (0.49 g; 1.7 mmol) in THF (3 ml) is added sodium azide (0.22 g; 3.4 mmol) and dimethylsulfoxide (1 ml). The reaction is stirred for 24 hours and diluted with CH2Cl2, washed with H2O 3× and brine, dried (MgSO4) and concentrated in vacuo. The product is purified by column chromatography using 50% CH2Cl2 /petroleum ether to yield 4-(benzoxazol-2-yl)benzylazide as a white solid which is used directly in Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1[C:24]2[CH2:25][N:19]([C:17]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[CH:35][CH:34]=3)=[O:18])[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution of 452 mg of 2,4-dichlorobenzoyl chloride in 6 ml of methylene chloride is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f][1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.72 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.254 g of the desired product as ivory crystals, m.p. 112°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
In a 50 mL round-bottomed flask, 5-bromo-2-nitropyridine (3.28 g, 16.2 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5 g, 16.2 mmol, Eq: 1.00) were combined with dioxane (80.0 ml) to give a light yellow solution. Cs2CO3 (10.5 g, 32.3 mmol, Eq: 2) and 3 mL H2O were added. The solution was degassed with Ar before bis(triphenylphosphine)palladium(ii) dichloride (1.13 g, 1.62 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 300 mL H2O and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine and dried over MgSO4. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 100% EtOAc/Hex gradient) to give a dark brown impure solid. The solid was triturated with Et2O to afford tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (685 mg, 69%) as a tan solid. LC/MS-ESI observed [M+H]+ 306.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-:17].[K+]>C(O)(C)C>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:1][CH:2]([OH:3])[CH2:4][O:17][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:12]=1[C:14](=[O:16])[CH3:15])(=[O:3])[CH3:1]
Reactant: [OH-]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: ClCC1CO1
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(O)c1C(C)=O

Procedure:
reacting 2,6-dihydroxyacetophenone with epichlorohydrin in the presence of potassium hydroxide and isopropanol to form 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (4.3 g) in methylene chloride (50 ml) was added drop by drop a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (2.9 g), dimethylaminopyridine (0.6 g) and triethylamine (1.7 g) in methylene chloride (50 ml), under ice cooling. The mixture was left to stand at the room temperature for 24 hours before being poured in ice water. The methylene chloride layer separated was washed with diluted hydrochloric acid, water 1N aqueous sodium carbonate solution and water in this order, dried over magnesium sulfate and distilled to obtain a crude objective compound. The compound was purified by toluene/silica gel chromatography and recrystallization from ethanol to obtain the titled compound (3.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][NH:19][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:9][CH3:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1nccc(Cl)c1Cl
Reactant: NOCc1ccccc1
Product: CCc1nccc(NOCc2ccccc2)c1Cl
Yield: 99 %

Procedure:
Preparation was carried out analogously to Example 1 from 3,4-dichloro-2-ethylpyridine and O-benzylhydroxylamine. Yield: 99%
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:26](=[O:27])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([CH3:12])([CH3:11])[S:9](=[O:10])[C@H:5]12)=[O:2].[Cl:28]N1C(=O)CCC1=O.ClC(Cl)CCl>>[CH3:11][C:8](=[CH2:12])[CH:7]([N:6]1[C:26](=[O:27])[CH:4]([NH:3][CH:1]=[O:2])[CH:5]1[S:9]([Cl:28])=[O:10])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC=O)[C@H]2S1=O
Solvent: ClCC(Cl)Cl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC=O)C1S(=O)Cl

Procedure:
A solution of 1.43 g. of p-nitrobenzyl 6β-formamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 500 mg. of N-chlorosuccinimide in 40 ml. of dry 1,1,2-trichloroethane was refluxed for 90 minutes. The mixture was cooled, washed with water and brine, dried over MgSO4, and the solvent was evaporated. The nmr spectrum indicates conversion to the title compound.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:17])(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)NC1.Cl.[CH2:19]([N:21]([CH2:24]CCl)[CH2:22]C)[CH3:20].[CH3:27][N:28](C)C=O>>[O:17]=[S:3]1(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)[CH2:27][N:28]1[CH2:20][CH2:19][N:21]([CH3:24])[CH3:22]
Reactant: O=S1(=O)CNc2cccc3cccc1c23
Reactant: CCN(CC)CCCl
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN1Cc2cccc3cccc(c23)S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.028 g of sodium hydride is suspended in 0.5 mL of dimethylformamide and 0.073 g of 2,3-dihydro-naphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 mL of dimethylformamide is added. Then 0.053 g of diethylaminoethyl chloride-hydrochloride are added batchwise. The reaction mixture is stirred for 18 hours at ambient temperature and then poured onto ice water. The mixture is extracted with dichloromethane and the organic extracts collected are dried with sodium sulfate. After evaporation in vacuo, the residue obtained is purified by chromatography. Yield: 0.035 g; m.p.: 97° C.–98° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[O:9]C(=O)[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15]>O>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]([NH:15][CH3:14])=[O:9]
Reactant: CN
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Solvent: O
Product: CNC(=O)c1c(N)cccc1F
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A round-bottomed flask was charged with 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (500 mg, 2.8 mmol) and 30 mL water. The reaction was stirred for 15 min and then methylamine was added. The reaction was then stirred for 2 h. It was then extracted three times with ethyl acetate. Organic layers were combined and dried over sodium sulfate, then concentrated. The product was identified as 2-amino-6-fluoro-N-methylbenzamide (365 mg, 2.4 mmol, 86% yield). MS: M(C8H9FN2O)=168.17, (M+H)+=169.3.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A suspension of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g (10.0 mmol) of anhydrous piperazine and 20 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and acetonitrile, and dried in vacuo to give 0.85 g of the title compound, mp 226°-228 ° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][N:14]([CH:17](O)[CH3:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-:21].[Cs+].[Cs+]>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:21][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)([O-:10])=[O:9]
Reactant: CC(O)N1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
As in Example 1 of WO 00/59883, 14.11 g (100 mmol) of 2-fluoronitrobenzene, 14.45 g (100 mmol) of morpholinoethanol, 35.8 g (100 mmol) of cesium carbonate and 100 mL of dimethylformamide were allowed to agitate at room temperature for 7 days. The mixture was then filtered, the dimethylformamide was removed in a rotary evaporator, and the residue was distilled in a bulb tube still at 4 mbar and a furnace temperature of 160 to 170° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.I.[C:12](SC)(=[NH:14])[CH3:13].[CH3:17]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[N:14][C:12]([CH3:13])=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CO
Reactant: NNc1ccc(Br)cc1F
Reactant: CSC(C)=N
Agent: I
Product: Cc1ncn(-c2ccc(Br)cc2F)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of (4-bromo-2-fluorophenyl)hydrazine (3.4 g) in methanol (25 mL) was added methyl ethanimidothioate hydroiodide (3.6 g), and the mixture was stirred at room temperature for 40 min. The solvent was evaporated under reduced pressure. To a mixture of the obtained residue in toluene (20 mL) were added methyl orthoformate (15 mL) and pyridine (15 mL), and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was allowed to cool to room temperature, and diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[C:5]([OH:16])=[CH:6][C:7]=1[S:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])=[O:9].C([O:20][C:21](=[O:25])[CH:22](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.O>[CH3:1][C:2]1[C:7]([S:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:6][C:5]2[O:16][CH:22]([C:21]([OH:25])=[O:20])[O:17][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2c(cc1S(=O)(=O)c1cccs1)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a manner analogous to that described in Example 4, 30.0 g (111 mmol) of 4-methyl-5-(2-thienylsulphonyl)-1,2-benzenediol, 17.4 g (111 mmol) of dichloroacetic acid ethyl ester and 76.7 g (555 mmol) of potassium carbonate in 300 ml of 1,2-dimethoxyethane are boiled under reflux. After 18 hours, the reaction mixture is poured into water, stirred for one hour at room temperature and then adjusted to pH 1-2 by means of hydrochloric acid. Some of the 1,2-dimethoxyethane is distilled off in vacuo and the mixture remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The resulting dark-red oil is chromatographed over silica gel. As eluant, a mixture of chloroform/methanol/concentrated ammonia in a ratio of 40:10:1 is used until elution of the starting diol, then an analogous mixture in a ratio of 12:5:1 is used. The uniform fractions are combined and concentrated almost completely by evaporation. Ice/water is added to the residue and the pH is adjusted to 1-2 with concentrated hydrochloric acid. The acidic solution is extracted with ethyl acetate. The combined organic phases are washed, dried and concentrated by evaporation. The residue is boiled in diisopropyl ether and the black sludge formed is removed by decanting. The clear solution is concentrated to a large extent and the substance which has crystallised out is filtered off with suction. The crystals are recrystallised from 1,2-dichloroethane, yielding 5-methyl-6-(2-thienylsulphonyl)-1,3-benzodioxole-2-carboxylic acid in the form of white crystals having a melting point of 162.5°-164.5°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:30][C@@H:31]([CH2:44][NH2:45])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:45][CH2:44][C@H:31]([OH:30])[CH2:32][O:33][C:34]4[C:42]5[NH:41][C:40](=[O:43])[NH:39][C:38]=5[CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.85 (m, 5H), 3.30-3.50 (m, 2H), 3.69 (s, 3H), 3.80-4.05 (m, 3H), 4.87 (s, 2H), 6.56 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.65-6.90 (m, 5H), 7.02 (d, J=9.0 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H), 10.60 (s, 1H), 10.75 (brs, 1H); MS (ES) m/z: 626.1 (MH+); HRMS Calcd. for C30H36N5O8S(MH+): 626.2285. Found: 626.2298.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:30]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:30]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.727 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (69 μL, 0.763 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=60/40→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (145 mg, 42%) as a colorless solid.