Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]I.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CCOCC>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:22])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]I
Solvent: CCOCC
Product: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1

Procedure:
30 ml of ether solution containing 4.0 g of indole were added to 10 ml of ether solution containing 5.0 g of methylmagnesium iodide. And then 30 ml of ether solution containing 5.7 g of anisoyl chloride were added dropwise to the solution. The reaction mixture was allowed to stand for several hours and further refluxed for 3 hours. After cooling, the reaction mixture was washed with aqueous solution of sodium hydrogencarbonate. The obtained organic layer was evaporated to dryness under reduced pressure. After purification by chromatography on silica gel and recrystallization from ethanol, 3-(p-methoxybenzoyl)indole (compound 1) was obtained in the form of white crystals. (Yield: 42%)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:37])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (80 mg, 65%), MS (ISP) m/z=491.5 [(M+H)+], mp 186.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahyfrofuran was treated while stirring with the dropwise addition of 1.8 g (0.01 mole) of 1-benzylpiperazine. After stirring for 2 hr, the reaction mixture was diluted with water (200 ml) and 1.4 g of potassium carbonate was added. The solid precipitate was collected by filtration (5.2 g). Recrystallization from benzene/ligroin yielded 3.4 g (79.1%) of white crystals, m.p. 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Br:30]N1C(=O)CCC1=O>C(#N)C.O>[Br:30][C:6]1[N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH3:13])[N:8]=[C:9]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (25 mg, described in Example 132), and N-bromosuccinimide (10 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (12.5 mg, 42%). MS (ES): M/Z [M+H]=501. 1H NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H), 4.82 (d, J=14.3 Hz, 1H), 5.05 (d, J=14.3 Hz, 1H), 7.14 (dd, J=9.0, 1.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.9 Hz, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H) and 8.71 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[N:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[C:4]([NH2:16])[N:3]=1.[C:17]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18]1>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1ccc(N=Nc2cccnc2)c(N)n1
Solvent: C1CCOC1
Product: Nc1nc(NC(=O)CCCC(=O)O)ccc1N=Nc1cccnc1
Yield: 38.6 %

Procedure:
To a mixture of 3.21 g (15 mmol) of 2,6-diamino-3-((pyridin-3-yl)azo)pyridine and 0.27 g (2.2 mmol) of N,N-dimethylamino-pyridine in 100 ml of tetrahydrofurane, 4.27 g (37.5 mmol) of glutaric anhydride was added at room temperature. The mixture was refluxed for 16 hours. The mixture was then filtered, the solvent was evaporated and the crude product was dissolved in ethylacetate and extracted three times with a 1N sodium hydroxide solution. The combined aqueous extracts were acidified with conc. HCI at 0° C. A precipitate was formed, and filtration yielded an orange solid. The solid so obtained was washed with water. After drying the product was recristallised in methanol/water mixture and 1.9 g (40% yield) of 5-[(6-amino-5-(3-pyridinyldiazenyl)-2-pyridinyl)amino]-5-oxopentanoic acid were obtained.
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:27][O:28][CH2:29][CH2:30][CH2:31][NH:32]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>>[ClH:21].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:11]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Conc. hydrochloric acid (0.4 ml.) was added to the solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.) in methanil (20 ml.), and stirred at room temperature for 1.5 hours. After evaporating the solvent from the resultant mixture in vacuo, methanol was added to the residue. The mixture was evaporated in vacuo. The residue was dried over phosphorous pentoxide in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.5 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[C:38]([O:42][C:43](=[O:48])[NH:44][CH2:45][CH2:46][NH2:47])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([NH:44][CH2:45][CH2:46][NH:47][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:9]4[CH:36]=[CH:37][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:48])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used. The nucleophile used was (2-amino-ethyl)-carbamic acid tert-butyl ester. Yield: 21 mg.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH3:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([CH3:13])[CH:12]=1.O>ClCCl>[CH3:15][O:14][C:9]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1]([Cl:5])(=[O:3])=[O:2])=[C:7]([CH3:6])[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C)cc(C)c1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Chlorosulfuric acid (2.3 eq) in dichloromethane (0.5 ml/mmol) was slowly added dropwise over 10 min to a solution of 3,5-dimethylanisol (1 eq) in dichloromethane (1 ml/mmol) cooled to 0° C. The reaction mixture was stirred for a further 10 min and then slowly dropped into iced water (5 eq relative to chlorosulfuric acid). The phases were separated and the aqueous phase extracted with dichloromethane (repeatedly, UV analysis). The combined organic phases were dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 82%
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc(CCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: CC(C)([O-])C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:21])[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1.[C:22]1([C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C(O)(C)(C)C.ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:21])[CH:15]([C:16]1[NH:20][CH:19]=[CH:18][N:17]=1)[CH2:33][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]([O:31][CH3:32])=[S:30]
Reactant: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reactant: C=C(C(=S)OC)c1ccccc1
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: COC(=S)C(CC(C(=O)c1ccc(Cl)cc1Cl)c1ncc[nH]1)c1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution (1 M) of tert-butoxide in tert-butanol (54.9 ml) was added to a stirred solution of 1-(2,4-dichlorophenyl)-2-imidazol-2-ylethan-1-one (0.11 M) and methyl 2-phenylthioprop-2-enoate (0.14 M) dissolved in dichloromethane (300 ml) and methanol (200 ml) at room temperature. The reaction, which developed a dark color, was typically stirred overnight (ca. 16 h) under argon. The reaction was monitored by TLC using 5% methanol in dichloromethane as the solvent system. Additional methyl 2-phenylthioprop-2-enoate was added as needed to consume all of the starting 1-(2,4-dichlorophenyl)-2-imidazol-2-ylethan-1-one. The reaction was quenched by the addition of sat. aq. NH4Cl (˜100 ml). The mixture was transferred to a separatory funnel and diluted with ethyl acetate (300 ml). The aqueous layer was removed and the organic layer was washed with sat. aq. NH4Cl (3×100 ml), brine (100 ml), and dried with Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography over silica gel. The column was eluted starting with 100% dichloromethane to remove the non-polar methyl 2-phenylthioprop-2-enoate. The product was eluted with 3% methanol in dichloromethane. After drying overnight in vacuo, methyl 5-(2,4-dichlorophenyl)-4-imidazol-2-yl-5-oxo-2-phenylthiopentanoate as a deep red glass was obtained in 71% yield. A further 10% yield of product could be obtained by resubmitting side product contaminated fractions to a second purification by flash chromatography.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:11][O:12]/[C:13](=[CH:19]/[C:20](=[CH2:26])[O:21][Si](C)(C)C)/[O:14][Si](C)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH2:19][C:20](=[O:21])[CH2:26][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C(/C=C(/OC)O[Si](C)(C)C)O[Si](C)(C)C
Reactant: c1ccc2cnccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)CC(=O)CC1c2ccccc2C=CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.6 %

Procedure:
To the mixture of isoquinoline (24) (2.05 g, 15.9 mmol) in 150 mL of CH2Cl2 at 0° C. was added (Z)-4-methoxy-2,2,8,8-tetramethyl-6-methylene-3,7-dioxa-2,8-disilanon-4-ene (25) (8.29 g, 31.8 mmol), followed by benzyl chloroformate (2.7 mL, 19.1 mmol). After stirring at room temperature overnight, 100 mL of NH4Cl (aq) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried over Na2SO4. After the desiccant was filtered off, the organic extracts were concentrated under reduced pressure to provide (26) as a yellow oil (6.73 g). 1H NMR indicated about a 1:2 ratio of keto:enol tautomers. This crude oil was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].S(Cl)([Cl:9])=O.[CH2:11](O)[CH:12]([CH3:14])[CH3:13]>>[ClH:9].[CH2:11]([O:5][C:4](=[O:6])[CH:2]([CH3:3])[NH2:1])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CO
Reactant: O=S(Cl)Cl
Reactant: CC(N)C(=O)O
Product: CC(C)COC(=O)C(C)N
Product: Cl

Procedure:
A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of iso-butanol was refluxed for 1.5 hours. The volatiles were removed at reduced pressure at 90° C. under reduced pressure to give the title compound as an oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH:29]=[CH:28]N=C1)(N1C=CN=C1)=[O:19].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=CC(N)=[CH:39][CH:38]=2)[CH:31]=1>>[CH3:17][N:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18]([NH:25][C:29]3[CH:28]=[CH:42][C:37]([O:36][C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:38][CH:39]=3)=[O:19])=[CH:7][CH:6]=2)[CH2:9]1)[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cc2)C1
Reactant: Nc1ccc(Oc2cccnc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(=O)N(C)C1CCN(c2ccc(NC(=O)Nc3ccc(Oc4cccnc4)cc3)cc2)C1

Procedure:
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(pyridin-3-yloxy)phenylamine by method A. This resulted in the product with the molecular weight of 445.53 (C25H27N5O3); MS (ESI): 446 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[CH:5](Cl)Cl.[OH-].[Na+].[H][H]>[Pd].[C].O>[CH3:5][C:4]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:3]=1[C:2]([F:13])([F:1])[F:14]
Reactant: FC(F)(F)c1cc(Cl)ccc1C(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 30 °C
Yield: 122.5 %

Procedure:
A 1000-ml autoclave which is equipped with a mechanical stirrer and made of stainless steel (SUS-316) was charged with 263.6 g (1.0 mol) of the isomeric mixture (the product of the first step) containing 0.72 mol of 2-trifluoromethyl-4-chlorobenzalchloride as a main component, 84 g (2.1 mol) of sodium hydroxide and 420 g of water. Then, 5.3 g (2.0 wt %) of a metal-carried catalyst (5%-Pd/carbon) was added to the autoclave. The atmosphere of the autoclave was replaced by hydrogen, and the autoclave was put into oil bath to increase the temperature to 30° C. At the same time, stir was started while the hydrogen pressure was maintained at 5 kg/cm2. This started absorption of hydrogen. After the lapse of 4 hr, stir was stopped, and the reaction liquid was allowed to cool down. By analysis, conversion of 2-trifluoromethyl-4-chlorobenzalchloride (purity: 72.1%) was 99.9%. Then, the catalyst and the salt were removed by vacuum filtration. The resultant solution was put into a 1000-ml separating funnel, and then the aqueous phase was removed. The organic phase was washed with 500 ml of water and dried with magnesium sulfate. Then, magnesium sulfate was removed by vacuum filtration. As the result, 171.6 g of 2-methyl-5-chlorobenzotrifluoride (purity: 63.8%) was obtained. The yield of this product was 79.0%.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:23])[NH:7][S:8]([C:11]1[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1)(=[O:10])=[O:9])CCC.C(Cl)(Cl)=O.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](NC)[N:31]=1>ClC1C=CC=CC=1.ClCCl>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([N:5]([CH3:1])[C:6](=[O:23])[NH:7][S:8]([C:11]2[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:9])=[O:10])[N:31]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ncccc1N(C)S(C)(=O)=O
Reactant: CNc1nc(OC)cc(OC)n1
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ncccc2N(C)S(C)(=O)=O)n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
63.0 g (0.17 mol) of 3-butyl-1-[3-(N-methyl-N-methylsulfonylamino)-2-pyridylsulfonyl]urea are suspended in 1 l of chlorobenzene, and the suspension is heated to 70° C. At this temperature, the experiment starts to pass a gentle stream of phosgene into the suspension, and heating is continued for approx. 20 minutes until an internal temperature of 120° C. is reached. After phosgene has been passed in for a further 20 minutes (approx. 50 g (0.5 mol) in total), the lower-boiling components together with approx. 300 ml of chlorobenzene are removed from the reaction mixture by distillation over a period of 30 minutes. After the mixture has cooled to room temperature, 29.0 g (0.17 mol) of 4,6-dimethoxy-2-methylaminopyrimidine dissolved in 500 ml of dichloromethane are added, and the mixture is heated for 7 hours at 40° C. The mixture is cooled, the organic phase is washed with 1×250 ml each of 1N HCl and water, dried and evaporated. After the crude product has been triturated with diethyl ether, 66.6 g (85% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-1-[3-(N-methyl-N-methylsulfonyl-amino)-2-pyridyloulfonyl]-urea of m.p. 167°-168° C. (decomp.) remained.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[C:19]1([CH3:32])[CH:24]=[CH:23][C:22]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:29]2[CH2:30][CH2:31][CH:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:32])=[CH:20][CH:21]=3)[CH2:27][CH2:28]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To a mixture of (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18, 4-(p-tolyloxy)piperidine (383 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (829 mg) were added chloroform (3 mL) and methanol (3 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (196 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 62.1 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (0.253 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.186 g), triethylamine (Aldrich; 0.104 g), and ethylene glycol (2 mL) give 0.249 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 110-112° C.; MS m/z 388, 390; IR (mineral oil) 1511, 1234, 1219, 1448, 1326 cm-1. 1H NMR (CDCl3) δ2.74, 3.16, 3.77, 6.87-6.98, 7.21, 7.48, 7.53, 8.24.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:23])=[CH:5][N:6]=1
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 87.5 %

Procedure:
To a solution of 2-amino-5-(4-aminophenylthio)thiazole (4.0 g) in a mixture of chloroform (140 ml) and N,N-dimethylformamide (20 ml) was dropwise added the solution of 3-chloroperbenzoic acid (4.65 g) in chloroform (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 4 hours. The precipitates were collected by filtration, washed with 10% aqueous sodium bicarbonate and water. The solid was dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (3.75 g, yield: 87.5%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[O:24][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Reactant: COc1ccccc1N
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1OC
Temperature: 55 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.97 mmol) and 2-methoxyaniline (1.46 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.90 g (71%) of the desired product.