Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:11][CH:10]=[CH:9][C:8]3[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: CS(=O)(=O)c1ccc(C=CCCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 21 %

Procedure:
Prepared from 4-methylsulphonyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 21% of theory, Melting point: 157°-161° C. (ether).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:19]CC2C=CC(OC)=CC=2OC)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:38][C:39]([CH3:41])=[O:40].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([S:16]([NH2:19])(=[O:17])=[O:18])[C:39]([OH:40])([CH3:41])[CH3:38])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cccc(OCc2ccccc2)c1)S(N)(=O)=O
Temperature: -75 °C

Procedure:
Under inert gas, 3.10 g of C-(3-benzyloxyphenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 60 ml of THF, and then, at a temperature of −75° C., 12.00 ml of a 1.8 N phenyllithium solution were added dropwise. The reaction mixture was allowed to come to 0° C. and stirred briefly, then cooled again to −75° C., and 3.80 ml of acetone were added dropwise. After stirring for 10 minutes, 3 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. After the removal of the solvent under reduced pressure, the residue was dissolved in 20 ml of dichloromethane and admixed with 5.00 ml of trifluoroacetic acid. After stirring at room temperature for 2.5 hours, the reaction solution was neutralized cautiously with 2 N aqueous sodium hydroxide solution and then stirred overnight. The precipitate formed was filtered off with suction, washed with dichloromethane and cold water, and coevaporated twice with toluene. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (2.06 g) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]2[C:10](=[O:12])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:14][CH:15]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(=O)C(c1ccc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2=O)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1-fluoro-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].S([O-])(=O)(=O)C.Cl.[CH3:21][O:22][CH2:23][CH2:24]O>CS(C)=O>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: O=C(O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOc1ccc(C(=O)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid (0.498 g) in dimethylsulfoxide (5 mL) under argon was treated with 4N sodium hydroxide (1.5 mL), stirred for 5 minutes and treated with the mesylate prepared from 2-methoxyethanol (0.462 g) . The mixture was heated at 60° C. for 3 hours and poured into excess 1N hydrochloric acid. The product was extracted into diethyl ether (3×50 mL) and the organic layers were washed in turn with water (2×25 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 0.56 g of crude product as a solid. Crystallization from ethyl acetate-hexane provided 0.3 g of 4-[[2-(methoxy)ethyl]oxy]-alphaoxobenzeneacetic acid, mp 129°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:23][C:24]([NH2:26])=[NH:25].O>CO>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:11][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCC(O)C2)cc1C
Reactant: N=C(N)N
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCCC(O)C2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 4.2 g of methyl 2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzoate [obtainable by reacting 3-hydroxypiperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 3.89 g of guanidine in 20 ml of methanol is stirred at 50° over a period of three hours. The solution is cooled, water is added, the mixture is stirred for 1 hour and the precipitate which is formed is separated off. After recrystallization from acetone/methanol, N-diaminomethylene-2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzamide is obtained, m.p. 194-196°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]([CH3:33])[CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH:34](O)=O.C=O.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]([CH3:33])[CH2:26][CH:27]2[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: O=CO
Reactant: Cc1cc(CN(C)CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(CN(C)CC2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 7-Methyl-5-[(methyl-piperidin-4-ylmethyl-amino)-methyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (30 mg, 0.065 mmol) in methanol (1.5 mL) was added formic acid (0.02 ml), formaldehyde (0.1 mL), and Sodium cyanoborohydride (0.2 mL, 0.1 M in THF) respectively. The mixture stirred at room temperature for 1 hour and was then diluted with water and extracted with ethyl acetate. The organics were washed with brin, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (15 mg, 38%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 2H), 7.21-7.14 (m, 4H), 4.78 (s, 2H), 4.22 (s, 2H), 3.48 (s, 2H), 2.94 (d, 2H), 2.75 (s, 3H), 2.33 (s, 3H), 2.23 (d, 2H), 2.16 (s, 3H), 2.01 (t, 2H), 1.84-1.80 (m, 2H), 1.54-1.51 (m, 1H), 1.25-1.20 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[CH2:9][CH2:8][CH2:7][N:6]3[S:5]1(=[O:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][N:4]3[C:14]4=[C:15]5[C:10](=[CH:11][CH:12]=[CH:13]4)[CH2:9][CH2:8][CH2:7][N:6]5[S:5]3(=[O:17])=[O:16])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: O=S1(=O)N(CCCl)c2cccc3c2N1CCC3
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCN2CCN(c3ccc(F)cc3)CC2)c2cccc3c2N1CCC3
Yield: 16.4 %

Procedure:
A solution of 1-(2-chloroethyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (3.4 g), 4-(4-fluorophenyl)piperazine (2.25 g) and triethylamine (1.75 cc) in dry N,N-dimethylformamide (50 cc) is heated to reflux for 3 hours and is then cooled and poured into a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height) and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 33 to 43 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from isopropyl ether (50 cc), 1 -[2-(4-(4-fluorophenyl)-1-piperazinyl)ethyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (0.85 g) is obtained, melting at 118° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1N.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N(OC(C)(C)C)=O>CCCCCCC>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1c(F)cc(F)c(F)c1F
Reactant: c1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CCCCCCC
Product: Fc1cc(F)c(-c2ccccc2)c(F)c1F

Procedure:
A stirred solution of 2,3,4,6-tetrafluoroaniline (50 g, 0.30 mole) in benzene (236.6 g, 3.03 mole) was heated under reflux. During a 45 minute period, t-butyl nitrite (46.8 g, 0.455 mole) was added to the reaction mixture. After complete addition the mixture was heated at reflux for 23/4 hours. n-Heptane (1 l) was added, and the solvent was distilled from the reaction flask until a head temperature of 101° was reached. The pot residue was cooled and subjected to column chromatography on silica gel, elution first with n-heptane, then toluene, to give 2,3,4,6-tetrafluoro-[1,1'-biphenyl] (mp, 89°-90°).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Cl:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Cl)c1-c1nccs1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nccs1
Yield: 1.3 %

Procedure:
The title compound was prepared from 4-chloro-3-(thiazol-2-yl)thiophen-2-amine (0.4 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (165 mg, 0.8 mmol) according to protocol A. The crude product was purified by column chromatography (4% methanol/methylene chloride) and HPLC to afford N-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (2.1 mg) as a white solid. LCMS m/z of 405.1/407.1 and retention of 3.670 min using the [7] LCMS method. 1H-NMR (300 MHz, CDCl3) δ 8.36 (d, J=4.9 Hz, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1, 5.1 Hz, 1H), 7.36 (d, J=3.4, 1H), 6.82 (s, 1H), 4.92 (s, 2H), 3.44 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12].C(OC)(=O)[CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][C:16](=[O:17])[CH:12]=[C:11]([OH:13])[CH2:10]1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)/C=C/c1ccc(F)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1

Procedure:
To a 500 mL recovery flask was added (E)-4-(2-bromo-4-fluorophenyl)but-3-en-2-one (1B, 11.9 g, 49.0 mmol, 1.0 eq.) and MeOH (200 mL). Dimethyl malonate (1C, 6.47 g, 49.0 mmol, 1.0 eq.) was added, followed by NaOMe (30% wt in MeOH, 9.6 mL, 51.4 mmol, 1.05 eq.). The reaction mixture was refluxed overnight upon which it was concentrated to a brownish-red solid. The residue was taken up in 1N NaOH (150 mL) and refluxed for 1 h, during which the reaction color proceeded from cloudy-brown, to clear brown, to clear solution with brown precipitate. Concentrated HCl was carefully added until the mixture was acidic by pH paper. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl. The aqueous phase was extracted with EtOAc (lx 75 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a foamy orange solid that was carried on to the next step without further purification (14.3 g, 100%). ESI-MS: m/z 285.2 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][C:2]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C)C=O>[Cl:19][CH2:20][C:21]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:1]=[C:2]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=[C:4]2[CH2:13]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cn2c(n1)CNc1ccccc1-2
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)CCl)c1ccccc1-2
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 2 g of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate in 20 ml of dry dimethylformamide was treated with 2 ml of chloroacetyl chloride and the mixture was stirred overnight. A white solid settled out and was filtered off and crystallized from ethanol to obtain 2.27 g (86% yield) of ethyl 4,5-dihydro-5-chloroacetylimidazo[1,2-a]quinoxaline-2-carboxylate melting at 178°-83° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=1.[C:24](=O)([O:27]C)[O:25]C>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH2:23][C:24]([OH:27])=[O:25])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of diisopropylamine (13.26 mL, 93 mmol, 4.0 equiv.) in THF (50 mL) was slowly added n-BuLi (37.2 mL, 93 mmol, 4.0 equiv.) at −78° C. The mixture was allowed to warm to 0° C. and stirred at that temperature for 5 min. The reaction was cooled back to −78° C. and to this mixture was slowly added 4-bromo-2-methylbenzoic acid (5.0 g, 23.25 mmol) and dimethyl carbonate (3.91 mL, 46.5 mmol, 2.0 equiv.) in THF (50 mL) and the mixture was stirred at −78° C. for 5 min. The dry ice bath was removed and the reaction was allowed to stir at room temperature for 4 h. Upon completion of the reaction, the mixture was quenched by the addition of 75 mL water and allowed to stir overnight. The aqueous layer was separated from the organic layer. The aqueous layer was acidified with conc. HCl until pH 2, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a white solid. The solid was recrystallized from hot EtOAc/hexanes to yield 5.65 g of 4-bromo-2-(carboxymethyl)benzoic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CN(C=O)C>[CH3:12][S:13]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
m-Nitrobenzyl chloride (4.21 g, 24.5 mmol) was dissolved in DMF (40 mL) and added sodium methanesulfinate (3.00 g, 29.4 mmol) and the resulting mixture was stirred at room temperature for 16 hours. After evaporation of the solvent in vacuo the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL) and the combined organic phases were dried (MgSO4) and evaporated in vacuo to afford 4.45 g (84%) 1-methylsulfonylmethyl-3-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([CH3:27])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH:29]1[CH2:33][C:32](=[O:34])[NH:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([CH3:27])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:29]4[CH2:33][C:32](=[O:34])[NH:31][CH2:30]4)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1C(=O)O
Reactant: O=C1CNCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (5 mL), imidazolidin-4-one hydrochloride (27.05 mg, 0.22 mmol, 1.00 equiv), HOBt (32.92 mg, 0.24 mmol, 1.10 equiv), triethylamine (33.59 mg, 0.33 mmol, 2.10 equiv), EDCI (63.85 mg, 0.33 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1). This resulted in 80 mg (68%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[Cl:15][C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[OH:24]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[C:20]([S:22][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:19]=[C:18]([Cl:23])[C:17]=1[OH:24]
Reactant: Oc1c(Cl)cc(S)cc1Cl
Reactant: C=CC(=O)N(C)CCc1ccccn1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(Cl)c(O)c(Cl)c1

Procedure:
The title compound was prepared according to the method of Example 4, from N-methyl-N-[2-(2-pyridinyl)-ethyl]-2-propenamide (2.5 g. 0.013 mole), 2,6 dichloro-4-mercaptophenol (2.56 g, 0.013 mole) and triethylamine (5 ml), m.p. about 120°-123° C. Analysis calc. for C17H18N2O2Cl2S (385.31): Calc.: C, 52.97; H, 4.71; N, 7.27; Cl, 18.40; S, 8.32. Found: C, 53.18; H, 4.89; N, 7 34; Cl, 18.59; S, 8 05.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19]>CS(C)=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=2)=[CH:14][C:13]=1[F:19]
Reactant: Nc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
Sodium hydride (1.1 g) was suspended in dimethyl sulfoxide (60 ml) under a nitrogen stream, and 4-chloro-2-pyridinamine (2.9 g) described in WO 02/32872 and then 4-amino-3-fluorophenol (3.6 g, 28 mmol) were added thereto at room temperature while stirring, followed by stirring under a nitrogen stream at 150° C. for 9 hrs. The reaction mixture was cooled down to room temperature, and partitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml). The organic layer was washed twice with 10% aqueous ammonia (150 ml). The combined aqueous layer was extracted with ethyl acetate (150 ml) again. The combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Crude fractions containing the target compound were concentrated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (1.3 g, 26%) as a purple solid.
Reaction SMILES: ClC(OCC(C)C)=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17](O)=[O:18])[CH:10]=1.CN1CCOCC1.[BH4-].[Na+]>COCCOC.O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[CH2:17][OH:18])[CH:10]=1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN1CCOCC1
Product: OC/C=C/c1cccnc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Isobutyl chloroformate (4.4 ml) was added dropwise to a suspension of (E)-3-(3-pyridyl)acrylic acid (5.0 g) and N-methylmorpholine (4.05 ml) in 1,2-dimethoxyethane (50 ml) under −18° C. After being stirred at the same temperature for 0.5 hour, a solution of sodium borohydride (1.86 g) in water (10 ml) was added to the mixture all at once. The resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-1-ol (1.0 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[NH2:33])([CH3:25])[CH3:24]>>[CH:39]([N:26]([CH:23]([CH3:24])[CH3:25])[CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([NH:33][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])([CH3:41])[CH3:40]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OCCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN(C(C)C)C(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-diisopropylaminoethoxy)-4-methoxyaniline (D4) following a procedure similar to that described in Example 1 (27%) mp 130°-131° C.