Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[C:4]([N+:20]([O-])=O)[C:3]=1[NH:23][C@@H:24]1[CH2:29][C@@H:28]2[CH2:30][C@@H:26]([C:27]2([CH3:32])[CH3:31])[C@H:25]1[CH3:33].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:20][C:4]1[C:3]([NH:23][C@@H:24]2[CH2:29][C@@H:28]3[CH2:30][C@@H:26]([C:27]3([CH3:31])[CH3:32])[C@H:25]2[CH3:33])=[C:2]([Br:1])[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:11])[N:5]=1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c([N+](=O)[O-])nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c(N)nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Yield: 43.1 %

Procedure:
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (32 mg, 0.0616 mmol) in ethyl acetate (3 mL) was stirred with tin (II) chloride dihydrate (72 mg, 0.319 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was basified to pH 9-10 with aqueous sodium hydroxide and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=6/1) to give the desired product (13 mg, 43% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:48])[CH3:47]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added N,N-diisopropylethylamine (6.0 equiv.) and acetyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 0. h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-{[4′-({[5-(acetylamino)-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine. LCMS MH+ (m/z) 550. 1H NMR (300 MHz, DMSO-d6): δ 10.50 ppm (s, 1H), 9.92 ppm (s, 1H), 8.00-7.34 ppm (m, 12H), 3.33 ppm (m, 1H), 1.89 ppm (s, 3 H), 1.76 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)C(C)C)(C)C.[F:15][C:16]([F:23])([F:22])[C:17](=[CH2:21])[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]([C:16]([F:23])([F:22])[F:15])=[CH2:21]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(=O)N(C)OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
16.6 g (167 mmol) of N,O-dimethylhydroxylamine hydrochloride were suspended in 900 ml of CH2Cl2 and 29.1 ml (167 mmol) of N,N-diisopropylethylamine added dropwise at 0° C. The resulting solution was added dropwise to a solution of 20.0 g (143 mmol) of 2-(trifluoromethyl)propenoic acid in 500 ml of CH2Cl2 at −40° C. Afterwards, 34.5 g (167 mmol) of N,N′-dicyclohexylcarbodiimide were added and the mixture stirred at 0° C. for 16 h. The resulting suspension was then filtrated and the filtrate carefully evaporated (the desired product is volatile!). Afterwards, 100 ml of n-pentane were added and the suspension stirred for 30 minutes at ambient temperature. The precipitate was removed by filtration, the filtrate was carefully evaporated. Chromatography on silica gel using ethyl acetate/n-pentane 1:4 yielded 22.8 g of the desired product. Rt=0.56 min (Method P).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])([CH3:23])C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1([CH3:23])[CH2:28][O:27][C:25](=[O:26])[NH:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCc1ccccc1OCc1ccccc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CCc2ccccc2OCc2ccccc2)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a solution of ethyl 4-(2-benzyloxyphenyl)-2-methoxycarbonylamino-2-methylbutanoate (5.2 g) in tetrahydrofuran (135 ml), under a nitrogen atmosphere, lithium borohydride (0.59 g) was added and the mixture was refluxed under heating for an hour. Then, a 2N hydrochloric acid (6.6 ml) was added thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (4.6 g).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[C:14]([N:21]([CH3:33])[C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[C:17]([O:16][C:14]([N:21]([CH3:33])[C@@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]([O:32][CH2:2][C:3]#[N:4])=[O:31])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: N#CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)OCC#N
Reaction time: 12 h
Yield: 89 %

Procedure:
Chloroacetonitrile (1.1 mL) and DIPEA (258 mg, 0.341 mL, 1.99 mmol) were added to Boc-MePhe-OH (497 mg, 1.78 mmol) in tetrahydrofuran (5 mL) and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (20-35% ethyl acetate in hexanes) afforded 505 mg of a pale yellow oil in 89% yield. Rf 0.3 in 20% ethyl acetate in hexanes; 1H NMR (500 MHz, CDCl3): δ 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 4.72-4.68 (m, 2H), 4.53-4.52 (m, 1H), 3.27 (m, 1H), 3.11-3.02 (m, 1H), 2.67 (d, J=17 Hz, 3H), 1.36 (d, J=12 Hz, 9H); 13C NMR (125 MHz, CDCl3): δ 169.9, 155.5, 136.8, 128.9, 128.6, 128.4, 126.8, 126.7, 114.2, 80.8, 61.5, 48.7, 35.4, 33.0, 28.1; HRMS (ESI) m/z calcd for C17H22N2O4Na [M+Na]+ 341.147. found 341.149.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
1-[1-(4-Chloro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]-pyrimidine was prepared according to General Procedure H by the reaction 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-chlorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.90-1.96 (m, 2H), 2.16-2.25 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.54 (s, 2H), 4.77-4.82 (m, 1H), 7.36-7.42 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH3:22])[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[N:16]=[C:17]([CH3:22])[CH:18]=[C:19]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:20]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(trifluoromethyl)phenylboronic acid (116.52 g, 613.5 mmol) in 1,2-dimethoxyethane (1200 mL) was added 2,4-dichloro-6-methylpyrimidine (100 g, 613.5 mmol). To this stirring solution was added a solution of sodium carbonate (195.07 g, 1840.5 mmol) dissolved in water (600 mL) giving some precipitation of the base and then bis(triphenylphosphine)palladium (II) dichloride (2.15 g, 3.07 mmol). The mixture was brought to 50° C. over about 1 hr then stirred at this temperature overnight. The reaction mixture cooled to approx. 30° C., filtered and washed with DCM (approx. 500 mL). The filtrate was evaporated to remove the bulk of the organic solvents. To the residues was added DCM (250 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×250 mL) and the combined extracts were washed with brine (250 mL), dried over magnesium sulphate, filtered and evaporated to a brown gummy solid. The solid was stirred in iso-hexane (150 mL) at 60° C. until the solid had dissolved. The heat was turned off and the flask allowed to cool in the heat-on block naturally. When the solution was at 30° C. seed crystals were added causing immediate crystallisation. The mixture was stood overnight then the crystalline material was crushed and filtered. The solids were washed with cold iso-hexane (2×50 mL) and dried to give the title compound (D5) as a slightly sticky tan solid, (96.17 g) consistent by NMR with that prepared by Method 1.
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([OH:19])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC([CH:26]([S+]([O-])CC(N)=O)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=CC=1.C[CH:40]([NH2:47])C1C=CC=CC=1>>[CH:1]([S:14]([CH2:16][C:17]([O-:19])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:40][NH:47][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Reactant: CC(N)c1ccccc1
Product: CNCc1ccccc1
Product: O=C([O-])CS(=O)C(c1ccccc1)c1ccccc1

Procedure:
Lafon also disclosed the use of an intermediate, a racemic mixture of benzhydrylsulphinylacetic acid to prepare an isomer of modafinil in U.S. Pat. No. 4,927,855, referring to French patent 2,326,181B. The racemic mixture of the acid was reacted with the (−)-α-methylbenzylamine to provide the (−)-benzhydrylsulphinylacetate of (−)-methylbenzylamine which is acidified with concentrated hydrochloric acid to provide (−)benzyhydrylsulphinylacetic acid. The levo-acid thus produced was then reacted with methylsulfate in water and sodium bicarbonate to provide methyl(−)benzhydrylsulphinylacetate. The acetate was then amidated with ammonia gas to provide (−)benzhydrylsulphinylacetamide.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C(N(CC)CC)C.CN(C=O)C>C(OCC)C.[Cu]I.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>[CH3:28][Si:29]([C:32]#[C:33][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NCc1ccc(Br)nc1)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 16 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide (105 mg, 0.247 mmol), trimethylsilyl acetylene (0.105 mL, 0.741 mmol), copper(I) iodide (4.7 mg, 0.025 mmol) and Pd(PPh3)2Cl2 (8.7 mg, 0.012 mmol) was added triethylamine (1.0 mL) and anhydrous DMF (0.25 mL). After 16 hours, the mixture was diluted with diethyl ether (50 mL) and quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was washed with saturated aqueous ammonium chloride (50 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude solid was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide as a tan solid.
Reaction SMILES: O1CCCC1.[C:6]12(N)[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[CH2:14]([N:16](CC)CC)C.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23]>C(OCC)C>[CH:6]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH2:8][CH:7]2[CH2:14][NH:16][S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25]
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)Cl
Reactant: NC12CCC(CC1)C2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Into a dry 1 lit. round bottom flask equipped with a magnetic stirrer, condenser and an addition funnel was added 500 ml of dry distilled tetrahydrofuran, 63 g (0.51 moles) of norbornyl amine and 125 ml (0.41 moles) of triethylamine. The reaction mixture was cooled to 0° C. To the mixture was added via the additional funnel 65 g (0.495 moles) of propanesulfonyl chloride and the reaction mixture was stirred overnight. The reaction mixture was filtered to remove the triethylammonium hydrochloride salt and the filtrate was rotovaped to remove tetrahydrofuran, resulting in an solid. The solid was dissolved in diethylether, and the resulting solution was extracted several times with deionized water. After treating with decolorizing carbon and drying over anhydrous sodium sulfate, the solution was filtered and the solvent was removed by rotary evaporation. The solid product was recrystallized from hexane's and dried under reduced pressure to yield 85%, mp 51-52° C. The product was identified by 1H and 13C NMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:19])=O>>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
In 2 ml of thionyl chloride was dissolved 1.03 g of 4-hexyloxybenzoic acid and the solution was refluxed for 1 hour. The excess thionyl chloride was distilled off and the residue was dried in vacuo to give 4-hexyloxybenzoyl chloride. Separately, 1.00 g of 2-(2-aminophenylthio)benzonitrile and 0.89 g of triethylamine were dissolved in 10 ml of ether and while the solution was stirred with ice-cooling, a solution of the above 4-hexyloxybenzoyl chloride in 5 ml of ether was added. The mixture was stirred overnight. Next morning, water and an aqueous solution of sodium hydrogen carbonate were added in the order mentioned and the resulting precipitate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane to give 1.27 g of the title compound as white prisms.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(NC(C)C)(C)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1.56 g) and diisopropylamine (1.68 ml) in dichloromethane (20 ml) was added dropwise under ice-cooling phenyl chloroformate (1.51 g). After stirring the mixture at room temperature overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Crystallization of the residue from diisopropyl ether afforded phenyl 4-fluoro-2-nitrophenylcarbamate (0.79 g, 29%) as crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[CH2:19]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH3:20].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.CO>[CH2:19]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]3[C:7]4[CH:18]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=4[O:10][C:9]3=[O:11])[CH2:17][CH2:16]2)[CH2:24][CH2:23]1)[CH3:20]
Reactant: CCOC1CCC(=O)CC1
Reactant: O=c1oc2ccc(F)cc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCO[C@H]1CC[C@H](N2CCC(n3c(=O)oc4ccc(F)cc43)CC2)CC1
Reaction time: 2 h

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one hydrochloride D138 (0.2 g), 4-(ethyloxy)cyclohexanone (WO2007107566) (0.2 g), and Hunig's base (0.1 g) in N-methylpyrrolidone (5 mL) was stirred for 2 hours then treated with sodium triacetoxyborohydride (0.5 g) was added and stirring was continued for four days. The mixture was diluted with methanol, loaded onto a SCX column and the column was eluted with methanol followed by 2M ammonia in methanol. The methanolic ammonia fractions were evaporated and the residue was purified by high pH MDAP. Two peaks were collected and evaporated separately. The fast eluting isomer gave 3-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one E52 as a white solid (7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH2:29][OH:30])[CH:28]=1)[CH2:5][NH:6][C:7]([NH2:25])=[N:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][S:14][C:15]=1[CH3:16])=[O:10].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].[CH3:44][N:45]1C[CH2:49][O:48][CH2:47][CH2:46]1.COCCN>C(Cl)Cl>[CH3:49][O:48][CH2:47][CH2:46][NH:45][C:44](=[O:33])[O:30][CH2:29][C:27]1[CH:26]=[C:4]([CH2:5][NH:6][C:7]([NH2:25])=[N:8][C:9]([C:11]2[C:12]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:13][S:14][C:15]=2[CH3:16])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:28]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(-c2nsc(C)c2C(=O)N=C(N)NCc2cc(Cl)cc(CO)c2)cc1
Reactant: CN1CCOCC1
Agent: COCCN
Solvent: ClCCl
Product: COCCNC(=O)OCc1cc(Cl)cc(CNC(N)=NC(=O)c2c(-c3ccc(OC)cc3)nsc2C)c1
Reaction time: 1.5 h

Procedure:
N-((3-chloro-5-(hydroxymethyl)benzylamino)(amino)methylene)-3-(4-methoxyphenyl)-5-methylisothiazole-4carboxamide (Example 251) (20 mg) was treated with 4-nitrophenyl chloroformate (45 mg) and N-methyl morpholine (100 mg) in CH2Cl2 overnight, then 2-methoxyethanamine (30 mg) was added and stirring continued for 1.5 hours. The title compound was obtained as a white solid after HPLC purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].BrC1C=CC(C[NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])=[CH:4][C:3]=1[Cl:10]
Reactant: O=Cc1ccc(Br)c(Cl)c1
Reactant: COC(CNCc1ccc(Br)cc1)OC
Product: COC(CNCc1ccc(Br)c(Cl)c1)OC

Procedure:
Starting from 4-Bromo-3-chloro-benzaldehyde, the title compound was prepared by the method described for (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1). Rt=0.94 min (Method C). Detected mass: 308.3/310.3 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:14]([CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[C:13]([C:29]([O:31][CH3:32])=[O:30])[C:12]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[C:14]([CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[C:13]([C:12]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:11][CH:10]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of tert-butyl 2-{2-[6-bromo-3-(2,2-dimethylpropionylamino)-2-methoxycarbonylphenyl]-ethyl}-pyrrolidine-1-carboxylate (Intermediate 36, 2.54 g) in DCM (15 mL) and the mixture was left to stand at room temperature for 30 minutes. The resultant solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and potassium carbonate solution. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give methyl 3-bromo-6-(2,2-dimethylpropionylamino)-2-(2-pyrrolidin-2-yl-ethyl)benzoate (2.05 g) as a white foam.