Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1.CC1C=CC(S([O-])(=O)=O)=CC=1>[I-].[K+].C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:27]3[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: O[C@@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@@H](O)C1
Yield: 97.1 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole), anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium iodide (0.007 g, 0.04 mmol) and (3R)-pyrrolidin-3-ol 4-methylbenzenesulfonate (salt) (See Intermediate 52) (0.13 g, 0.51 mmol) to give the title compound as a pale orange oil (0.15 g): MS (m/e) (79Br/81Br): 351, 353(M+1)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[C:12]1([CH3:33])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.O>C1COCC1>[C:12]1([CH3:33])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]([OH:30])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:32]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: [Li]CCCC
Reactant: Cc1ccccc1-c1cccc(Nc2ccc(C=O)cc2)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC(O)c1ccc(Nc2cccc(-c3ccccc3C)c2)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (28.5 mL of a 2.5 M hexane solution, 71.3 mmol) was added dropwise to a slurry of 2,5-bis(triphenylmethylenephosphonium)-1,4-dimethoxybenzene (26.8 g, 35.2 mmol) in dry THF (450 mL) at −78° C.; the reaction mixture immediately became very dark. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 2 h before recooling to −78° C. and adding a solution 4-(m-tolylphenylamino)benzaldehyde (21.2 g, 73.8 mmol) in dry tetrahydrofuran (100 mL) dropwise. The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 2 h before cautiously adding water (300 mL). The mixture was extracted with diethyl ether until the extracts were almost colorless and the combined ether layers were dried on magnesium sulfate. After filtration silica gel was added and the solvent removed under reduced pressure leaving the product absorbed onto the silica The crude product was transferred to the top of a silica gel column which was eluted with toluene. The first fraction was found to be an approximately statistical mixture of the geometric isomers of 3,5-bis[4-(m-tolylphenylamino)styryl]-1,4-dimethoxybenzene. Further elution gave a trace of an unidentified material, possibly impure 1-[4-(m-tolylphenylamino)phenyl]-pentan-1-ol on the basis of its 1H NMR spectrum, and then 4-(m-tolylphenylamino)benzaldehyde. The mixed isomers were dissolved in toluene (1 L) and heated under nitrogen with a few crystals of iodine. After 48 h, the solution was passed through a silica plug. The solvent was removed under reduced pressure and the solids were recrystallized from hot toluene to afford the pure E,E isomer as a bright yellow powder (12.82 g, 18.2 mmol, 52%). 1H NMR (CD2Cl2) δ 7.43 (d, J=8.6 Hz, 4H), 7.36 (d, J=16.5 Hz, 2H), 7.27 (t, J=ca. 8 Hz, 4H), 7.19-7.00 (m, ca. 16H), 6.94 (br s, 2H), 6.91-6. (br m, 4H) 3.91 (s, 6H), 2.27 (s, 6H); 13C NMR (75 MHz, CD2Cl2) δ 151.7, 148.0, 147.8, 147.7, 139.6, 132.2, 129.5, 129.4, 128.5, 127.6, 126.7, 125.7, 124.7, 124.4, 123.7, 123.2, 122.2, 121.6, 109.0, 56.6, 21.5; UV (THF) λmax 305 (ε305 37000), 426 (ε426 84000) nm; m.p 254° C.; High resolution EIMS calcd. for C50H44N2O2 M+ 704.3403, found 704.3404; Anal. calcd for C50H44N2O2: C, 85.20; H, 6.29; N, 3.97. Found: C, 85.44; H, 6.40; N, 3.86.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH:20]([NH:24]C(OC(C)(C)C)=O)[CH:21]([CH3:23])[CH3:22])=[N:8][CH:7]=1)=[O:5])[CH3:2].Cl.O1CCOCC1.[C:39]([O:43][C:44](=[O:50])[NH:45][CH2:46][CH2:47][CH:48]=O)([CH3:42])([CH3:41])[CH3:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH:20]([NH:24][CH2:48][CH2:47][CH2:46][NH:45][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:50])[CH:21]([CH3:23])[CH3:22])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CCOC(=O)c1cnc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To 1-Benzyl-2-(1-tert-butoxycarbonylamino-2-methyl-propyl)-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (14.22 g from previous step) was added a solution of 4M HCl in 1,4-dioxane (50 mL, 200 mmol) and the reaction was stirred at room temperature for 2.0 h. The reaction was concentrated in vacuo and the residue was dissolved in water and washed with ether. The aqueous layer was basified with 1 N NaOH and extracted into ether. The ether layer was washed with water, dried (Na2SO4), and concentrated to give a crystalline orange solid. This solid (7.08 g, 21.5 mmol) was dissolved in dry CH2Cl2 (100 mL) and to this was added (3-Oxo-propyl)-carbamic acid tert-butyl ester (3.076 g, 17.76 mmol) in dry CH2Cl2 (50 mL) followed by portionwise addition of sodium triacetoxyborohydride (5.65 g, 26.64 mmol). The reaction was stirred for 72 h at room temperature under N2 at which time the reaction was made basic with saturated sodium bicarbonate. The layers were separated, the aqueous layer was extracted with methylene chloride, and the combined organics were washed with brine, dried (Na2SO4), and evaporated to dryness. The residue was purified by flash chromatography on silica gel (1:1 hexanes:EtOAc) to give the title compound as a pale yellow foam (5.59 g, 32%, 3 steps). MS(ES+) m/e 487 [M+H]+.
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:14]1([C:20](OC)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]1([NH:9][C:10]2[S:11][C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:20](=[O:21])[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: NC(=S)NC1CCCCCCC1
Product: O=C1N=C(NC2CCCCCCC2)SC12CCCCC2

Procedure:
Synthesis was performed from N-cyclooctylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonylvaline (1.0 g, 4.6 mmol) and pyridine (0.39 ml) in methylene chloride (11 ml) is dropped cyanuric fluoride (1.87 g, 13.8 mmol) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylvaline fluoride.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:7](=[O:15])[CH:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.IC.[CH3:22]C([O-])(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:13])[CH3:14])[C:7](=[O:15])[C:6]3([CH3:22])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Reactant: CC(C)(C)[O-]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reaction time: 8 h
Yield: 7.8 %

Procedure:
2-Chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (1.20 g, 4.24 mmol) and iodomethane (1.324 mL, 21.22 mmol) were mixed in DMSO. The mixture was frozen, 2-methylpropan-2-olate (1.224 g, 12.73 mmol) was added, covered by a layer of DMSO and refrozen. The mixture was allowed to room temperature and stirred overnight. Another 1 eq of 2-methylpropan-2-olate and iodomethane was added and the mixture stirred overnight at 30° C. The solution was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was absorbed onto silica and purified by column chromatography using 10-60% EtOAc in hexanes then 5% methanol in dichloromethane as eluent. Relevant fractions were evaporated in vacuo to give 98 mg (8%) 2-chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] Found 297.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[O:25][CH2:26][CH2:27][NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g 4-(oxirane-2-ylmethoxy)-9H-carbazole (II), 80.0 g of 2-(2-methoxyphenoxy)ethylamine hydrogenchloride monohydrate (IV) and 52.4 g of anhydrous calcium carbonate in 330 ml isopropanol is, with intensive stirring, heated at 80° C. for 4 hours. When the epoxide has reacted, the mixed salts are filtered off from the reaction mixture and isopropanol is distilled off from the filtrate. The obtained honey-like concentrate is dissolved, when hot, in 210 ml of ethylacetate, the solution is cooled to the temperature of 40° C., inoculated and stirred at the temperature of 40° C. for 30 minutes. After the crystal precipitates, the mixture is cooled to 0° C., and is kept like that with stirring for a minimum of four hours. After filtration and washing with cooled ethylacetate, 65 to 70 g of wet crude Carvedilol is obtained (HPLC contents>98 area %, HPLC contents of the bis-derivative 1.2-1.5 area %).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8]O.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8][Cl:33]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
34.8 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl alcohol were suspended in 200 parts by volume of absolute toluene, 8 parts by weight of pyridine were added, and 13.1 parts by weight of thionyl chloride were added dropwise at 0° C. Thereafter the reaction mixture was stirred for a further 2 hours at 110° C., was cooled, and was extracted with 75 parts by volume of 3N hydrochloric acid and with five times 250 parts by volume of water. The organic phase was separated off, dried with magnesium sulfate and concentrated under reduced pressure. 32 parts by weight (88% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl chloride were obtained in the form of an initially oily residue which crystallized when triturated with pentane, to give crystals of melting point 55°-60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=C(C)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11]([OH:14])(=[O:13])[CH3:12]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:12]([CH:7]=[CH:8][CH:9]=1)[C:11]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 3.33 h
Yield: 75.5 %

Procedure:
Similarly to Example 1, 250 g of m-nitrotoluene was oxidized in the presence of 150 g of acetic acid, 4.5 g of cobalt acetate tetrahydrate and 2 g of sodium bromide at a pressure of 25 bar, a temperature of 135°-145° C. and a gas exhaust rate of 3 1/min, within a period of 200 minutes. The reaction mixture, diluted with 400 g of 69% acetic acid, was cooled to 5° C. with stirring, filtered, twice washed with 125 g of 50% acetic acid at 5° C. and once with 150 g of water, the mother liquor (514.5 g) and the combined washing filtrates (441 g) being recovered separately. After drying, 230 g of m-nitrobenzoic acid was obtained.
Reaction SMILES: [N+]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].C(O)C>C(OC(=O)C)C.O>[CH2:8]([CH:9]([C:10]#[N:11])[C:12]#[N:13])[C:7]1[CH:14]=[CH:15][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(C#N)=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
4.5 Grams of 4-nitrobenzylidenemalononitrile, prepared according to Example 1, was dissolved in 200 milliliters of ethylacetate. To this was added an aqueous solution of 0.54 gram of sodium borohydride in 5 milliliters of water, and the mixture was stirred at ambient temperature for 1/2 hour. The organic layer was separated, using a separatory funnel, and washed three times with water. The organic extract was dried over anhydrous sodium sulfate, and evaporated to dryness. The crude reaction product was crstallized from ethanol to obtain 3.07 grams(67.5% yield) of the product. IR(nujol) analysis showed bands at 3100, 2950-2850, 2250, 1980, 1595, 1505, 1450, 1440, 1370, 1340, 1290, 1175, 1100, 1010, 885, 860, 845, 755 and 710 cm-1. NMR analysis (CDCl3) showed signals at 8.30 (d, 2H, J=7.8 Hz), 7.56 (d, 2H, J=7.8 Hz), 4.05 (t, 1H, J=6.3 Hz) and 3.42 (d, 2H, J=6.3 Hz) ppm. Elemental analysis: C10H7N3O2 requires: C=59.7; H=3.48; N=20.90%. Found: C=59.62; H=3.39; N=20.81%.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1c1cc(Cl)nc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CO[C@H](CN=[N+]=[N-])CN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A mixture of crude [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methyl methanesulfonate (1.53 g, about 85% pure, 3.88 mmol) and sodium azide (0.382 g, 5.88 mmol) in DMF (75 mL) was stirred at 80° C. under nitrogen for 20.5 hours. Another portion of sodium azide (0.094 g, 1.45 mmol) was then added and stirring continued at 80° C. for an additional 6.5 hours. The mixture was then cooled, diluted with EtOAc (200 mL), washed with water (2×150 mL) and brine (1×150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (60 g SiO2, 1:1 hexanes/CH2Cl2 to 45:45:10 hexanes/CH2Cl2/CH3CN gradient) to give the title compound (890 mg) as a thick colorless oil. LC-MS (ES) m/z=284, 286 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([N:7]([CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.1 %

Procedure:
To a solution of tert-butyl 4-((4-fluorobenzylamino)methyl)benzylcarbamate (654 mg, 1.90 mmol, Aldrich) in CH2Cl2 (5 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (497 mg, 0.50 mmol, Aldrich) and diisopropylethylamine (1.34 mL, 9.50 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution and brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (604 mg, 53%) as a white solid. MS (ESI): m/z 566.9.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=4)[C:28]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>O1CCCC1.CO.O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=4)[C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}acetate (136.8 mg, 0.263 mmol) in tetrahydrofuran (4 ml) was added a solution of lithium hydroxide-water (22.1 mg, 0.526 mmol) in MeOH-water (1:1) (2.8 ml) at 5° C. and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N-hydrochloric acid (0.8 ml) at 5° C. and extracted with EtOAc. The organic layer was washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo to give (±)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}acetic acid (129.0 mg, 100%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1C=CC=CC=1.C(OCC)(=O)C.O>[C:1]([C:3](=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (11.0 mL, 126 mmol), ammonium acetate (0.976 g, 12.6 mmol) and acetic acid (0.715 mL, 12.6 mmol) were added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate 8-1 (25.0 g, 126 mmol) in 200 mL of benzene at ambient temperature. After stirring at reflux with azeotropic removal of water (Dean-Stark apparatus), the reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 mL). The organics were washed with saturated aqueous sodium bicarbonate, brine, dried (magnesium sulfate), and concentrated in vacuo to give a crude residue. Purification of the crude residue by recrystallization from 10% ethyl acetate/hexanes afforded 8-2 as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=34)[S:21]2(=[O:33])=[O:32])[CH2:14][CH2:13]1.[H-].[Na+].[CH3:36]I.O>CN(C)C=O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:36])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=34)[S:21]2(=[O:32])=[O:33])[CH2:16][CH2:17]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(CC2CCN(CCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2cc(F)ccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) in dimethylformamide (40 cc) is added in the course of 15 minutes to a 50% strength dispersion of sodium hydride (0.27 g) in liquid paraffin, under a stream of argon, while the temperature is maintained in the region of 20° C. The reaction medium is stirred for 1 hour at a temperature in the vicinity of 20° C. and a solution of methyl iodide (0.4 cc) in dioxane (20 cc) is then added in the course of 15 minutes. Stirring is maintained for 15 hours at a temperature in the vicinity of 20° C. The reaction mixture is taken up with distilled water (25 cc) and the organic phase is extracted with dichloromethane (4×50 cc), then washed with distilled water (25 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column under a stream of argon at moderate pressure (0.5-1.5 bar) with dichloromethane and then a mixture of ethyl acetate and methanol (97:3 by volume) as eluent. 2-{2-[4-((5-Fluoro-1-methyl-3-indolyl)methyl)piperidino]ethyl} naphtho[1,8-cd]isothiazole 1,1-dioxide (0.8 g) is obtained in the form of a yellow oil, which is converted to an acid oxalate, m.p. 150°-152° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 500 cm3 round-bottomed flask, equipped with a magnetic stirrer and pressure equalising dropping funnel, was added butanol (55,6 g, 0.75 mol), triethylamine (55.7 g, 0.55 mol) and dichloromethane (300 cm3). Methanesulfonyl chloride (57.3 g, 0.05 mol) was then added dropwise over a two-hour period from the dropping funnel, with cooling from an ice bath. The mixture was stirred for a further 24 hours at room temperature. The reaction mixture was filtered, concentrated on a rotary evaporator, and distilled (bp −80−90° C. at 5 mm Hg). This gave 68.1 g (98%) of a colourless oil.