Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:22][CH:21]=3)[N:10]2[CH3:32])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:22][CH:21]=3)[N:10]2[CH3:32])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccn3)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 2.7 g of 1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one, 1.8 g of potassium carbonate, 73 ml of ethanol and 8 ml of water was refluxed under heating for 9 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration and dried under reduced pressure. The resulting crude crystals were suspended in chloroform, and the suspension was adjusted to pH 2 to 3 with dilute hydrochloric acid. The crystals were collected by filtration and dried under reduced pressure to give 1.6 g of the title compound as pale gray crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].CC1C=CC(S(O[CH2:31][C@@H:32]2[CH2:34][O:33]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:31][C@@H:32]2[CH2:34][O:33]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Cl)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H]3CO3)c(=O)c1Cl)C2(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Chloro-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (120 mg, 0.425 mmol) in N,N-dimethylformamide (2 mL) was mixed with (2S)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (117 mg, 0.513 mmol) and potassium carbonate (71 mg, 0.0514 mmol) at room temperature and stirred at 80° C. for 3 hours. After cooling, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The resulting crude product was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:38]([O:40][CH2:41][C:42]#[CH:43])=[O:39]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:38]([O:40][CH2:41][C:42]#[CH:43])=[O:39])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Reactant: C#CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 500 mg, 0.96 mmol) and 4-dimethylaminopyridine (350 mg, 2.9 mmol) in dichloromethane (25 ml) at 0° C. under nitrogen was added propargyl chloroformate (170 mg, 1.44 mmol) and the resulting mixture stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with citric acid solution (3×50 ml) and water (2×50 ml), dried (MgSO4) and concentrated in vacuo to give a solid. The crude product was purified by flash chromatography on silica (40 g) eluting with hexane:ethyl acetate (3:2). The pure fractions were combined and concentrated in vacuo to give the title product (462 mg, 80%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([N:6]2[CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[O:22])[N:4]=[CH:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: ClCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
4-Chloromethyl-1-(3,4-dichloro-phenyl)-1H-imidazole (1.31 g, 5.0 mmol) was dissolved in DMF (10 ml), 2-imidazolecarboxaldehyde (0.48 g, 5.0 mmol) and cesium carbonate (0.82 g, 2.5 mmol) was added and the resulting mixture was stirred at 60° C. for 12 h. After evaporation of the solvent the residue was dissolved in AcOEt and washed with H2O. The organic phase was dried (Na2SO4), concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)] to obtain 0.98 g (61%) of the title compound as an off-white solid. Mp. 130-131° C. (CH2Cl2/iPr2O), MS: m/e=320 (M+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[O:6][C:5](/[CH:7]=[CH:12]/[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Br)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-furaldehyde (5.26 g, 0.0300 mol) and nitromethane (2.2 ml, 2.43 g, 0.0300 mol) in methanol (40 ml) were added to NaOH (1.20 g, 0.0300 mol) in water (40 ml) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then diluted with ice-cold water (25 ml). The resulting solution was added slowly to 10% HCl (10 ml) at <0° C. The separated precipitate was filtered off, washed with water and heptane and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6): 6.90 (1H, d), 7.30 (1H, d), 7.77 (1H, d), 7.96 (1H, d)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1Cl>O1CCCC1.CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1[O:1][CH2:2][CH:3]1[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1
Reactant: O=C1NCC2(CCC(CO)CC2)O1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cnc(OCC2CCC3(CC2)CNC(=O)O3)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 385C (325 mg, 1.755 mmol) in a mixture of tetrahydrofuran (16 mL) and N,N-dimethylformamide (8 mL) was added sodium hydride (281 mg, 7.02 mmol) and the mixture was stirred for 30 minutes. 5,6-Dichloropyridine-3-sulfonamide (389 mg) was added and the reaction was stirred for 42 hours. The reaction was quenched with water (5 mL) and concentrated. The residue was diluted with 75% brine (200 mL) and extracted with methylene chloride (3×200 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel and eluted with a 1, 5, and 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:12]#N)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:28].[Na+].[OH2:30].Cl>C(O)C>[C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:12]([OH:30])=[O:28])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
To a solution of the 1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carbonitrile (0.80 g, 2.2 mmol), prepared using procedures similar to those described in Kozikowski and Fauq Synlett 1991, 11, 783-4, in ethanol (30 mL) was added solid sodium hydroxide (7.5 mmol), and the resulting mixture was stirred at room temperature for 3 days. Water (6 mL) was added to the reaction mixture and stirring was continued at 90° C. for 2 h. The pH of the reaction mixture was adjusted to 5 with concentrated hydrochloric acid and a white solid precipitated. The mixture was cooled, diluted with water (50 mL) and the solid was collected, washed with water then dried in vacuo to give the 1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxylic acid (0.75 g, 88% yield), MS (EI) for C24H24N2O2: 373 (MH+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.CN(C=O)C.[Cl-].[Na+].O>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[CH2:26][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3ccccc3N2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of phenol (1.715 g, 18.22 mmol, 1.2 eq) in THF (100 mL) was slowly added sodium hydride (0.915 g, 22.87 mmol, 1.5 eq) and the reaction was stirred at rt 1 hour. (S)-2-(Toluene-4-sulfonyloxymethyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6.077 g, 15.14 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (50 mL) and DMF (50 mL) were added and the mixture was heated at reflux overnight. After cooling, it was poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (15/85) as an eluent to give the title compound as a colorless oil (3.371 g, 74%). NMR (400 Mz, DMSO-d6): consistent
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C(OCC)(=O)C>[CH2:1]([NH:3][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[Cl:4])[CH:9]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Yield: 90.7 %

Procedure:
Ethyl acetate (50 ml) was added to 1.4 g of an aqueous ethylamine solution (70%), and an ethyl acetate solution containing 3.0 g of 3-(2,5-dichlorophenoxy)benzoic acid chloride was dropwise added thereto with stirring, during which the reaction mixture was cooled in an ice bath. After the addition was finished, the mixture was stirred for 1 hour at room temperature. The reaction mixture was washed with 1 N hydrochloric acid, water, 1% aqueous sodium hydroxide solution and water saturated with sodium chloride in this order and dried over anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation to obtain 3.1 g of crude crystals. On recrystallizing the crude crystals from a benzene-hexane mixed solvent, 2.8 g of N-ethyl-3-(2,5-dichlorophenoxy)benzamide were obtained. Melting point, 74.5°-75.5° C. Elementary analysis: Calcd. for C15H13Cl2NO2 : C, 58.08%; H, 4.22%, N, 4.52%; Cl, 22.86%. Found: C, 58.16%; H, 4.25%, N, 4.49%; Cl, 22.97%. NMR: δCCl 4: 1.15 (t 3H), 3.34 (quintet 2H), 6.65-7.61 (8H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])N[C:5]([C:9]2([O:13][CH2:14][CH2:15][CH2:16]O)[CH2:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl-].[CH2:24](N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:1][C:2]1[C:7](=[O:8])[CH:24]2[CH2:16][CH2:15][CH2:14][O:13][C:9]3([CH2:12][CH2:11][CH2:10]3)[C:5]2=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1nc(C2(OCCCO)CCC2)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(=O)C2CCCOC3(CCC3)C2=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A cold (0° C.) solution of ethyl 5-hydroxy-2-(1-(3-hydroxypropoxy)cyclobutyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3.0 g, 9.6 mmol) in tetrahydrofuran (25 mL) was treated with methanesulfony chloride (3.30 g, 29 mmol) followed by dropwise addition of triethylamine (4.7 mL, 33.6 mmol). The reaction was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the mixture was dissolved in ethanol (50 mL) and dimethylformamide (25 mL). To the slurry was added potassium carbonate (1.36 g, 9.7 mmol) and the reaction was stirred at room temperature for 16 hours, followed by heating (80° C.) for 3 hours. The solvent was removed in vacuo. The crude product was diluted with ethyl acetate (50 mL) and washed with 1N hydrochloric acid (2×50 mL), extracted with ethyl acetate (2×25 mL) then brine ((50 mL). The solution was then dried (sodium sulfate), filtered and concentrated to give the title compound (0.534 g, 19%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ: 10.64 (1H, br s), 4.45 (2H, q, J=7.0 Hz), 4.38 (2H, br), 3.91 (2H, t, J=5.0 Hz), 2.81 (2H, br), 2.36-2.44 (2H, m), 1.87-1.97 (1H, m), 1.82-1.86 (2H, m), 1.67-1.75 (1H, m), 1.43 (3H, t, J=7.2 Hz).
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22].[ClH:24]>CCOCC>[ClH:24].[C:20]([CH2:21][CH2:22][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:23]
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCOCC
Product: N#CCCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A 10 ml round bottom flask was charged with 0.503 g of cis 1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine followed by 1 ml of acrylonitrile. The resulting mixture was stirred for 1/2 hour at room temperature under nitrogen and then heated at 60° for 1 hour. The reaction mixtue was diluted with 10 ml of ether and treated with 4 ml of ether saturated with HCl. After stirring for 15 minutes, the precipitated salt was filtered, washed with ether, and dried to give 0.68 g (99.8%) of crystalline solid, m.p. s 205, 213°-215°. Recrystallization from ethanol afforded 0.50 g (73.3%) of crystals, m.p. s 213, 216°-219°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21][N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCCCOc1cc2oc(=O)ccc2cc1OC1CCCC1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: O=c1ccc2cc(OC3CCCC3)c(OCCCN3CCN(c4ccccc4)CC3)cc2o1
Yield: 68 %

Procedure:
Method B (25 h at 40° C.); starting materials: 6-(cyclo-pentyloxy)-7-[3-(methanesulfonyloxy)propoxy]-2H-1-benzopyran-2-one (example 72) and 1-phenylpiperazine; yield 68%; fusion point 101°-103° C. (from TBME and isopropanol). Fumarate: method E; yield 88%; fusion point 171°-173° C. (from acetone).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[O:29]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Reactant: O=S1(=O)CCCN1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1
Yield: 24.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(p-tolyloxy)piperidin-1-yl]methanone (548 mg) described in Preparation Example 193 and isothiazolidine 1,1-dioxide (177 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (146 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I.BrC1C=CC(C(C)=C)=C([Cl:37])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[C:4]([Cl:37])[CH:3]=1
Reactant: CC1(c2ccc(Br)cc2)CC1
Reactant: C=C(C)c1ccc(Br)cc1Cl
Agent: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: CC1(c2ccc(Br)cc2Cl)CC1
Yield: 88 %

Procedure:
The title compound was synthesized in analogy to 1-bromo-4-(1-methylcyclopropyl)-benzene (described in example S87) using diethyl zinc (2.59 ml, 1M solution in hexane, 2.59 mmol), trifluoroacetic acid (200 μl, 2.59 mmol), CH2I2 (209 μl, 2.59 mmol) and 4-bromo-2-chloro-1-isopropenylbenzene (300 mg, 1.30 mmol). The isolated residue was purified by flash column chromatography (100% pentane) to give 4-bromo-2-chloro-1-(1-methylcyclopropyl)-benzene (280 mg, 88%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.48 (d, J=2.0 Hz, 1H), 7.30 (dd, J=2.0, 8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 1.32 (s, 3H), 0.81-0.73(m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH:12]([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:5][CH:4]=1.[Li+].[CH3:29]C([N-]C(C)C)C.IC.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][C:14]=3[O:13][C:12]([CH3:29])([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CC(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1ccc(CN2CC(C)(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 4[(4-methoxyphenyl)methyl]-6-(trifluoromethoxy)-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (290 mg, 0.76 mmol) in tetrahydrofuran (7 mL), under N2 atmosphere and cooled to −50° C., was added LDA (1.5 mL of 2 M, 3.03 mmol). The mixture was stirred for 2 h at −50° C. then treated with iodomethane (430 mg, 188 μL, 3.03 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. 30 mL water was added and the solution acidified to ˜pH 3 with 1 N HCl. The solution was extracted with ethyl acetate (3×10 mL) and the organic layer washed with brine, dried over Na2SO4, filtered and dried down to provide 4-[(4-methoxyphenyl)methyl]-2-methyl-6-(trifluoromethoxy)-3H-1,4-benzoxazine-2-carboxylic acid as an orange oil (300 mg, quantitative yield). LC/MS m/z 398.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 4.45 (d, J=15.7 Hz, 1H), 4.30 (d, J=15.7 Hz, 1H), 3.73 (s, 3H), 3.67 (d, J=11.8 Hz, 1H), 3.15 (d, J=11.8 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:17][C:18]([O:20][C:21]([CH3:24])(C)C)=[O:19])[C:5]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:7])[CH3:6].[CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[O:31][C:30]=2[C:29]([C:39]2[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].[C:54]1(C)C=CC=C[CH:55]=1>C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH:4]([NH:17][C:18]([O:20][CH2:21][CH2:24][CH2:54][CH3:55])=[O:19])[C:5]([S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:42]2[CH:43]=[CH:44][C:39]([C:29]3[C:30]4[O:31][C:32]5[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=5[C:34]=4[CH:26]=[CH:27][CH:28]=3)=[CH:40][CH:41]=2)=[CH:14][CH:15]=1)([CH3:6])[CH3:7]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)SCc1ccc(Br)cc1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCOC(=O)NC(C(=O)OC)C(C)(C)SCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(4-bromophenylmethylsulfanyl)-3,3-dimethylpropanoic acid methyl ester (0.432 g, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.305 g, 1.05 mmol) and Pd(PPh3)4 (0.052 g, 5 mol %) in toluene (10 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave the desired product (430 mg, 72%) as an oil. 1H NMR (CDCl3), δ 8.01 (d, J=8 Hz, 2 H), 7.94 (d, J=8 Hz, 2 H), 7.78 (d, J=8 Hz, 2 H), 7.66 (m, 4 H), 7.42 (m, 5 H), 5.44 (d, J=9 Hz, 1 H), 4.46 (d, J=9 Hz, 1 H), 3.87 (s, 2 H), 3.81 (s, 3 H), 1.44 (s, 9 H). LCMS 618 (M++23).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O1CCCC1.O.[OH-].[Li+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 80 °C
Yield: 96.5 %

Procedure:
Ethyl (1R,2R)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylate (2.0 g, 7.84 mmol., 1.0 eq.), water (60 mL) and tetrahydrofuran (50 mL) were charged into a 250 mL round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (0.523 g, 12.94 mmol., 1.65 eq.) was added portion wise and the reaction mixture heated at 80° C. for 15 hours. TLC analysis of the reaction mixture (heptanes:ethyl acetate, 1:1) showed full consumption of the starting material. The reaction mixture was left to cool down to ambient temperature and diluted with ethyl acetate (50 mL). The organic phase was discarded, and the aqueous phase washed further with ethyl acetate (50 mL). The aqueous phase was acidified to pH 3 by slow addition of 1M hydrochloric acid then extracted with ethyl acetate (2×80 mL). The organic extracts were pooled, washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated to dryness to give 1.72 g (96%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.67-5.86 (m, 1 H), 5.31 (d, J=17.10 Hz, 1 H), 5.18-5.28 (m, 1 H), 5.15 (d, J=10.32 Hz, 1 H), 2.20 (q, J=8.86 Hz, 1 H), 1.70-1.92 (m, 1 H), 1.50-1.65 (m, 1 H), 1.46 (s, 9 H). LC-MS: purity 100% (ELS), tR 1.56 min, m/z [M−H]-226.10.