Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[C:37]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]3[C:35]2=[O:44])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.73 g, 1.8 mmol), N-(2-bromoethyl)phthalimide (0.686 g, 2.7 mmol), triethylamine (0.5 ml, 3.6 mmol) and a catalytic amount of potassium iodide was dissolved in dry dimethylformamide (30 ml). The mixture was stirred for 24h at 70° C., cooled to room temperature and evaporated in vacuo. Water (60 ml) was added and extraction with methylene chloride (3×60 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded an oil. Purification twice on silica gel (Eluent 1: Heptane/ethyl acetate (1:1) and eluent 2: Petroleum ether/diethylether (2:1)) gave (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2-phthalimidoethyl)pyrrolidine (0.64 g, yield: 61%) as an oil.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([O:28][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of tri-n-butylphosphine (0.362 mL), methyl(7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (122.8 mg), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (102 mg) and THF (4.5 mL) was added ADDP (305 mg) at room temperature. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (196 mg). The compound was crystallized from EtOAc-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18](Cl)[N:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:31]([C:33]1[N:34]([C:18]2[N:17]=[C:16]3[C:21]([N:22]=[C:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[N:15]3[CH3:30])=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:19]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 83.1 %

Procedure:
A mixture of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)piperidine-1-carboxylic acid tert-butyl ester (375 mg, 0.858 mmol), 2-ethylbenzimidazole (151 mg, 1.03 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (421 mg, 1.29 mmol) in dioxane (5 mL) was degassed with nitrogen bubbling for 15 minutes. Tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol) was added and the mixture was heated to 120° C. for 20 hours. The reaction mixture was diluted with EtOAc, filtered, concentrated in vacuo and purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 40-90%) affording 647 (390 mg, 83%). LCMS: RT 4.54 min, [M+H]+ 547.24 1H NMR (400 MHz, DMSO): δ 8.00-7.99 (m; 1 H); 7.68-7.60 (m; 1 H); 7.25-7.24 (m; 2 H); 4.45-4.12 (m; 4 H); 4.12-4.01 (d; J=13.26 Hz, 2 H); 3.85-3.70 (m; 6 H); 3.25-3.10 (m, 4 H); 3.04-2.82 (m, 2 H); 2.00-1.90 (d; J=13.26 Hz, 2 H); 1.76-1.59 (m, 2 H); 1.43 (s; 9 H); 1.35 (t, J=7.44 Hz, 3 H).
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: NCc1ccccc1
Product: c1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and benzylamine (0.5 ml) as described above; yield: 0.072 g (26.2%); MS m/z: 276.5 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.39 (s, 2H); 6.99-7.01 (m, 2H); 7.20-7.29 (m, 3H); 7.63 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.83 (d, 1H, 3J=8.7 Hz); 7.93 (br s, 1H); 8.79 (s, 1H); 9.09 (s, 1H); HPLC (METHOD [A]): rt 7.81 min (100%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:37][CH2:36]1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclopropane (1.8 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.097 g, 9%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]>C(O)C>[CH:12](=[N:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]
Reactant: NC1CCOc2ccccc21
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1C=NC1CCOc2ccccc21
Reaction time: 8 h

Procedure:
A 90 g (0.60 mole) portion of 4-chromanamine and 450 ml of ethanol were placed in a 2-l, 3-necked flask, equipped with a stirrer and reflux condenser fitted with a drying tube, and treated with 75 g (0.61 mole) of salicylaldehyde. The reaction mixture was refluxed for 8 hrs., stored overnight at room temperature, cooled and filtered. The yellow crystalline solid was washed with 150 ml of ethanol, ether and dried; m.p. 123°-126°. Yield: 126 g (83%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=O)[S:5][C:6]=1[I:7].CN(C=O)C.N1C(Cl)=NC(Cl)=NC=1Cl>O>[I:1][C:2]1[CH:3]=[C:4]([C:8]#[N:10])[S:5][C:6]=1[I:7]
Reactant: NC(=O)c1cc(I)c(I)s1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(I)c(I)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
An oven-dried round-bottomed flask was charged with 4,5-diiodothiophene-2-carboxamide (5.68 g, 15.0 mmol) and 20 mL of DMF under an argon atmosphere. The solution was cooled on an ice-water bath, and cyanuric chloride (1.81 g, 9.8 mmol) was then added in one portion. After stirring at 0° C. for 1 h, the reaction mixture was warmed to room temperature, and stirred for a further 3 h. 100 mL of water was added. A white solid was formed, which was collected through suction filtration, washed with water, and dried together with phosphorous pentoxide under vacuum to afford 4.87 g (90%) of product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39](O)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=2)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29]
Reactant: CCOC(=O)c1ccc(NCC2CCCN2)cn1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
To a stirred mixture of ethyl 5-[(2-pyrrolidinyl)methylamino]pyridine-2 carboxylate (230 mg, 0.923 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (290 mg, 0.923 mmol), 4-DMAP (145 mg, 1.15 mmol) in DMF (7 ml) was added EDC.HCl (225 mg, 1.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica gel (30 ml) column chromatography with CHCl3-EtOH (98:2, v/v) as eluent to give ethyl 5-[[1-[3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]pyridine-2-carboxylate (400 mg, 80%) as fine needles. IR (KBr) n 3325, 1709, 1618, 1585, 1531 cm−; 1H-NMR (CDCl3) δ 1.39 (t, J=7 Hz, 3 H), 1.73–2.07 (series of m, 4 H), 2.28 (s, 3 H), 3.12 and 3.49 (each m, each 1 H), 3.60 (s, 2 H), 4.39 (br q, J=7 Hz, 2 H), 4.53 (m, 1 H), 6.07 (br s, 1 H), 6.23 (br s, 1 H), 6.75–6.77 (series of s and m, 2 H), 6.82 (dd, J=3.0 and 8.5 Hz, 1 H), 7.09–7.22 (series of m, 3 H), 7.49 (d, J=8.0 Hz, 1 H), 7.90 (d, J=8.5 Hz, 1H), 7.98 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H); MS (FAB) m/z 546 (M++1); Anal. Calcd for C30H35N5O5.1.5×H2O: C, 52.92; H, 6.69; N, 12.23. Found: C, 63.11; H, 6.48; N, 11.96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>C(=O)(O)[O-].[Na+].O1CCCC1>[C:15]([CH:10]([CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12])([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(CCC(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 4 h
Yield: 51.6 %

Procedure:
4-(4-aminophenyl)butanoic acid (250 mg, 1.4 mmol) in a 10 mL flask was dissolved in a mixture of 10% aqueous sodium bicarbonate (0.29 mL) and tetrahydrofuran (2.1 mL) then cooled in an ice/water bath. 9-fluorenylmethyl chloroformate (390 mg, 1.4 mmol) was added in small portions over 3 min. After 4 h the cooling bath was removed. After additional 4 h at room temperature, the reaction was extracted with deionized water (2 mL) and ethyl ether (2 mL) and the aqueous layer was brought to pH 4 with dilute HCl and placed in a refrigerator. After 1 h solid was collected by vacuum filtration and washed with deionized water then dried under vacuum to give 290 mg of product (52% yield). Mass spectrum C25H23NO4 (M+Na)+ calcd for 424.1. found 424.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[CH2:13]([O:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccccc12)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of tryptamine 1.0 g (6.2 mmol) in a mixture of CHCl3 and H2O, was added 1.1 g (6.2 mmol) benzylchloroformate, followed by dropwise addition of sat. NaHCO3 solution to maintain alkaline conditions. The reaction was stirred for 2 hrs. The reaction was extracted with CHCl3 and the organic layer was concentrated to dryness giving a dark yellow oil. The oil was crystallized from ethanol/water to give an off-white crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2S[CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:29](=[O:33])(=[O:31])[CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)C1=Cc2cc(OC)ccc2SCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC)ccc2S(=O)(=O)CC1

Procedure:
Into a solution of methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate (3.00 g) in THF (30 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (6.5 g), and the resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for one hour. The reaction mixture was mixed with an aqueous solution of sodium thiosulfate, was stirred for a few minutes and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium bicarbonate (3 times) and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-methoxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (3.15 g) as colorless crystals.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Br:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19]>CN(C=O)C>[Br:15][C:10]1[CH:9]=[C:8]([S:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:19])(=[O:7])=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)NC(C)C)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of N-isopropyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks; 200 mg; 0.68 mmol) in anhydrous DMF (4 mL) was treated with NaH (33 mg; 0.82 mmol) and stirred at RT for five minutes. The resulting mixture was treated with iodomethane (43 μl; 0.68 mmol) and the reaction mixture was stirred for 16 hours. The mixture was treated again with iodomethane (21 μl; 0.34 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was quenched with an aqueous (5 N) solution of NaOH and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, concentrated and purified flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as a colorless sticky solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][C:13]#[N:14])[C:4]=2[CH:3]=C1.C([OH:17])C>>[CH:3]([C:4]1[C:5]([OH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]#[N:14])=[O:17]
Reactant: N#CCCOc1cccc2occc12
Reactant: CCO
Product: N#CCCOc1cccc(O)c1C=O

Procedure:
3-(4-Benzofuranyloxy)propionitrile (0.935 g, 8 μM) was dissolved in absolute ethanol (225 ml) and ozonised in an analogous manner to that described in example 5(B) to give 3-(2-formyl-3-hydroxyphenoxy)propionitrile which was recrystallised from ethyl acetate/petrol, m.p. 84°-86° C. (Found: C, 62.56; H, 4.79; N, 6.99. C10H9NO3 requires C, 62.38; H, 4.71; N, 7.33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])Br)=[CH:6][CH:5]=1.[CH2:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O.C(O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:31]2[CH:32]=[CH:33][C:28]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=C(Br)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(C=C(C(=O)OCc2ccccc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
4-(2-Benzyloxycarbonyl-2-bromo-vinyl)-benzoic acid methyl ester (2.0 g, 5.33 mmol) was added to a 100 mL RB flask containing 4-isobutylphenylboronic acid (2.85 g, 15.99 mmol), sodium carbonate (2.83 g, 26.65 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(II) (544 mg, 0.69 mmol). Dimethoxyethane (16 mL), ethanol (8 mL), and water (4 mL) were added, and the reaction was stirred at 120° C. for 1 hour at which point TLC analysis indicated that the reaction had gone to completion. The reaction was filtered hot through celite and concentrated to dryness. Purification by flash column chromatography was performed on an ISCO Sg-100c system, using a 40 gram pre-packed column and eluting with a linear gradient of ethyl acetate in hexanes starting at 10% EtOAc and ending at 40% EtOAc over 22 minutes. This afforded the desired product, 4-[2-Benzyloxycarbonyl-2-(4-isobutyl-phenyl)-vinyl]-benzoic acid methyl ester as a pale oil, 1.8 g, 79%. LC-MS m/z=429 [C28H28O4+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[CH:11][CH:12]=[C:13]([C:15](OC)=[O:16])[CH:14]=2)=[CH:5][CH:4]=1.BrB(Br)Br>ClCCl.C([O-])(=O)C.[Na+]>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:11][CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c1
Agent: BrB(Br)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: OCc1ccc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)c1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
2.7 g of methyl 4,4″-dimethoxy-(1,1′:2′,1″-terphenyl)-5′-carboxylate (product prepared according to J. Med. Chem. (1989) 32 1814-1820) in 30 ml of dichloromethane is cooled down to −30° C., under an inert atmosphere, 2.7 ml of tribromoborane is added and agitation is carried out at −30° C. for 16 hours. The reaction medium is diluted with a saturated solution of sodium acetate, the aqueous phase is extracted with ethyl acetate, the organic phase is dried then evaporated. The crude reaction product is chromatographed on silica eluting with a cyclohexane/ethyl acetate mixture . 70/30. In this way 814 mg of expected product is obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:14]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:15][C@H:14]1[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9][C@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(F)ccc2O[C@@H](Cc2ccccc2)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1C(=O)Nc2cc(F)ccc2O[C@H]1Cc1ccccc1

Procedure:
The title compound was prepared by hydrogenation of (+)-(6S,7R)-6-benzyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 287.1 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1O)[C:6]#[N:7].[CH:12](N(C(C)C)CC)(C)[CH3:13].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([Sn](CC)(CC)CC)C.[Li+].[Cl-]>C(Cl)Cl.CN(C=O)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:12][CH3:13])[C:6]#[N:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C#N)ccc1O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC[Sn](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C#N)cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxy-4-hydroxybenzonitrile (7-1, 2.0 g, 13.4 mmol) in DCM (67 mL) at −78° C. was added diisopropylethylamine (3.0 mL, 17.4 mmol) followed by triflic anhydride (2.7 mL, 16.0 mmol) and stirred at −78° C. for 1 h. The mixture was poured into a separatory funnel containing a few pieces of ice and then partitioned between ice water and ether. The organic phase was washed with 1N HCl and then 10% Na2CO3, dried over Na2SO4, filtered and concentrated to yield a pale yellow oil. To a solution of this oil (2.7 g, 9.60 mmol) in DMF (96.0 mL) was added tetraethyl tin (3.80 mL, 19.2 mmol), bis(tri-t-butylphosphine) palladium(0) (0.491 g, 0.960 mmol) and LiCl (1.22 g, 28.8 mmol) and the system was heated to 80° C. for 1 h in an oil bath. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the desired compound (7-2) as a pale yellow crystalline solid. ESI+MS [M+H]+ C10H11NO: 162.1 found, 162.2 required.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 1.0 mmol), 4-fluoro-2-trifluoromethyl-benzonitrile (208 mg; 1.01 mmol) and potassium carbonate (276 mg; 2.0 mmol) in dimethylsulfoxide (3 mL) is heated to 100° C. over night. Water is then added and the precipitate formed is collected to afford the desired compound (250 mg; 0.68 mmol).