Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O1CCC[CH2:14]1.CO.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:14][O:8][C:7]([CH:4]1[CH2:3][CH2:2][CH:1]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[O:9]
Reactant: O=C(O)C1CCC(C(=O)O)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold, stirred solution of cyclohexane-1,4-dicarboxylic acid (3.0 g, 17 mmol) in a mixture of 2:1 tetrahydrofuran/methanol (24 mL) was added trimethylsilyl diazomethane (9 mL of a 2.0 M in hexanes, 18 mmol). The reaction mixture was stirred at room temperature for 2 h. Acetic acid (5 mL) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 10:1:0.01 hexanes/ethyl acetate/acetic acid) provided 4-(methoxycarbonyl)cyclohexanecarboxylic acid (1.00 g): 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.53-2.47 (m, 2H), 1.97-1.89 (m, 4H), 1.74-1.66 (m, 4H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]2([CH2:22][NH:21][C:20](=O)[CH2:19][O:18]2)[CH2:15]1)([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>C1COCC1.CCCC(C)C>[CH:1]([N:14]1[CH2:17][C:16]2([CH2:22][NH:21][CH2:20][CH2:19][O:18]2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Temperature: 25 °C

Procedure:
Borane-methyl sulfide complex in THF (13.38 mL) was added in one portion to 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (2.5 g) (WO2009098448, example 33, step e) in THF (50 mL) at room temperature under argon. The resulting solution was stirred at reflux for 90 minutes. The reaction was cooled to room temperature then the reaction mixture was quenched with methanol (50.0 mL). N,N′-Dimethylethylenediamine (5.18 mL) was added and the reaction mixture allowed to stir at room temperature for 1 week. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (250 mL), and washed with water (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was dissolved in iso-hexane (10 mL) and was purified by flash silica chromatography, eluting with 10% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane. Yield 1.647 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH3:38].N(C(OCC)=O)=NC(OCC)=O>>[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)\[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:45][CH:44]=1)[CH3:38]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(\c1ccccc1)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(F)cc2)cc1)OCC
Yield: 84.9 %

Procedure:
Reaction of (E)-3-(4-fluorophenyl)-3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg, 0.92 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (200 mg, 0.84 mmol) and diethyl azodicarboxylate (160 mg, 0.92 mmol) in an identical manner to example 1 gave the title compound (320 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].C([O-])(=O)C.[Pb+4:34].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([Pb+3:34])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: [Pb+4]
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 55.5 %

Procedure:
4′-Chloro-3-methylbiphen-4-ylboronic acid (6.0 g, 0.024 mol) is added in one portion to a mixture of lead tetraacetate (13.0 g, 0.029 mol) and mercuric acetate (0.38 g, 5 mol %) in chloroform (50 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hrs. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange colored solid. Trituration with hexane (50 ml) to afford a yellow solid which was dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (42.5 g, 0.3 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-yllead triacetate (7.8 g) as a cream colored solid.
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[O:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)oc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzoxazole-7-yl)-acetonitrile (66 mg 0.23 mmol) (Starting Material 7) was suspended in concentrated H2SO4 /H2O (1/1, 2 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (120 mg, 1.85 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[5,4-e]indol-7-one. (Yield 17 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OO)(C)(C)C>>[Cl:12][CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[CH:5]=1)=[CH2:10]
Reactant: C=C(C)c1cc(Cl)nc(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)OO
Product: C=C(CCl)c1cc(Cl)nc(Cl)c1
Temperature: 180 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
A mixture of 26.3 g of 2,6-dichloro-4-isopropenylpyridine, 33.4 g of N-chlorosuccinimide, 2 g of t-butylhydroperoxide and 30 ml of carbon tetrachrolide was stirred at 180° C. for 5 hours while being irradiated with light. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:20) to obtain 9.86 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=O)=[C:9]([CH:14]=1)[C:10](OC)=[O:11].Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[CH:14]=[C:9]2[C:8]([CH2:15][N:29]([C@H:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[OH:35])[C:10]2=[O:11])=[C:7]([CH3:17])[C:6]=1[CH3:18]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1C=O
Reactant: N[C@H]1CCC[C@@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2F)cc2c(c1C)CN([C@H]1CCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A solution of methyl 5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.17 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g), triethylamine (0.06 mL) and anhydrous magnesium sulfate (0.10 g) in THF (3.40 mL) was stirred at room temperature for 10 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.40 mL) and THF (3.40 mL), sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.07 g).
Reaction SMILES: [Cl:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl-].[Br:16][C:17]1[C:18]([OH:45])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl-:1].[Br:16][C:17]1[C:18]([O:45][C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(C(=O)Oc2c(Br)cc(OC)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 66 %

Procedure:
With the exclusion of air, 43.9 g of 4-chlorocarbonyl-1-ethoxycarbonyl-piperidine are dissolved in 250 ml of anhydrous acetonitrile (degassed) and 53.4 g of [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride are added to the solution. In the course of 30 minutes, at 25° to 30°, 20 g of pyridine are added dropwise to the resulting suspension. The mixture is heated for 5 hours under reflux and is then hydrolysed with 100 ml of sodium carbonate solution (15%); the organic phase is separated off, washed in succession with 100 ml of 1N hydrochloric acid and 100 ml of water and concentrated by evaporation in vacuo and the oily residue that remains is dissolved in 50 ml of dichloromethane. In the course of 30 minutes, at 20°, with vigorous stirring, 200 ml of ethyl acetate are added dropwise to that solution and the product crystallises out. The resulting crystal suspension is concentrated to 150 ml under a weak vacuum using a rotary evaporator and then stirred for 2 hours at 0°. Filtering with suction and drying yield [(3-bromo-2-[(1-ethoxycarbonylpiperid-4-yl)carbonyloxy]-5-methoxy-phenyl)methyl ]-triphenyl-phosphonium chloride [m.p.: 196°; IR (KBr): 3415, 3060, 2855, 2780, 1600, 1565, 1385, 1270, 1190, 1165 cm-1 ; 1 H-NMR (360 MHz, CDCl3); 1.28 (t, 3H, CO2CH2CH3), 1.45 (m, 2H), 1.75 (m, 2H), 2.58 (m, 1H), 2.87 (m, 2H), 2.47 (s, 3H, OCH3), 4.00 (m, 2H), 4.13 (q, 2H, CO2CH2CH3), 5.37 (br, d, 2H, CH2P+), (dd, 1H), 7.07 (dd, 1H), 7.54 to 7.87 (m, 15H) ppm]; yield 66% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([O:20][CH3:21])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:22][CH:23]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(Cl)cc1
Product: CON(Cc1ccc(Cl)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-chlorobenzyl)-O-methyl-hydroxylamine (Kawase, M. et al., J. Chem. Soc. Perkin Trans. 1, 1979, 643–645) as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 129–130° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.69 (3H, s, OCH3), 4.79 (2H, s, NCH2), 6.39 (1H, s, CH), 7.4 (4H, s, aromatics). Anal. calcd. for C15H16ClNO5: C, 55.31; H, 4.95; N, 4.30. Found: C, 55.32; H, 4.95; N, 4.27.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:8]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tert-Butyl 3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate (from Step 5) was dissolved in DMF (0.18 M). NaH (60% suspension in mineral oil, 1.5 eq.) was added and the resultant mixture stirred for 5 min at RT, then for another 5 min at 50° C. The solution was allowed to reach RT, and then neat 2-chloro-N,N-dimethylacetamide (1.6 eq.) was added dropwise. After 1 h analytical RP HPLC indicated complete conversion of the starting material. The mixture was diluted with EtOAc, and then washed with water (3×) and brine. Drying over Na2SO4 and evaporation gave a colorless solid, which was purified by flash chromatography on silica gel using PE/EtOAc (3:1, then 2:1) as the eluent. The resulting colorless solid was immediately dissolved in a mixture of DCM and TFA (0.05 M, 1:1, v/v). After stirring for 30 min at RT, the solvents were removed in vacuo to give after drying under high-vacuum, the title compound as a light yellow foam. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.12-1.31 (m, 3H), 1.60-1.75 (m, 5H), 1.80-1.92 (m, 2H), 2.53-2.59 (m, 1H), 2.80 (s, 3H), 2.89 (s, 3H), 4.84 (s, 2H), 7.31 (d, J 6.4, 2H), 7.48-7.53 (m, 3H), 7.64 (d, J 8.4, 1H), 7.81 (d, J 8.4, 1H), 7.92 (s, 1H,); MS (ES+) m/z 405 (M+H)+
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:15])[CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>CN(C)C=O.O>[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[C:19](=[O:26])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]3[CH:8]([C:7](=[O:14])[CH2:6][CH2:5][C:4]([CH3:3])=[CH2:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:28]2)=[CH:33][CH:32]=1
Reactant: C=C(C)CCC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCC(=O)C(C(=O)OCC)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.7 g of an oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature of about 10° C. 9.8 g of ethyl 6-methyl-3-oxo-6-heptenoate in 25 cm3 of anhydrous dimethylformamide are subsequently added. The suspension is stirred for 30 minutes and the temperature is allowed to return to about 20° C., followed by the addition of 11.6 g of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone. The reaction mixture is stirred for 4 hours at a temperature of about 20° C. and is then poured into 250 cm3 of water. The aqueous phase, which is acidified by the addition of 25 cm3 of aqueous 1N hydrochloric acid solution, is extracted twice with 200 cm3 of dichloromethane. The organic phases are combined and washed twice with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue is purified by chromatography on silica [eluent:ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After crystallization in diisopropyl ether, 9.4 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate (mixture of A and B forms) are thus obtained, melting at 125° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15]([N:1]([C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])[S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-methylisoxazole (0.179 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). 4-Biphenylsulfonyl chloride (0.509 g, 2.2 mmol) was added with stirring at ambient temperature. N,N-Dimethylaminopyridine (5 mg) was added, and stirring was continued at 50° C. for 16 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (2×50 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography using 8:2, hexanes/ethyl acetate, to give 0.390 g (60% yield) of N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: FC(F)(F)c1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3-(trifluoromethyl)benzene (Aldrich, 85 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.76 (m, 1H), 7.81-7.96 (m, 2H), 7.98 (s, 1H), 8.20-8.30 (m, 2H), 8.41 (dt, J=8.1, 1.9 Hz, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 9.17 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: O=C(Cl)OCCOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCCOCc1ccccc1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
32.2 G. (150 mmoles) of 2-benzyloxyethylchloroformate is added dropwise with protection from moisture to a stirred suspension of 30.1 g. (150 mmoles) of 2(4-thiazolyl)-benzimidazole in 200 ml. of pyridine. The addition is complete in 30 minutes whereupon all of the starting material is dissolved and pyridine hydrochloride begins to precipitate. The reaction mixture is stirred at room temperature for 15 1/2 hours and filtered to remove pyridine hydrochloride. The solid material is washed with a small volume of pyridine and the combined filtrate and washing are evaporated to dryness in vacuo. The residual oil is dissolved in 300 ml. of methylene chloride and allowed to stand during which time a substantial amount of solid material precipitates. The solid is removed by filtration and the filtrate washed twice with 250 ml. of 0.25 N HCl containing ice followed by 200 ml. of saturated sodium bicarbonate solution containing 50 ml. of ice. The methylene chloride fraction is dried with magnesium sulfate, treated with charcoal, filtered and evaporated to dryness in vacuo affording 38.9 g. of a yellow-orange oil which begins to solidify on standing. The material is recrystallized from toluenecyclohexane affording 23.8 g. of 1-(2-benzyloxyethoxycarbonyl)-2-(4-thiazolyl)-benzimidazole, m.p. 93°-95° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:10])[CH3:9])[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].O>C(OCC)(=O)C>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([NH:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:9])[CH3:10])[OH:4])=[O:46]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN)C(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CNC(=O)C(C)(C)C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.035 g of tert-butyl {1-(2-amino-1-hydroxyethyl)-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 0.60 ml of ethyl acetate is admixed successively with 0.60 ml of 2M sodium carbonate solution and 0.012 ml of pivaloyl chloride and stirred at room temperature over a further 1 hour. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:20])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc2cc(Br)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3 g, 13.4 mmol) and NCS (2.47 g, 18.5 mmol) in THF (50 mL) according to method C to yield 2.2 g (64%) of yellow solid: 1H NMR (DMDO-d6): δ 7.34 (1H, d, J=8.87 Hz), 7.69 (1H, dd, J=1.75 Hz, J=6.09 Hz), 7.79 (1H, d, J=8.96 Hz), 7.96 (1H, d, J=9.03 Hz), 8.17 (1H, d, J=1.75 Hz), 10.68(1H, s); MS (ESI) m/z 255/257/259 (M−H)−.