Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.[I:20]I.O>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[C:15]=2[I:20])=[CH:4][CH:3]=1
Reactant: O=c1cc(/C=C/c2ccc(Cl)cc2)nc2sccn12
Reactant: II
Solvent: O
Solvent: CC#N
Product: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Step 2 intermediate (3.0 g, 0.018 mmol), iodine (2.75 g, 0.018 mmol) and ceric ammonium nitrate (CAN) (4.93 g, 0.009 mmol) in CH3CN (30 ml) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature. Distilled water (50 ml) was added to the residue obtained after concentration of the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was filtered, dried under vacuum to give 5.30 g of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 6.87 (d, J=15.6 Hz, 1H), 6.94 (d, J=4.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.73 (d, J=15.6 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 289.37 (M+H)+.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>CC(C)=O>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Thiobenzamide (10.0 g) and 1,3-dichloroacetone (9.25 g) were dissolved in acetone (200 mL), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, methanol (200 mL) was added, and the mixture was refluxed for 1.5 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (5.1 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6]2.[S:22](Cl)([Cl:24])=[O:23].CCCCCC>CCOCC>[Cl:24][S:22]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:18]([O:20][CH3:21])=[O:19])=[O:23]
Reactant: COC(=O)c1cc2cc(OC)ccc2n1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)c1c(S(=O)Cl)c2cc(OC)ccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of 4.0 g (0.014 mole) of 5-methoxy-1-phenyl-1H-indole-2-carboxylic acid, methyl ester in 7.0 ml (11.4 g; 0.096 mole) of thionyl chloride (under a nitrogen atmosphere) was stirred at ambient temperature for ten minutes. After the addition of 50 ml of 20% hexane in ether solution, the new mixture was cooled in ice for 30 minutes to precipitate the crude intermediate sulfinyl chloride. The solid was filtered and washed with hexane to yield 3.0 g (63% crude yield) of 3-(chlorosulfinyl)-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid, methyl ester.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C1CO1.OCC1OCCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C1.[C:41]1([CH:51]2[CH2:53][O:52]2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][OH:65])=[O:55]>>[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][O:65][CH2:53][CH:51]([C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)[OH:52])=[O:55]
Reactant: O=CN1CCN(C=O)C(CO)C1
Reactant: c1ccc2c(C3CO3)cccc2c1
Agent: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: c1ccc2cc(C3CO3)ccc2c1
Product: O=CN1CCN(C=O)C(COCC(O)c2cccc3ccccc23)C1

Procedure:
The same procedure as in (1) of Production Example 16 was repeated, except that the 2-(2-naphthyl)oxirane and the 2-hydroxymethyl-4-tritylmorpholine were replaced by 2-(1-naphthyl)oxirane and 1,4-diformyl-2-piperazinyl methanol, respectively, to obtain oily 2-[(1,4-diformylpiperazin-2-yl)methoxy]-1-(1-naphthyl)ethanol (compound No. 270).
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)O)sc2ccsc12
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCc1csc2ccsc12
Temperature: 260 °C
Yield: 207.2 %

Procedure:
A mixture of compound 62 (14.6 g, 0.054 mol), copper powder (2.00 g), and quinoline (80 mL) is heated at about 260° C. in a Woods metal bath. When no further bubbles of CO2 are detected (about 2 hours), the mixture is allowed to cool to room temperature, and hexane (200 mL) is added. The mixture is washed repeatedly with HCL (1-2 M in water) to remove the quinoline. The organic layer is dried over MgSO4 and concentrated by evaporation. The residue is purified by column chromatography (SiO2/hexanes) to yield compound 58 (25.1 g, 90.3% yield). GC/MS: 224 g/mol (M). 1H NMR (CD2Cl2): δ 7.36 (m, 1H), 7.25 (m, 1H), 7.01 (m, 1H), 2.73 (t, 2H), 1.69 (m, 2H), 1.34 (m, 6H), 0.89 (t, 3H). 13C NMR: 140.39, 139.13, 135.39, 127.01, 122.19, 120.26, 32.01, 30.29, 29.43, 23.01, 14.24.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17]C)=[C:6]2[N:5]=[CH:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])=[C:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1-c1cnn2c(O)ncnc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccccc1-c1cnn2c(O)ncnc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
A mixture of 4-hydroxy-8-(2-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine (242 mg), aluminum chloride (799 mg) and nitrobenzene (3 ml) is stirred at 80°-90° C. for 5 hours. The reaction mixture is cooled and poured into ice water. The precipitate is separated by filtration, washed with water and dried to give the title compound (140 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[H-].[Na+].[CH3:23]I.Cl>C1COCC1.O1CCOCC1>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:2][O:1][CH3:23])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COCc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of Example 417A (142 mg, 0.5 mmol) in THF (3 mL) at room temperature was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol) and methyl iodide (0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:16])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C(NN)=NN=C(N(CCO)CCO)C=1.Cl.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[CH3:17])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNc1ccc(N(CCO)CCO)nn1
Solvent: c1ccncc1
Product: Cc1ncccc1C(=O)Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 100 °C

Procedure:
A solution of 6-chloro-7-fluoro-9H-β-carbolin-8-ylamine (100 mg, 0.424 mmol) in pyridine (2.5 ml) was stirred at RT. 2-methyl nicotinic acid (70 mg, 0.509 mmol) was added, followed by EDCI (130 mg, 0.678 mmol). The suspension was stirred at 100° C. for a day. The pyridine was removed under reduced pressure and the resulting dark oil was triturated with saturated aqueous NaHCO3. The precipitate which formed was filtered and washed with MeOH. The material was treated with 2M HCl in Et2O to yield a gray solid, the di-HCl salt N-(6-chloro-7-fluoro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide (110 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:25]12[CH:31]([CH2:32][CH2:33][NH2:34])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:34][CH2:33][CH2:32][CH:31]2[CH:25]3[CH2:30][CH2:29][CH:28]2[CH2:27][CH2:26]3)=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C(=O)O)s1
Reactant: NCCC1C2CCC1CC2
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 moles of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 moles of 2-(bicyclo[2.2.1]hept-7-yl)ethylamine in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured in 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]-thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([NH:1][S:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Product: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(F)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-fluorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([O:15][C:16]([NH:18][C@:19]([C:28]1[O:32][C:31]([C:33]2[CH:34]=[C:35]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[CH:36]=[C:37](Br)[CH:38]=2)=[N:30][N:29]=1)([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:35][N:40]([CH3:45])[S:41]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:37]1[CH:36]=[C:35]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[CH:34]=[C:33]([C:31]2[O:32][C:28]([C@@:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])([CH3:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:29][N:30]=2)[CH:38]=1)(=[O:43])=[O:42]
Reactant: CN(c1cc(Br)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(-c2nccn2S(=O)(=O)N(C)C)c1)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N-dimethylsulfamoyl)imidazole (Preparation described in Winter, J., Retey, J. Synthesis. 1994, 3, 245-246; 47 mg, 0.27 mmol) in 1 mL THF, cooled to −78° C. was added n-butyllithium (2.5 M solution in hexanes, 0.12 mL, 0.29 mmol) dropwise. The reaction was stirred at −78° C. for 15 min and zinc chloride (0.5 M solution in THF, 1.6 mL, 0.81 mmol) was added. After warming to rt over 1 h, 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-bromo-N-methyl-N-(methylsulfonyl)benzenamine (100 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.8 mg, 0.018 mmol) were added. The mixture was heated in a microwave oven to 80° C. for 0.75 h, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine. Drying, solvent evaporation and flash chromatography (50-100% EtOAc/hexanes) gave 3-(1-(dimethylsulfamoyl)-1H-imidazol-2-yl)-5-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(methylsulfonyl)benzenamine. 1H NMR (CDCl3) δ 8.26 (m, 1H), 8.15 (m, 1H), 7.87 (m, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.26 (m, 3H), 7.18 (d, J=1.6 Hz, 1H), 7.08 (m, 2H), 3.60 (d, J=12 Hz, 1H), 3.40 (m, 4H), 2.95 (s, 3H), 2.64 (s, 6H), 1.71 (s, 3H), 1.42 (bs, 9H).
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:47].[ClH:1].[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:39]=[CH:40][C:35]([N:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[N:36][CH:37]=2)=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: Clc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Yield: 91 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.570 g), to furnish the title compound as an off-white solid (0.478 g, 91%).
Reaction SMILES: Cl.C([NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]3[CH:20]=[N:21][CH:22]=[C:15]23)=[CH:10][CH:9]=1)(C)(C)C.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:22]1[N:21]=[CH:20][N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]#[N:6])=[CH:13][CH:12]=3)[C:15]=12
Reactant: CC(C)(C)NC(=O)c1ccc(C2CCCn3cncc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C2CCCn3cncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1.74 mmol of N-tert-Butyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride and 1.4 ml of thionyl chloride in 30 ml of chloroform is stirred under reflux for 7 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in dichloromethane and mixed with saturated aqueous sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×). The combined organic phases are dried with sodium sulphate and evaporated. Following flash chromatography (SiO2 60F) of the residue, the resulting solid is stirred in 1:1 diethyl ether/tert-butyl methyl ether, filtered and dried. The title compound is obtained as a cream-colored solid. Rf=0.37 (toluene:methanol=85:15); Rt=4.88
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:49].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:51]([O:50][C:48]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C:2]2=[O:7])[CH:10]=1)(=[O:25])=[O:26])=[O:49])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(CN3C(=O)CCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(CN2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-(3-pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (95.0 mg, 0.205 mmol; see step (f)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (91.3 mg, 0.616 mmol) and butyl chloroformate (261.1 μL, 2.05 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by LCMS (Liquid Chromatography Mass Spectrum; 25-100% CH3CN in water) to give the title compound in 76% yield, over two steps, (79.1 mg, 0.156 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[CH:13]1([C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[CH2:15][CH2:14]1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:13]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH2:7][CH2:8]3)[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:15]1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O=C(C1CC1)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1ccc2c(c1)C(N1CCN(C(=O)C3CC3)CC1)CC2
Reaction time: 20 h

Procedure:
An intimate mixture of 6-methoxy-1-indanone (1.6 g, 10 mmol), 1-cyclopropanecarbonylpiperazine (1.5 g, 10 mmol) and titanium(IV) isopropoxide (4 mL, 12 mmol) was heated on the steam bath for 10 minutes. Additional titanium isopropoxide (1 mL, 3 mmol) was added and the mixture stirred for 20 hr. The material was dissolved in ethanol and sodium borohydride added (0.9 g, 22 mmol). After stirring for 1 hr the solution was heated to reflux and more sodium borohydride (0.9 g, 22 mmol) added. When solution had occurred 15% NaOH solution (50 mL) was added. The insoluble material was removed and discarded. The solution was concentrated in vacuo and the residue mixed with ether. The mixture was washed with water and 1N HCl solution. The acid washes were made basic and the mixture was extracted with ether to give the product as an oil which was converted to the fumarate salt and crystallized from acetone to give the salt (1.8 g).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[CH:9](O)[C:10]([O:12][CH3:13])=[O:11].[Na+].[Cl-]>>[Br:2][CH:9]([C:8]1[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=1[O:6][CH3:5])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(O)c1ccccc1OC
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)C(Br)c1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
146.6 ml (1.57 moles) of phosphorus tribromide are added dropwise to 109.7 g (0.562 mole) of methyl 2-methoxymandelate, while cooling well. After 3 hours stirring at room temperature, the mixture is poured into 3N NaCl solution, and extracted with methylene chloride. After washing the organic phase with water, it is dried with Na2SO4 and is concentrated. 140.7 g of the title compound are obtained as a yellowish oil which is used further without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.[Cl:18][C:19]([Cl:23])([Cl:22])[CH:20]=O>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10]([CH:20]([C:19]([Cl:23])([Cl:22])[Cl:18])[O:8][C:7]2=[O:9])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCOc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1ccc2c(c1)C(=O)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To a stirred solution of 6.6 g (40 mmoles) of 3-ethoxybenzoic acid in 50 ml. of concentrated sulfuric acid were added dropwise over fifteen minutes 8.0 g (55 mmoles) of trichloroacetaldehyde (chloral). The reaction mixture was stirred for twelve hours at 25° C., and then an additional 8.0 g of chloral were added in one portion and the mixture was stirred for an additional three hours. The reaction mixture was next added to 50 g of ice and 50 ml of water, and the aqueous mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with aqueous sodium bicarbonate and then with fresh water, and dried. The solvent was removed by evaporation under reduced pressure to provide an oil. The oil solidified and then was crystallized from ethanol to afford 1.1 g of 6-ethoxy-3-(trichloromethyl)phthalide. m.p. 112°-114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O and 15.2 mg (0.15 mmol) of triethylamine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: C([O:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[C:12]([O:14]C)=[O:13])(=O)C.[Li+].[OH-].CCCCCC.CCOC(C)=O>O.CC(OC)(C)C.CC(O)=O>[OH:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C1CCC(C)=CC1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC1=CC(O)C(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar and nitrogen inlet was charged with the acetate ester 14 (5.306 g, 25 mmol) and a solution of LiOH (8.392 g, 200 mmol) in 53 mL of H2O. The reaction was stirred for 3 h at room temperature. TLC (2:1:0.5 Hexane:EtOAc:HOAc) indicated reaction was complete. 20 mL of MTBE was added and the aqueous phase removed to a separate flask. The aqueous solution was cooled to ˜5-10° C. and acidified to pH˜2 with concentrated HCl. A small amount of precipitate was removed by filtration at room temperature. The filtrate was extracted with 3×40 mL of MTBE and the combined organic layers dried over sodium sulphate and rotovaped to a yellow oil that solidified upon cooling to give 2.798 g (72%) of the hydroxy acid 16.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:13])=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:13])=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)cncc2c1
Agent: Br
Product: Cc1cncc2cc(O)ccc12

Procedure:
A mixture of 17.3 g. (0.1 mole) of 7-methoxy-4-methylisoquinoline and 100 ml. of 48% hydrobromic acid is refluxed for sixteen hours and evaporated in vacuo. The residue is dissolved in water, neutralized with ammonium hydroxide and filtered to yield 7-hydroxy-4-methylisoquinoline.