Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=1)(=[O:25])=[O:24]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:35])[CH:27]=2)(=[O:25])=[O:24])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1Cc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 85.1 %

Procedure:
The tile compound was prepared according to the procedure in Example 4 using 4-(2-butyl-benzofuran-3-ylmethyl)-phenol (0.500 g, 1.78 mmol) and 4-chlorosulphonyl -2-hydroxybenzoic acid (0.844 g, 3.56 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.728 g (86%) of the title compound as an orange solid, mp 135-138° C. 1H NMR (DMSO-d6) δ0.84 (t, 3 H), 1.27 (sextet, 2 H), 1.58 (quintet, 2 H), 2.76 (t, 2 H), 3.97 (s, 2 H), 6.96 (d, 2 H) 7.10 (dt, 1 H), 7.17 (dt, 1 H), 7.22-7.31 (m, 5 H), 7.43 (d, 1 H), 7.95 (d, 1 H). IR (KBr) 3300,2950, 1675, 1390 and 1175 cm−1. mass spectrum (−ESI) m/z 479 (M−H). Anal. Calcd. for C26H24O7S 0.2H2O: C, 64.50; H, 5.08; N, 0.00. Found: C, 64.50; H, 5.07; N, 0.06.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(O)C(=O)c2ccccc2)cc1C

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and o-xylene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 20 minutes. Using the same procedure as in Example 1, 3',4'-dimethylbenzoin was obtained as crystal (258.7 mg, 54.0% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7](=S)[NH:8][C:4]=2[CH:3]=1.[BrH:13].BrBr.[O-]S([O-])(=O)=O.[Na+].[Na+]>CO>[Br:13][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Br
Reactant: S=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Agent: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1cc2nc(Br)[nH]c2cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5,6-dichloro-2,3-dihydro-1H-1,3-benzodiazole-2-thione (2 mmol, 438 mg) was dissolved in MeOH (20 ml). The reaction mixture was cooled to 0° C. and hydrobromic acid (0.4 ml) was added, then bromine (8 mmol, 1.3 g) was added. The resulting mixture was stirred at RT overnight, then Na2SO4 was added. Next MeOH was evaporated. The aqueous layer was extracted with DCM. The product was purified on silica gel using EA/hex (1:1) to afford yellow solid (1 mmol, 260 mg), m/z 266.7; rt 2.8 min.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4].[Cl:36]N1C(=O)CCC1=O.O>CN(C=O)C>[F:35][C:2]([F:1])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:30])([F:31])[F:32])[C:14]=2[Cl:36])=[CH:9][C:8]=1[CH3:33])(=[O:5])=[O:4]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2c(Cl)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl trifluoromethanesulfonate (0.185 g, 0.339 mmol) in DMF (2 mL) was added N-chlorosuccinimide (0.227 g, 1.70 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 72 hours. The reaction mixture was added water (20 mL) and extracted with ethyl acetate/hexane/ether=2/1/1 (20 mL×2). The organic layer was washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (4/1) to give the subtitle compound (0.117 g, 59.7% yield).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)c1nc(CCl)co1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1coc(C(C)(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of 2-tert-butyl-4-chloromethyl-1,3-oxazole (10.42 g) and triethyl phosphite (19.94 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-tert-butyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (16.51 g, yield 100%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2]1.C1C=CN=CC=1.[FH:15].O>CCOCC>[F:15][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][OH:1]
Reactant: F
Reactant: CCCCCC1CO1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(F)CO
Reaction time: 0.5 h

Procedure:
A solution of 1.14 g (10.0 mM) of (+)-1,2-epoxyheptane ([α]D +15.1° (neat)) in 5 ml of dry ether was quickly added dropwise into ice-cooled 2 ml of hydrogen fluoride/pyridine. After the addition, the mixture was stirred for 30 minutes in an ice bath, followed by addition of 10 ml of cold water and 3 times of extraction with 10 ml of ether. The extract liquid was washed 3 times with 10 ml of 1N-sodium carbonate, followed by drying with anhydrous magnesium sulfate, removal of ether by vacuum distillation and distillation with Kugelrohr distillation apparatus, to obtain 0.492 g of crude (-)-2-fluoroheptanol. Further, by repeating the above operations, 1.35 g of the crude product was obtained and rectified by means of a Claisen flask to obtain 0.80 g (600 mM) of objective (-)-2-fluoroheptanol. Yield: 20.0%. The product showed the following properties:
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([C:10](Cl)=[O:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1.[C:13]([O:17][C:18](=[O:44])[N:19]([CH:21]([C:23](=[O:43])[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[N:36]3)[CH:28]=[C:27]([NH2:42])[N:26]=1)[CH3:22])[CH3:20])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([O:17][C:18](=[O:44])[N:19]([CH:21]([C:23](=[O:43])[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[N:36]3)[CH:28]=[C:27]([NH:42][C:10]([C:7]2[N:6]=[CH:5][C:4]3[CH2:3][O:2][CH2:1][C:9]=3[CH:8]=2)=[O:11])[N:26]=1)[CH3:22])[CH3:20])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C(Cl)c1cc2c(cn1)COC2
Reactant: Cc1ccc2ncccc2c1-c1cc(N)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2ncccc2c1-c1cc(NC(=O)c2cc3c(cn2)COC3)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1H,3H-furo[3,4-c]pyridine-6-carbonyl chloride M1 (33 mg, 0.2 mmol) is added to tert-butyl-N-(1-{[6-amino-4-(6-methylquinolin-5-yl)pyridin-2-yl]carbamoyl}ethyl)-N-methyl-carbamate J1 (60 mg, 0.14 mmol) and DIPEA (59 μl, 0.34 mmol) in THF (1 ml) and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 17 mg (21%). HPLC-MS: M+H=583; tR=1.01 min (Method—2).
Reaction SMILES: [N:1]1([CH2:10][C:11](OC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)Cn1ccc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1ccc2ccccc21
Yield: 99.4 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 6.20 g of methyl indol-1-yl-acetate (prepared as described in Preparation 12), 1.50 g of lithium aluminum hydride and 220 ml of anhydrous tetrahydrofuran were used, to give 5.25 g of the title compound having Rf=0.33 ion silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][NH:18][CH2:19][C:12]=2[CH:11]=1.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(O)C.CCOCC>[Cl:9][C:10]1[N:15]=[N:14][C:13]2[CH2:16][CH2:17][N:18]([C:26]([C:21]3[C:20]([CH3:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:27])[CH2:19][C:12]=2[CH:11]=1
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1

Procedure:
Produced in a manner analogous to that described in Example 8 (g), from 28.5 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 16.9 g of o-toluoyl chloride. Reaction time 24 hours. M.P. 123°-126° (decomp., from 95% ethanol/ether).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][C:4]([C:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])=[CH:3][CH:2]=2)[CH2:10][CH2:11]1)[CH3:16]
Reactant: O=C1CCC(=O)O1
Reactant: CC[C@H]1CC[C@H](CCc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](CCc2ccc(C(=O)CCC(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 1-phenyl-2-(trans-4-ethylcyclohexyl)ethane (200.0 g, 0.93 mol), pulverized succinic acid anhydride (111.6 g, 1.11 mol) and CS2 (500 ml) was cooled with ice down to 0° to 5° C. Pulverized anhydrous aluminum chloride (248.0 g, 1.86 mol) was gradually added to the mixture. After removing the ice bath, the mixture was agitated for one hour and successively agitated for 2 hours on a water bath at 60° C. The resulting material was allowed to stand overnight. The reaction material was poured into a mixture of ice (500 g) and 6N-HCl (300 ml). The mixture was agitated sufficiently and CS2 and water were distilled off on a water bath, to obtain a residue. Toluene was added to the residue and then heated under reflux. After separating water by means of a DeanStoke type water separator, the resulting liquid was filtered off while hot and recrystallized to obtain the following 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)benzoyl)propanic acid (214 g, m.p.: 141.2°-142.6° C.). ##STR8##
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][N:32]([CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1)[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CNCC1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (420 mg) and 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg) in acetonitrile (10 mL) was added potassium carbonate (250 mg). The reaction mixture was heated at 80° C. for 4 h and then allowed to cool to room temperature. The mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) and the organic layer washed with brine (20 mL), dried (MgSO4), reduced in vacuo and purified on column chromatography to give 2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (487 mg).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[O:11].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+].OCC[NH2+]CCO>O1CCCC1.O>[OH:4][CH2:3][CH2:2][NH2+:1][CH2:5][CH2:6][OH:7].[SH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([NH:18][CH2:19][C:20]([O-:22])=[O:21])=[O:17])=[O:11]
Reactant: OCCNCCO
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: OCC[NH2+]CCO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Reaction time: 8 h

Procedure:
A solution of 1.82 ml. diethanolamine (2 g., 0.0189 mole) in 10 ml. of tetrahydrofuran is added to a mixture of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole), 5 mg. of disodium edetate, 4 ml. of water and 40 ml. of tetrahydrofuran under an atmosphere of nitrogen during a 5-minute period at room temperature. The resulting mixture is first warmed to 40°-45° C. for 20 min. and then cooled in a dry ice-ethanol bath for 0.5 hr. to promote crystallization. Cooling is discontinued and the mixture stirred overnight under an atmosphere of nitrogen and filtered. The material collected is washed with tetrahydrofuran and then dried under vacuum over calcium chloride to provide 5.8 g., of the bis-(2-hydroxyethyl) ammonium salt of N-[3 -(mercaptoacetylamino)benzoyl]glycine, m.p. 64°-74.5° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34][OH:35])=[N:26][C:27]=2[O:32][CH3:33].CC([OH:39])C.O.C(OCC)(=O)C>CC(C)=O>[C:34]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[C:27]([O:32][CH3:33])[N:26]=1)([OH:39])=[O:35]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(=O)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Reaction time: 0.17 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.14 g) in acetone (5 mL) was added this solution in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature overnight. To the reaction mixture was added 2-propanol (2 mL), and the mixture was stirred at room temperature for 20 minutes. To the mixture were added water and ethyl acetate, and the insoluble material was removed by filtration. The insoluble material was washed with water, ethyl acetate and diethyl ether successively. The filtrate and washings were combined, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=1/1) to give the title compound (4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([O:15][C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]4[CH2:41][CH2:40]4)[CH:28]=3)[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.08 mmol) was dissolved in CH2Cl2 (2 ml) and pyridine (50 μl), then methanesulfonyl chloride was added (11 mg, 0.1 mmol) at 0° C. The mixture was stirred at RT for 2 hours, then diluted with CH2Cl2 (20 ml) and quenched with HCl 1N aqueous solution (30 ml). The two phases were separated, and the organic phase washed with HCl 1N aqueous solution (2×20 ml), dried over Na2SO4 and evaporated under vacuum. The crude was purified by preparative HPLC (Method 2) to yield 41 mg of the title compound. (Yield 75%). 1H NMR (400 MHz, acetone) δ ppm 8.71-8.92 (m, 1H), 8.22 (s, 2H), 7.73 (m, 1H), 7.59 (m, 2H), 7.15-7.30 (m, 2H), 7.05 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.15 (dd, J=9.70, 4.85 Hz, 1H), 4.49 (s, 2H), 4.44 (d, J=3.53 Hz, 2H), 3.98 (d, J=7.06 Hz, 2H), 3.55 (dd, J=14.11, 9.26 Hz, 1H), 3.32 (dd, J=14.11, 4.85 Hz, 1H), 3.05 (s, 3H), 1.29 (m, 1H), 0.55-0.69 (m, 2H), 0.27-0.47 (m, 2H); MS/ESI+ 686.51 [MH]+.
Reaction SMILES: O[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:6]=2[O:5][CH:4]=1.[OH-].[Na+].[C:15]([O:18]C(=O)C)(=O)[CH3:16].C(Cl)(Cl)(Cl)[Cl:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(O)C.O.C(Cl)Cl>[Cl:23][CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:15](=[O:18])[CH3:16])=[CH:11][C:6]=2[O:5][CH:4]=1
Reactant: OCc1coc2cc(O)ccc12
Reactant: CC(=O)OC(C)=O
Reactant: ClC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)Oc1ccc2c(CCl)coc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 3-hydroxymethyl-benzofuran-6-ol (4.72 g, 28.6 mmol) in iPrOH (120 mL) was added NaOH (2.30 g, 57.5 mmol) in H2O (25 mL) followed by acetic anhydride (5.4 mL, 57.5 mmol) and the reaction mixture was stirred (rt, 1 h). The reaction was concentrated in vacuo and the resulting residue was partitioned with saturated NaHCO3 (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and treated with CCl4(3.2 mL, 32.9 mmol) and triphenylphosphine (8.64 g, 32.9 mmol) as a solution in CH2Cl2 (50 mL) and stirred (rt, 12 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography using DCM:hexanes (0-100%) to provide the title compound as a white solid (3.45 g, 65%). MS (ESI): mass calcd. for O11H9Cl3, 224.0; m/z found, 225.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.68-7.64 (m, 2H), 7.28 (d, J=2.0, 1H), 7.05 (dd, J=8.5, 2.0, 1H), 4.73 (d, J=0.8, 2H), 2.33 (s, 3H).
Reaction SMILES: [OH-].[Li+].[O:3]=[S:4]1(=[O:38])[C:10]2[CH:11]=[C:12]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5]1.CC(O)=O>C1COCC1.O>[O:38]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 96.3 %

Procedure:
Lithium hydroxide (0.062 g) was added to a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 45; 0.448 g, 0.865 mmol) in THF/H2O (2/1, 6 ml). After 1 hour AcOH (0.5 ml) was added and most of the solvent was removed under reduced pressure. The crude product was purified by HPLC (MeCN) to give the title compound 0.408 g (96%) as a white solid. NMR (400 MHz, CD3OD): 0.75-0.85 (m, 6H), 1.00-1.30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (brs, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90-7.30 (m, 5H),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[OH:10].Br[CH:12]([CH:14]1[CH2:16][CH2:15]1)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:14]1[CH2:16][CH2:15]1
Reactant: OCc1ccc(Cl)c(O)c1
Reactant: OC(Br)C1CC1
Product: OCc1ccc(Cl)c(OCC2CC2)c1

Procedure:
The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenol and bromocyclopropylmethanol according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.29-1.33 (1H, m), 1.76 (1H, s), 3.89 (2H, d, J=6.8 Hz), 4.64 (2H, s), 6.84-6.86 (1H, m), 6.94 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=8.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)CCC1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49](CC)[CH:50]=1)C(O)=O)=[O:41])CC>>[CH2:25]([NH:35][CH2:13][C@@H:11]([OH:12])[C@@H:10]([NH:14][C:15](=[O:24])[C:44]1[CH:48]=[CH:49][CH:50]=[C:42]([C:40]([N:39]([CH3:36])[CH2:53][CH2:54][CH3:55])=[O:41])[CH:43]=1)[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:34]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCCc2ccccc21
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: CCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2ccccc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), H2N—CH2-phenyl (VI) and (CH3—CH2—CH2—)(CH3—)N—CO—(CH3—)phenyl-CO—OH (IX) where the attachment to the -phenyl-ring for the carbonyls is 1-,3- and 5- for the methyl group, the title compound is obtained, MH+=510.