Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)nc2N)cc1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)c2ccc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(4-methoxy-phenyl)-methanone (Example 35) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 405.1595, calcd for (M+H)+: 405.1591.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccn1
Reaction time: 3 h

Procedure:
1.1 equivalents of pivalic acid chloride dissolved in 100 ml of dichloromethane are added dropwise at 0° C. to a solution containing one equivalent of 2-aminopyridine and 1.25 equivalents of triethylamine in 400 ml of dichloromethane. Once the addition is complete, the reaction mixture is brought to room temperature for three hours, and then the reaction mixture is washed with a saturated NaHCO3 solution. After drying of the organic phase, filtration and concentration under reduced pressure, the resulting residue is crystallised from hexane, enabling the expected product to be isolated by filtration.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([Br:7])=[N:4][C:3]=1[Br:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:17][CH2:16][N:4]1[C:3]([Br:8])=[C:2]([Br:1])[N:6]=[C:5]1[Br:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCOCc1ccccc1
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1nc(Br)n(COCc2ccccc2)c1Br
Reaction time: 18 h

Procedure:
Tribromoimidazole (2.0 g, 6.6 mmol) in 25 mL of DMF solution was treated with powdered K2CO3 (12.7 g, 91.6 mmol). To the vigorously stirring suspension was added dropwise benzyl chloromethyl ether (1.4 g, 9.2 mmol). After 18 hours, the reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was chromatographed as described previously. The product was used immediately in Example 39.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:4][NH2:1])=[CH:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc2cc(Cl)ccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc2cc(Cl)ccc2o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(azidomethyl)-5-chloro-1-benzofuran (500 mg, 2.44 mmol) in tetrahydrofuran (10 ml) and water (1 ml) was added PPh3 (759 mg, 2.89 mmol) and the contents were stirred for 3 hours at 60° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography eluting with methanol in dichloromethane to afford (5-chloro-1-benzofuran-2-yl)methanamine as a colorless liquid (420 mg, crude). (ES, m/z): [M+H]+ 182.0; 1H NMR (400 MHz, CDCl3): δ 7.55-7.58 (m, 1H), 7.50-7.47 (m, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.50 (s, 1H), 3.99 (s, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][CH2:19][OH:20]>C(Cl)Cl>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (4.98 g, 49.2 mmol) and methanesulfonyl chloride (3.38 g, 29.5 mmol) is added to a solution of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (5 g, 24.6 mmol) in 100 mL of DCM at 0° C. The resulting mixture is stirred at RT overnight. The mixture is then washed with water and brine, and the organic solution is dried over anhydrous magnesium sulfate and concentrated to give methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14](/[C:17](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:18](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:19][CH3:20])=[CH:13][CH:12]=1>>[C:21]1(/[C:18](/[CH2:19][CH3:20])=[C:17](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)\[C:14]2[CH:15]=[N:16][C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCN1CCCCC1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCCCC2)nc1)c1ccccc1
Yield: 83.1 %

Procedure:
Following the same procedure as described in example 3, 2-(piperidin-1-yl)ethanol (385 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenyl but-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (106 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.16-7.21 (m, 2H), 7.01-7.15 (m, 6H), 6.88 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 5.63 (d, J=8.0 Hz, 1H), 4.25 (t, J=5.6 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.40-2.62 (m, 6H), 1.63-1.75 (m, 4H), 1.44-1.56 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); m/z=429 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:40]([NH:39][C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[F:31])=[O:41])[CH:25]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cc(C)ccc3F)c2)c1

Procedure:
A solution of methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate (85.6 mg, 0.2 mmol, 1 eq) and 2-fluoro-5-methylphenyl isocyanate (29 μL, 1.1 eq) in anhydrous DMF (2 mL) was stirred at room temperature overnight. The reaction was then diluted with EtOAc, washed sequentially with aq NH4Cl, saturated aq NaHCO3, brine, and lastly dried with sodium sulfate. The clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex from 1:1 to neat EtOAc). The product containing fractions were concentrated to give the title compound as a white foam (86.2 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH3:22]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Reactant: N
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(Oc2ccccc2C(N)=O)cc1

Procedure:
2-[4-Methylphenoxy]benzoic acid, prepared as described by D. J. Carini in J. Medicinal Chem., 33, 1330- (1990), is converted to the corresponding acid chloride with phosphorous trichloride in benzene. The acid chloride is reacted with ammonia to give 2-(4-methylphenoxy)-benzenecarboxamide. The carboxamide is then dehydrated by treatment with thionyl chloride to give 2-(4'-methylphenoxy)benzonitrile.
Reaction SMILES: [K].CCOCC.[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CCO>[CH2:15]([O:14][C:7](=[O:13])[C:8](=[O:10])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by adapting the procedure described by Gagliardi S., el al., in J. Med. Chem., 1998;41:1568 using potassium (1.66 g, 42.4 mmol), Et2O (200 mL), EtOH (10 mL), diethyl oxalate (7.56 g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene (prepared in ExampleWW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Brc1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 3-bromo-1H-indazole (500 mg) synthesized according to a method of the literature (V> Auwers, et al., J. Prakt. Chem., 1924, 314) in toluene (25 mL, manufactured by Wako Pure Chemical Industries, Ltd.), 3,4-dihydro-2H-pyrane (640 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) and p-toluenesulfonic acid monohydrate (10 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was heated for one hour at 80° C. The reaction solution was cooled to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added thereto. The mixture was extracted with ethyl acetate (3×20 mL), washed with brine (40 mL), and dried (MgSO4), and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 570 mg of the title compound. LC-MS: HPLC retention time 4.93 minutes, m/z 281 (M+H), condition B-1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)COC1CCCCO1
Yield: 95.8 %

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadiene-1-ol (1.81 g, 8.52 mmol) and dihydropyran (1.17 ml, 12.8 mmol) in dichloromethane (6 ml) was stirred, and p-toluenesulfonic acid (40 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After addition of saturated aqueous sodium bicarbonate (30 ml), the product was extracted with hexane/ether (5:1.1) (30 ml). The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a residue, which was purified with silica gel column chromatography to give 1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene (2.42 g, 96%). ##STR58##
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4,6-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]([N:8]1[CH:14]([CH3:15])[CH2:13][C:12]2[CH:16]=[C:17]3[O:22][CH2:21][O:20][C:18]3=[CH:19][C:11]=2[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:9]1)=[S:7])=[O:4].BrBr.CO>C(Cl)(Cl)Cl>[CH3:15][CH:14]1[CH2:13][C:12]2[CH:16]=[C:17]3[O:22][CH2:21][O:20][C:18]3=[CH:19][C:11]=2[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:9][N:8]1[C:6]1[S:7][N:2]([CH3:1])[C:3](=[O:4])[N:5]=1
Reactant: CNC(=O)NC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nc(=O)n(C)s1)OCO3
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To an ice cooled stirred solution of 0.44 g (1.0 mmol) of the starting material XXVII in 8 ml of chloroform a solution of 0.19 g (1.2 mmol) of bromine in 3 ml of chloroform was added. After 0.5 h the reaction mixture was diluted with 15 ml of chloroform and washed with sodium hydrogen carbonate solution and water. The residue obtained on concentration was stirred with methanol and filtered to yield 0.36 g (82%) of the title compound. Mp.: 296° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[CH:75]=C(C(OCC)=O)[O:73][N:72]=2)=[CH:67][CH:66]=1>>[F:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[CH:75]=[C:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([O:6][CH3:7])=[O:5])[C:9]5=[O:37])=[CH:14][CH:13]=4)=[CH:22][CH:21]=3)=[O:25])[O:73][N:72]=2)=[CH:69][CH:70]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)no1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(F)cc5)no4)cc3)cc2C1=O

Procedure:
The compound of example 615 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 3-(4-fluorophenyl)isoxazole-5-carboxylate.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]([O:21]CC)=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([N:4]([CH2:18][C:19]([OH:21])=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CN(C1CC1)S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(CC(=O)O)C2CC2)c(C)c1
Yield: 83 %

Procedure:
A solution of ethyl 2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)acetate (2.7 mmol, 1 eq.) and LiOH (5 eq.) in THF/H2O (1:1) was stirred at room temperature for 12 h. The solvent was removed completely, in vacuo. The crude product was taken up in water and the mixture was washed with ethyl acetate. The aqueous phase was acidified to pH=4 with 1 M HCl and then extracted with ethyl acetate. The organic phase was dried over Na2SO4. After the solvent had been distilled off completely, the crude product was obtained, and was employed in the next stage without further purification. Yield: 83%
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14][CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:12]=2[CH:27]=1>C1COCC1>[NH2:1][C:7]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)[C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14][CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:12]=2[CH:27]=1
Reactant: N
Reactant: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(Cl)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(N)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 5 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
NH3/2-propanol (10 ml) was added dropwise at 5° C. under N2 flow to a mixture of 7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one (described in Example B11a) (0.00247 mol) in THF (15 ml). The mixture was stirred at 5° C. for 1 hour and at room temperature for 2 hours, then poured out into ice water and extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.35 g, 27%). was crystallized from acetonitrile and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 0.28 g (22%) of 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, mp. 218° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>O1CCCC1>[I:25][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 17A (2.16 g, 11.12 mmol) in anhydrous tetrahydrofuran (50 mL) under N2 was cooled to −78° C. and treated dropwise with 1.7 M tert-butyl lithium in pentane (16.35 mL, 27.8 mmol). The mixture was stirred at −78° C. for 15 minutes, warmed to −30° C. and stirred for 2.5 hours. The dark brick-red solution was re-cooled to −78° C. and a solution of iodine (7.06 g, 27.8 mmol) in anhydrous tetrahydrofuran (18.5 mL) was added dropwise over 20 minutes to give a thick reaction mixture that was difficult to stir. The mixture was swirled at −78° C. for 15 minutes, warmed to −30° C., stirred for 40 minutes and warmed to 0° C. The mixture was quenched by addition of H2O (100 mL) and treated with solid Na2SO3 until a constant yellow color was achieved. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated by rotary evaporation. Purification by chromatography on silica eluting with 10%-20% ethyl acetate in dichloromethane afforded the title compound as an amber oil which crystallized upon standing (2.32 g, 65%). MS (DCI+) m/z 321 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](OCC)=[O:33])#[N:28].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](=[O:33])[CH2:10][C:9]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])#[N:28]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide (prepared from N,N-bis(phenylmethyl)amine and acetyl chloride by refluxing for 2 hours in toluene) (120 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperature between -30° C. to -45° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -35° C. to -20° C. and transferred to a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide as an oil. This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (12 g, 0.32 mol) is added over 30 minutes. The reaction is maintained at -78° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (20 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (300 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (300 mL). The ethyl acetate solution is concentrated by vacuum distillation to give crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as an oil which is used without further purification;