Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:18]
Reactant: O=Cc1ccccc1
Reactant: Cc1csc2ccccc12
Product: Cc1c(C(O)c2ccccc2)sc2ccccc12

Procedure:
Using general procedure B, 3-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a pale yellow solid. MS: 236.8 ([M+H—H2O]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ClCl>COCCO.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Agent: ClCl
Solvent: COCCO
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C)CC3)cc21
Reaction time: 6 h
Yield: 53 %

Procedure:
A solution of 4.3 g (0.015 mol) of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 9 g of 1-methylpiperazine in a mixture of methyl cellosolve (45 cm3) and dimethylformamide (10 cm3) was heated to reflux temperature. After 6 hours, 75% of the theoretical amount of ionized chlorine (1 atom) had been released into the mixture. Heating was continued for a further 2 hours. The solution was concentrated to dryness in vacuo. The residue was taken up in 20 cm3 of ethanol. The solid, which was filtered off and recrystallised from methyl cellosolve, gave 2.78 g of 6-chloro-1-ethyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 260° C., which was identical to the compound described in Example 1.
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[C:5](=O)[CH:6]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[CH2:7][CH2:8][CH2:9]\1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:46]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]4[CH:11]=[C:12]([F:18])[C:13]([F:17])=[C:14]([F:16])[CH:15]=4)[C:5]=3[N:45]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1/CCCC(c2cc(F)c(F)c(F)c2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2cc(F)c(F)c(F)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-[1-dimethylamino-meth-(Z)-ylidene]-6-(3,4,5-trifluoro-phenyl)-cyclohexanone (120 mg, 0.42 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (131 mg, 0.35 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (64 mg, 64%). MS ISP (m/e): 466.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.57 (s, 1H), 8.36 (s, 1H), 7.60 (m, 2H), 7.01-7.18 (m, 4H), 6.98 (s, 1H), 4.18 (m, 1H), 3.55 (s, 3H), 2.73 (m, 2H), 2.13 (s, 3H), 1.70-2.20 (m, 4H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[NH:19][C:11]2[NH:12][C:13]([S:17][CH3:18])=[N:14][C:15](=O)[C:10]=2[CH:9]=1)[CH3:7].CN(C)C1C=CC=CC=1>>[CH3:18][S:17][C:13]1[NH:12][C:11]2=[N:19][C:8]([CH2:6][CH3:7])=[CH:9][C:10]2=[C:15]([Cl:3])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc2c(=O)nc(SC)[nH]c2[nH]1
Solvent: CN(C)c1ccccc1
Product: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Phosphorous oxychloride (21 mL) was carefully added to a mixture of 5.66 g (27.0 mmol) of 1,7-dihydro-6-ethyl-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-4-one and 1.70 mL of N,N-dimethylaniline. The reaction was heated to 95° C. for 12 hours. At this time the reaction was cooled and concentrated under vacuum. The residue was combined with 60 g of ice and stirred for 1 hour. The solids were collected by filtration, washed with 30 mL of water and suspended in 100 mL of water. The solids were again collected, washed with 30 mL of water, and dried in vacuo (40° C., 10 torr) to provide 5.50 g (89.6%) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as a yellow solid. nmr (500 MHz, dmso-d6) δ1.24 (t, J=7.5 Hz, 3H), 2.52 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 6.21 (s, 1H), 12.27 (s, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH2:15][Cl:16].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:16][CH2:15][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:8]([CH:9]=[O:10])[C:7]=1[OH:12]
Reactant: COCCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Yield: 72 %

Procedure:
A mixture of 12.0 g of 5-nitrosalicylaldehyde and 100 ml of chloromethyl methyl ether was cooled on an ice bath, and 43.9 g of anhydrous aluminum chloride was added portionwise to said mixture, and the resultant mixture was stirred at room temperature for 10 minutes and then heated under reflux for 22 hours. Then, the reaction mixture was cooled on an ice bath and 200 ml of water was added thereto with vigorous stirring, whereupon white crystals precipitated out. These white crystals were taken out and dissolved in hot hexane, and the solution was filtered, and the mother liquor was cooled to give 14.9 g of 3-chloromethyl-5-nitrosalicylaldehyde as colorless needles (yield 72%).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[CH:15]1([O:27][CH2:28][C:29](O)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1.[K+].[Br-]>ClCCl.CN(C)C1C=CN=CC=1>[CH:15]1([O:27][CH2:28][C:29]([C:1]2[C:6](=[O:7])[S:5][CH2:4][C:2]=2[OH:3])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CSC(=O)C1
Reactant: O=C(O)COC1CCCCCCCCCCC1
Agent: CN(C)c1ccncc1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCCCCCCCCCC1)C1=C(O)CSC1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.37 g (3.2 mmol) of thiotetronic acid in 20 mL of dry dichloromethane at 0° C. is added 0.4 mL (2.9 mmol) of triethylamine followed by 0.11 g (0.9 mmol) of 4-dimethylaminopyridine. After stirring at 0° C. for 5 minutes, 0.7 g (2.9 mmol) of cyclododecyloxyacetic acid is added, followed by 1.35 g (3.2 mmol) of 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate. After 10 minutes the ice bath is removed and the reaction mixture is allowed to stir overnight. The reaction mixture is quenched with 1N HCl. The layers are separated and the organic layer is washed twice with aqueous sodium bicarbonate and then twice with 2N HCl. The organic phase is then dried over MgSO4 and the dichloromethane evaporated. The residue is flash chromatographed on acidic silica gel using 50% ether/hexanes and then recrystallized from hexanes to give a yellow solid: m.p. 93°-95° C.; IR (KBr) 2920, 2840, 1690, 1660, 1580 cm-1 ; NMR (DMSO-d6) δ 1.2-1.6 (m, 10H), 3.4 (m, 1H), 3.95 and 4.4 (s, 2H), 4.6 (bs, 2H); MS (EI) M+340.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(OC)c2)c(N)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A mixture of 3-amino-6-chloro-1-ethoxycarbonyl-2-(3-methoxybenzoyl)indole (step 1, 998 mg, 2.68 mmol) and K2CO3 (3.70 g, 26.8 mmol) in 70% aqueous ethanol (45 ml) was refluxed for 6.5 h and then cooled to room temperature. The mixture was concentrated to ca. 20 ml, diluted with ethyl acetate (150 ml), and the organic layer washed with water (50 ml×2) and dried (Na2SO4). After removal of solvent the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford 549 mg (68%) of the title compound as a syrup. 1H-NMR (CDCl3) δ: 7.62 (1H, br s), 7.55-7.30 (5H, m), 7.23 (1H, d, J=1.5 Hz), 7.10 (1H, ddd, J=1.1, 2.6, and 8.1 Hz), 5.60 (2H, br s), 3.88 (3H, s)
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([NH:23][C:24](=[O:31])[C@@H:25]1[CH2:29][CH:28]([F:30])[CH2:27][NH:26]1)[CH3:22]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:26]1[CH2:27][CH:28]([F:30])[CH2:29][C@H:25]1[C:24]([NH:23][CH2:21][CH3:22])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCNC(=O)[C@@H]1CC(F)CN1
Product: CCNC(=O)[C@@H]1CC(F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 530 mg of the compound obtained in Step 11-4 as starting materials, respectively 708 mg (Isomer A: colorless amorphous) and 501 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:11]1([C:14]2[C:15]([O:28][CH2:29][C:30]3([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=2)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:11]1([C:14]2[C:15]([O:28][CH2:29][C:30]3([CH3:37])[CH2:35][CH2:34][C:33](=[CH2:1])[CH2:32][CH2:31]3)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=2)[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:13][CH2:12]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(=O)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
To a cooled (−20° C.) suspension of methyltriphenylphosphonium bromide (1.44 g, 4.02 mmol) in tetrahydrofuran (12 mL) was added lithium hexamethyldisilazide (1M solution in tetrahydrofuran, 4.0 mL, 4.00 mmol). After 90 minutes, a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)methoxy)benzoate (1.00 g, 2.68 mmol) in tetrahydrofuran (6 mL) was added. The reaction mixture was slowly warmed to ambient temperature and stirred for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with ethyl acetate (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.83 g, 82%) as a colourless oil: MS (ES+) m/z 319.1 (M−55).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 70 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[C:12](=[O:14])[CH3:13].Cl>CO>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 12 ml of methanol at 0° C. was added 1.55 g (41.1 mmol, 1.7 eq) of NaBH4, followed by a solution of 1-(2,6-dichloro-3-fluorophenyl)ethanone (5.0 g, 24.1 mmol, 1.0 eq) in 10 ml of methanol. The reaction was warmed to room temperature (r.t.) and stirred for 2 hours. A 1.0M HCl solution was added, and the solution was extracted with dichloromethane (DCM), dried, and evaporated to a white solid, 5.6 g, in 111% crude yield. The product was used for next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Br:15]Br.C(Cl)(Cl)Cl>ClCCl>[Br:15][CH2:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: CC(=O)c1cc2cc(C#N)ccc2o1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2oc(C(=O)CBr)cc2c1
Yield: 70.1 %

Procedure:
21.0 g of 2-acetyl-5-benzofurancarbonitrile was dissolved in 300 ml of dichloromethane. With stirring at a temperature of -10° C., 30 ml of dichloromethane solution containing 18.2 g of bromine was added dropwise to the above solution. After gradually warming up to ice-cold temperature, the resulting reaction solution was mixed with chloroform and washed with 10% sodium thiosulfate aqueous solution. After drying the organic layer and subsequent concentration to dryness, the resulting residue was recrystallized from a benzene/n-hexane mixture to obtain 21.0 g of 2-(2-bromo-1-oxoethyl)-5-benzofurancarbonitrile in the form of colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)(O)[O-].[K+]>BrC1C=CC=CC=1.[Cu]I>[C:4]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [K+]
Solvent: Brc1ccccc1
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 124.2 %

Procedure:
A suspension of indole (8.2 g), potassium bicarbonate (12 g) and copper (I) iodide (2.7 g) in bromobenzene (70 mL) was refluxed for 3 hours under nitrogen atmosphere. To the mixture copper (I) iodide (11 g) was added and the mixture was refluxed for additional 6 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1 to 20:1) to provide 8.4 g of the title compound. Yield 62%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]([CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:4][C:3](=[O:11])[CH2:2]2.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:7]12([OH:9])[CH2:8][CH:1]3[CH2:10][CH:5]([CH2:4][CH:3]([CH2:2]3)[O:11]1)[CH2:6]2
Reactant: O=C1CC2CC(=O)CC(C1)C2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC12CC3CC(CC(C3)O1)C2
Yield: 87.6 %

Procedure:
386.6 mg (2.54 mmoles) of bicyclo[3.3.1]nonane-3,7-dione is dissolved in 5 mL of methanol and treated with sodium borohydride (100 mg, 2.64 mmoles) at 0° C. for 2 hours. The solution is treated with 5 mL of saturated aqueous sodium bicarbonate for 1 hour at 25° C. and extracted with 3×10 mL portions of chloroform. The combined chloroform extracts are combined, dried over sodium sulfate, stripped of solvent in vacuo, and purified by column chromatography (silica, eluant=50% hexanes, 50% ethyl acetate) yielding 343 mg (88%) of the desired product. 1HNMR (CDCl3, 500 Mhz): d 1.563 (d, 2H), 1.70-1.76 (m, 1H), 1.788 (d, 2H, J=11.1 Hz), 1.839 (d, 2H, J=13.1 Hz), 1.925 (d, 2H, J=13.0 Hz), 2.310 (s, 2H), 2.690 (s, 1H), 4.283 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C@@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C@@H:18]([NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Nc1nc(C)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
To a solution of 2-chloro-3-nitro-6-picoline (200 mg, 1.16 mmol) in DMF (3 mL) were added (R)-3-amino-3-phenylpropanoic acid ethyl ester hydrochloride (319 mg, 1.39 mmol) and DIPEA (0.5 mL, 2.90 mmol). The reaction mixture was stirred at 70° C. for 12 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford 398 mg (100%) of the title compound as orange oil. The resulting residue was used for the next reaction without further purification. LCMS, M++1, m/z: 330.29.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([O:22][CH2:23][CH3:24])[CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:23]([O:22][C:8]1[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(OCC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc(CO)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 79.7 %

Procedure:
To the above synthesized 2-ethoxy-4′-trifluoromethyl-biphenyl-4-carboxylic acid ethyl ester (0.515 g, 1.52 mmol), dissolved in 6 ml of abs. THF, was added drop wise at −10° C. DIBAL-H solution in toluene (3.81 ml 1M, 2.5 eq.). After additional 60 Min. at ambient temperature, the reaction mixture was carefully poured onto crashed ice/dil. HCl-solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 0.359 g of the title alcohol was isolated as white solid, sufficiently pure for the next step.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CO>O1CCCC1.Cl.O1CCOCC1>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(CO)cc3C2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of 2-(4-(2-cyclopentylacetamido)phenylcarbamoyl)isoindoline-5-carboxylic acid (18 mg, 0.044 mmol) in tetrahydrofuran was added 1M borane in tetrahydrofuran (0.18 mL, 0.18 mml) dropwise. The mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and treated with several drops of 4M HCl-dioxane and methanol and then the clear solution was stirred at room temperature for 2 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.26 (s, 1H), 7.45 (s, 4H), 7.28-7.32 (m, 2H), 7.22-7.26 (m, 1H), 5.18-5.22 (m, 1H), 4.72-4.73 (bs, 4H), 4.50-4.53 (bs, 2H), 2.17-2.32 (m, 3H), 1.70-1.80 (m, 2H), 1.44-1.67 (m, 4H), 1.13-1.24 (m, 2H); MS (ESI(+)) m/e 394 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:13]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].I.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](SC)=[NH:32]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][C:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)=[NH:32])=[CH:21][C:13]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A stirred suspension of tert-butyl methyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (650 mg, 1.839 mmol) and palladium, 10 wt. % on activated carbon (196 mg, 0.184 mmol) in ethanol (10 mL) was stirred under an atmosphere of hydrogen (balloon pressure) at room temperature for 2 hours. To the mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (787 mg, 2.76 mmol), and the resulting suspension was stirred at room temperature overnight. The mixture was filtered to remove palladium, diluted with water and saturated sodium carbonate, and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 2:3 ethyl acetate:hexanes to afford the desired product (420 mg, 52.8%). 1H NMR (DMSO-d6) δ 7.72-7.68 (m, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.09-7.05 (m, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.38-6.21 (m, 3H), 6.08 (d, J=8.4 Hz, 1H), 3.64-3.56 (m, 2H), 3.42-3.33 (m, 4H), 3.03-2.94 (m, 2H), 2.81 (s, 3H), 1.36-1.22 (m, 9H); ESI-MS (m/z, %): 433 (MH+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[CH:15]=[N:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11][C@H:10]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[ClH:26].C([OH:29])C>>[ClH:26].[ClH:26].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]2[C:15](=[O:29])[NH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11][C@H:10]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C[C@H]2C=Nc3ccccc3S[C@H]2c2ccccc2)CC1
Reactant: CCO
Agent: Cl
Product: CN1CCN(C[C@H]2C(=O)Nc3ccccc3S[C@H]2c2ccccc2)CC1

Procedure:
5.2 g of cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)-methyl]-2-phenyl-1,5-benzothiazepine prepared as described in Example 18 or 19 was dissolved in 15 ml of ethanol and 3.6 ml of concentrated hydrochloric acid was added to the solution with stirring. The precipitated crystals were separated by filtration and recrystallized from aqueous methanol to obtain cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one dihydrochloride as colorless needles having a melting point of 231° C. (with decomposition). [α]D20 =-56° (c=0.4, water).