Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[CH2:32][O:33][CH2:34][C:35]([CH3:37])=[CH2:36]>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[CH2:36][C:35]([CH2:34][O:33][CH2:32][C:26]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])([CH3:37])[O:6][N:5]=1
Reactant: C=C(C)COCc1c(F)cccc1F
Reactant: ON=Cc1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(COCc2c(F)cccc2F)CC(c2ccccc2Cl)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
224 mg of 2-chlorobenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane and then washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 400 mg of 3-(2-chlorophenyl)-5-((2,6-difluorobenzyloxy)methyl)-5-methyl-4,5-dihydroisoxazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:16][C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=3[NH:9][C:5]=2[CH2:4][CH2:3]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:17])[CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=3[NH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2[nH]c3cc(C#N)ccc3c2C1
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1c2c([nH]c3cc(C#N)ccc23)CCC1(C)C
Yield: 108.3 %

Procedure:
Using the procedure of Example 9, 5.6 g of the carbonitrile from Example 5 was alkylated with 6.35 g of 1-bromooctane to give 9.1 g (96.4%) of 5,6,7,8-tetrahydro-8,8-dimethyl-9-octyl-9H-dibenzo[b,d]pyrrole-3-carbonitrile as a yellow oil. This material was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O1[CH2:15][CH2:14][O:13][CH2:12]C1.[OH-].[Na+].C(C1OC1)Cl>O.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:15][CH:14]1[O:13][CH2:12]1
Reactant: COc1ccccc1O
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: ClCC1CO1
Product: COc1ccccc1OCC1CO1

Procedure:
To 2-methoxyphenol(76 g) dissolved in about 60 ml of water and 200 ml of dioxane containing 29 g of sodium hydroxide is slowly added a large excess of epichlorohydrin (80 g). The solution is stirred at reflux temperature for 3 hrs. The mixture is diluted with ether, washed with two portions of water and dried using anhydrous magnesium sulfate. Evaporation of the dried extract, followed by distillation of the residue produced the product, 1-(2-methoxyphenoxy)-2,3-epoxypropane.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:57])[CH2:41][N:42](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:36][C:35]=1[NH:58][S:59]([CH3:62])(=[O:61])=[O:60])C1C=CC=CC=1>>[OH:57][CH:40]([C:37]1[CH:38]=[CH:39][C:34]([OH:33])=[C:35]([NH:58][S:59]([CH3:62])(=[O:61])=[O:60])[CH:36]=1)[CH2:41][NH:42][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 230) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84(t, J=7.0 Hz, 3 H), 1.15–1.40 (m, 12 H) 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.92 (m, 7 H), 3.50–3.65 (m, 2 H), 4.49 (dd, J=8.0, 4.1 Hz, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.04 (d, J=8.0 Hz, 2 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 597.1 (MH+); HRMS Calcd. for C28H45N4O6S2 (MH+): 597.2781. Found: 597.2776.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH2:18][F:19])([CH2:16][F:17])[CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:21]>>[F:19][CH2:18][C:5]1([CH2:16][F:17])[CH:4]=[C:3]([C:1]([NH2:2])=[O:21])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: O=S(=O)(O)O
Reactant: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Product: NC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 36 h

Procedure:
A mixture of 3 g of 4-cyano-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran and 20 ml of sulfuric acid was stirred for 36 hours. The reaction mixture was poured into ice water and the separated crystal was collected by filtration. The above-obtained crystal was diluted with ethyl acetate and the organic layer was washed with water and dried. The solvent was distilled off to obtain 3 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboamide represented by the following formula.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].[C:18]([C:22](Cl)=[O:23])([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>ClCCl.CCCCCC>[C:18]([C:22]([O:17][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([OH:8])[CH:16]=1)=[O:23])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
Triethylamine (5 ml) was added to a stirred suspension of 2,4-dihydroxybenzaldehyde (12 g) in dichloromethane (50 ml) at -8° C. To this mixture was added t-butylcarbonyl chloride (4.4 ml) and the mixture was allowed to warm to ambient temperature and was stirred at this temperature for 16 hours. The reaction mixture was washed consecutively with aqueous 1N hydrochloric acid (20 ml), water (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml) and then dried (MgSO4). The residue obtained on removal of the solvent was subjected to chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:9 v/v) to give 4-(t-butylcarbonyloxy)-2-hydroxy-benzaldehyde (5.82 g; 35%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>ClCCl>[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH:26][C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2ncccc2C#N)C[C@H]1OC
Temperature: 70 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
A mixture of 1.66 parts of 2-chloro-3-pyridinecarbonitrile, 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.3 parts of sodium carbonate and 22.5 parts of N.N-dimethylacetamide was stirred for 20 hours at 70° C. The reaction mixture was taken up in dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.19 parts (21.6%) of cis-4-amino-5-chloro-N-[1-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 134.0° C. (compound 32).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.I[CH2:45][C@@H:46]1[CH2:51][O:50][CH2:49][CH2:48][O:47]1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:47]1[CH2:48][CH2:49][O:50][CH2:51][C@H:46]1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: IC[C@@H]1COCCO1
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using (R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-2-(iodomethyl)-1,4-dioxane (Kim, H. Y. et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, (8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (51%) as a colorless solid: mp 198-199° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.8, 1.1 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H), 6.24 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.98-3.78 (m, 4H), 3.75-3.56 (m, 4H), 3.47-3.38 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.9, 155.3, 144.7, 142.7, 138.4, 132.4, 128.9, 123.8, 123.5, 121.3, 111.7, 109.6, 99.5, 80.1, 73.3, 69.2, 66.7, 66.5, 64.6, 64.0, 58.1, 41.8; MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21]1([C@H:27]([N:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]2([OH:35])[CH2:33][CH2:34][N:29]([C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])[CH2:30][CH2:31]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccccc1)N1CCC(=O)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@H](c1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 121.8 %

Procedure:
175.2 g (666 mmol) of 4-benzyloxybromobenzene was dissolved in 1.4 L dry THF (MS 4 A) under argon. The solution was cooled to −75° C. and a solution of 416 mL 1.6 M butyllithium (666 mmol) in hexane was added during 40 min. After stirring for 1 h a solution of 113 g (555 mmol) (R)-1-(1-phenyl-ethyl)-piperidin-4-one in 400 mL dry THF was added during 1 h at −75° C. The mixture was stirred for another 1 h and, after heating to room temperature, poured into 1.5 L of ice water. The mixture was extracted with 1 L ethyl acetate. The organic phase was washed with 1 L of a half-saturated NaCl solution, dried over Na2SO4 and concentrated to yield 262 g of (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-piperidin-4-ol.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:24][C:23]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:22][N:21]=4)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:32]([O:37][CH2:38][CH2:39]Br)(=[O:36])[C:33]([CH3:35])=[CH2:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:32]([O:37][CH2:38][CH2:39][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[O:24][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)[CH:15]=3)=[N:21][N:22]=2)[CH:26]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)OCCBr
Reactant: Oc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 21 h

Procedure:
To a solution of 3-(5-(3-carbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (0.80 g, 1.98 mmol) and 2-bromoethyl methacrylate (0.40 g, 2.07 mmol) in DMF (15.0 ml) was added K2CO3 (4.0 g, 28.94 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 21 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After removal of solvent, Methanol (120.0 ml) was added into this glass-like solid. After removal of methanol, White solid product was obtained and collected from water by filtration. After vacuum dry, the product as white solid in 038 g (76.4%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.34 (m, 1H), 8.26 (m, 111), 8.15 (dd, J1=8.0 Hz, J2=0.8 Hz, 2H), 7.78-7.66 (m, 4H), 7.42 (m, 5H), 7.31 (m, 2H), 7.10 (m, 1H), 6.12 (t, J=1.2 Hz, 1H), 5.56 (m, 1H), 4.51 (m, 2H, OCH2), 4.27 (m, 2H, OCH2), 1.93 (t, 3=1.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.25, 164.71, 163.88, 158.97, 140.61, 138.73, 135.86, 130.86, 130.37, 126.19, 125.85, 125.78, 125.43, 124.80, 123.56, 120.45, 120.37, 119.85, 118.88, 112.42, 109.54, 66.21, 62.84, 18.27. [M]+ calcd for C32H25N3O4, 515.2. found 515.2. Anal. Calcd for C32H25N3O4: C, 74.55; H, 4.89; N, 8.15. Found: C, 74.26; H, 4.83; N, 8.03.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10]1
Reactant: O=C1N[C@@H]2CCCC[C@@H]2N1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of cis-(+/−)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one Hydrochloride salt (263 mg, 1.01 mmol) in MeOH (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (241 mg, 1.21 mmol). The mixture was stirred at room temperature for 30 min before sodium cyanoborohydride (95 mg, 1.52 mmol) was added. The mixture was stirred overnight at room temperature, additional amount of tert-butyl 4-oxopiperidine-1-carboxylate and sodium cyanoborohydride (1 eq each) were added and stirred at room temperature for 3 more days. MeOH was concentrated in vacuo, the residue dissolved in dichloromethane (20 mL) and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. To provide the title compound (244 mg, 59%) MS (M+1): 407.4
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:3]1=2.B.C(OCC)(=O)C>O1CCCC1.O>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2Sc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 5.1 gm. of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylic acid in 100 cc. of tetrahydrofuran and add 35 cc. of 1M borane in tetrahydrofuran at room temperature under a nitrogen atmosphere. Stir the mixture at room temperature for 3 hours. Slowly dilute the reaction mixture with water and then with ethyl actate. Wash with aqueous sodium chloride, dry and evaporate to an oil.
Reaction SMILES: [C:1]1([CH:7]([NH:14][S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.C(OC(=O)C)C>C(COC)OC.[Li+].[OH-]>[C:1]1([CH:7]([NH:14][S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1

Procedure:
0.2 g of Ethyl 3-phenyl-3-{[3′-(1,3-thiazol-2-ylamino)[1,1′-biphenyl]-3-yl]sulfonylamino}-propanoate 15.1.1 were saponified in 15 ml dimethoxyethane 12 ml water and 0.2 g LiOH. After aqueos work-up and flash chromatography (dichloromethane/methanol 10+1) 65 mg were obtained.
Reaction SMILES: [OH:1][CH:2]1[C:6](=O)[N:5]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][C@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].B>O1CCCC1>[OH:1][CH:2]1[CH2:6][N:5]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:4][C@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Agent: B
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(O)[C@@](C)(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 30.5 %

Procedure:
To a solution of tert-butyl(3S)-4-hydroxy-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (5.13 g, 16.1 mmol) in tetrahydrofuran (100 mL), 1.17M solution of borane in tetrahydrofuran (45.3 mL, 53.1 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 13 hours. After concentrating the reaction mixture under reduced pressure, water (10 mL), ethanol (100 mL), and triethylamine (5 mL) were added to the concentrate, and the mixture was heated under reflux in an oil bath at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (200 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (200 mL ×2). The resulting organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1→1:2) to obtain 1.50 g (31%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:6])=[S:5])C.CN(C1C=CC=CC=1)C(N)=S>>[CH3:1][N:3]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:5][C:4]1=[NH:6]
Reactant: CCN(C(N)=S)c1ccccc1
Agent: CN(C(N)=S)c1ccccc1
Product: Cn1c(=N)sc2ccccc21
Yield: 95.6 %

Procedure:
When the reaction is carried out as described in Example 23 with the exception that instead of N-ethyl-N-phenylthiourea an equimolar amount of N-methyl-N-phenylthiourea is used, 3-methyl-2-iminobenzthiazoline melting at 122° C. is obtained in a yield of 95.6% and with an equally good purity.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=3[CH3:37])[N:21]=2)[N:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:2].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:69][N:70]([CH3:77])[CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([N:74]4[CH2:75][CH2:76][CH:71]([N:70]([CH3:77])[CH3:69])[CH2:72][CH2:73]4)=[O:33])=[CH:30][C:29]=3[CH3:37])[N:21]=2)[N:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)O)cc3C)ncc2C)n(C)c1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)N4CCC(N(C)C)CC4)cc3C)ncc2C)n(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
A suspension of 4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-5-methyl-pyrimidin-2-ylamino}-3-methyl-benzoic acid (177 mg, 0.356 mmol) in anhydrous dimethylformamide (10 mL) was treated with N-ethyl-N,N-diisopropylamine (0.60 mL, 3.55 mmol) and TBTU (183 mg, 0.569 mmol). The mixture was then treated with dimethyl-piperidin-4-yl-amine (91 mg, 0.711 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with water and the resulting precipitate was collected by filtration. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 9/1) to afford 118 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:20])[CH:14]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 1 h

Procedure:
A solution of 88 parts of 3,4,5,6-tetrahydrophthalic anhydride in 2000 parts of glacial acetic acid was treated with 84 parts of 4-chloro-2-fluoroaniline at once and stirred for one hour. After refluxing for 19 hours, 1000 parts of acetic acid were distilled from the reaction mixture. The residue from the distillation was poured over 3000 parts of ice. The resulting crystals were filtered and recrystallized from 700 parts of methanol at -40° after activated carbon treatment, to yield 117 parts off-white crystals of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 76.5-78.0°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6]>CCOC(C)=O.CO>[F:1][C:2]([F:17])([F:18])[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C(/c1cccc(OC)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC(c1cccc(OC)c1)C(F)(F)F
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A 250 mL flask containing a solution of 6.1 (2.20 g, 8.5 mmol) in 1:1 EtOAc/MeOH (40 mL) was purged with N2. To the mixture was added palladium, 10 wt. % (dry), on carbon powder, wet (0.90 g, 0.85 mmol). The vial was then purged with H2, and the contents were stirred overnight under a H2 balloon. The black mixture was filtered through a pad of Celite and concentrated to afford 6.2 (2.19 g, 99% yield).