Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.C[CH:7](O)[C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1[CH3:29].[ClH:32]>CC1C(CC)=NC=CC=1>[Cl:32][CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1[CH3:29]
Reactant: Cl
Reactant: CC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: CCc1ncccc1C
Agent: CS(=O)(=O)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.8 ml of methane sulphonyl chloride is added at 10° C. to a mixture, under an inert atmosphere, of 15 g of methyl 16α-methyl-21-hydroxy-pregna-1,4,9(11)-triene-3-20-dione in 40 ml of methyl ethyl pyridine, and the whole is agitated at ambient temperature for 5 hours. It is poured into an ice+water mixture, acidified by the addition of hydrochloric acid, filtration is carried out, followed by washing and drying. 16.2 g of expected crude product is obtained which is purified by chromatography, eluting with a benzene/ethyl acetate mixture 8/2. 13.4 g of expected pure product is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[S:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[S:20][C:19]([CH3:18])=[CH:23][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)s2)C=CN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (150 mg, 0.75 mmol) in NMP (1 mL) were added powdered KOH (294 mg, 5.25 mmol) and 2-methyl-5-vinyl-thiophene (186 mg, 1.50 mmol), and the reaction mixture stirred at 90° C. for 5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH-DCM) followed by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(5-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.22 (s, 1H), 7.08 (d, 1H), 6.5 (d, 1H), 6.3 (d, 1H), 4.6 (d, 1H), 4.2-4.4 (m, 3H), 3.7 (m, 2H), 3.2 (m, 3H), 3.03 (s, 3H), 2.7 (m, 1H), 2.38-2.42 (m, 6H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](=[O:15])[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])(=O)[CH3:2].ClCC[S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.[OH-].[K+].CO>O>[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:7](=[O:15])[CH2:6][CH2:5][S:4][CH2:1][CH2:2][S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NCCNC(=O)CCSC(C)=O
Reactant: ClCCSC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NCCNC(=O)CCSCCSC1CCCCO1
Temperature: 75 °C

Procedure:
A quantity of the S-{2-[N-(2-acetylaminoethyl)carbamoyl]ethyl} thioacetate, prepared above, (3.2 g, 23 mmol), 2-(2-chloroethylthio)tetrahydropyran (2 g, 11 mmol), potassium hydroxide (2.5 g, 44 mmol), methanol (10 cm3) and water (5 cm3) were mixed together and heated at 75° C. for 30 min. The mixture was allowed to cool and then partitioned between chloroform (50 cm3) and water (50 cm3). The organic layer was separated and the aqueous layer extracted with a further portion of chloroform. The combined chloroform extracts were then dried (MgSO4) and volatile components removed under reduced pressure to leave the crude product as an oily solid. A quantity of this material was purified firstly by chromatography on silica using a mixture of ethyl acetate, and methanol (95:5) as the eluant and then by reverse phase h.p.l.c. using aqueous methanol as the eluant. The pure N-(2-acetylaminoethyl)-3-[2-(tetrahydropyran-2-ylthio)ethylthio]propionamide was obtained as a white solid (0.3 g).
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.CC1(C)C2C(CC=CC=2)C(C)(C)CC1.[CH3:24][C:25]1([CH3:40])[C:34]2[C:29](=[CH:30][C:31]([N+:35]([O-])=O)=[CH:32][CH:33]=2)[C:28]([CH3:39])([CH3:38])[CH2:27][CH2:26]1>C(O)(=O)C.[Fe]>[CH3:24][C:25]1([CH3:40])[CH2:26][CH2:27][C:28]([CH3:39])([CH3:38])[C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][C:34]1=2
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: CC1(C)CCC(C)(C)C2CC=CC=C21
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of HNO3 [63%] (0.94 mL) and H2SO4 (1.5 mL) was added to 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene 5 (2.0 g, 10.6 mmol) at −10° C. and the reaction mixture was stirred for 1 h. The reaction mixture was poured into ice:water and the product was extracted with CH2Cl2. The organic layer was washed with NaOH (1N), H2O, brine, dried over MgSO4 to give after solvent evaporation 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (1.87 g, 76%). ref. Kagechika, H., Kawachi, E., Hashimoto, Y., Shudo, K., Himi T., J. Med. Chem., 31, 2182-2192, 1988. To a stirred solution of 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (0.593 g, 2.5 mmol) in glacial acetic acid (10 mL) was added iron powder (0.77, 13.8 mmol) over a period of 15 min. The reaction mixture was stirred at 60° C. for 3 hours. The volatiles were evaporated and the resulting oil was partitioned between EtOAc and water. Organics extracts were washed with brine, dried over MgSO4 to obtain 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine 6 (0.232 g, 46% yield) as a brown solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)COC([PH2]=C)=O)C=CC=CC=1.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=[O:29].Br[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:34]=[CH:35][C:30]([C:28](=[O:29])/[CH:27]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:31][CH:32]=2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(CBr)c1ccc(-c2ccc(F)cc2)cc1
Agent: C=[PH2]C(=O)OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 18.5 gm (0.0538 mol) of triphenyl-carbethoxy-methylenephosphoran and 260 cc of absolute benzene was heated to boiling, 7.6 gm (0.026 mol) of 2-bromo-4'-(4-fluoro-phenyl)-acetophenone were added, and the mixture was stirred for two hours at the boiling point. Thereafter, the precipitated triphenyl-carbethoxy-methylphosphonium bromide was separated by vacuum filtration, the clear filtrate was admixed with 4.35 gm (0.026 mol) of ethyl bromoacetate to tie up the triphenyl-phosphine, and the mixture was again boiled for two hours. Thereafter, the reaction mixture was allowed to cool, was then filtered, the filtrate was evaporated, and the residue was recrystallized first from methanol and subsequently from cyclohexane, yielding 4.2 gm (54% of theory) of the compound of the formula ##STR9## having a melting point of 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3S(C3C=CC=C(C(F)(F)F)C=3)(=O)=O)=[C:16]([O:36][CH3:37])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:38]OC(=O)C1C=CC(N)=CC=1Cl>>[CH3:38][O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][NH:20]3)=[C:16]([O:36][CH3:37])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N)cc1Cl
Product: COC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1Cl

Procedure:
2-Chloro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 555.3 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 4 was performed using 4-amino-2-chlorobenzoic acid methyl ester, yielding 2-chloro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester. This was reacted with 3-trifluoromethyl-benzenesulfonyl chloride in step 5, yielding 2-chloro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-chloro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (78.4 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][S:10]([C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[CH:40][N:41]=2)=[C:33]([F:42])[C:32]=1[F:43].ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[F:43][C:32]1[C:33]([F:42])=[C:34]([C:37]2[O:38][CH:39]=[CH:40][N:41]=2)[CH:35]=[CH:36][C:31]=1[CH2:30][N:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][OH:1])[S:10]([C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(C(F)(F)F)nc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Yield: 51.4 %

Procedure:
The title compound was synthesized from N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (50 mg, 0.15 mmol), cesium carbonate (72 mg, 0.22 mmol), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (50 mg, 0.18 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (41 mg, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (d, J=2.01 Hz, 1H), 8.23 (dd, J=8.18, 1.89 Hz, 1H), 7.73-7.84 (m, 3H), 7.44-7.52 (m, 1H), 7.34 (s, 1H), 4.54-4.63 (m, 1H), 4.43-4.53 (m, 1H), 3.77 (td, J=11.58, 3.02 Hz, 1H), 3.60 (dd, J=11.96, 3.15 Hz, 1H), 3.21 (dd, J=11.83, 2.27 Hz, 1H), 3.16 (br. s., 1H), 1.63-1.80 (m, 3H), 1.40-1.61 (m, 2H), 1.35 (dd, J=11.71, 2.14 Hz, 1H), 1.04-1.28 (m, 3H). Analytical HPLC R.T.=22.34 min. HRMS [M+H]+ calc'd 532.1329, found 532.1323.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@@H:60]([OH:59])[CH3:65])[C@@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (230 mg, 0.5 mmol), dicyclohexylcarbodiimide (160 mg, 0.77 mmol), 1-hydroxybenzotriazole (70 mg, 0.51 mmol), and (S)-3-hydroxybutyric acid (107 mg, 1.0 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (131 mg, 48%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[OH:25][C:22]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
1-Methylimidazole (4.1 mL, 50 mmol) in dry tetrahydrofuran was treated with n-butyllithium (25 mL, 50 mmol) at room temperature and heated at 40° C. for 3 hours. The reaction was cooled to −78° C. and 4-oxo-piperidine-1-carboxylic acid tert-butylester (9.96 g, 50 mmol) added. The mixture was allowed to warm to room temperature, stirred for 6 hours the heated to 40° C. for an additional 3 hours. The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was recrystallized from methanol to provide the title compound (8.2 g, 84%) as white solid. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.8 (d, 2H, J=15 Hz), 2.1 (m, 2H), 3.3 (t, 3H, J=15 Hz), 3.8 (s, 4H), 6.8 (dd, 2H, J=9, 3 Hz); MS (DCI/NH3) m/e 282 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][OH:35]>CN(C=O)C>[C:1]([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([NH:32][CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][OH:35])=[O:8])(=[O:3])[CH3:2]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)NC(CO)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-acetamido-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (0.569 g; 2 mmol) in dry DMF (8 ml), 1,1'-carbonyldiimidazole (0.34 g; 2.1 mmol) was added portionwise at 5°-8° C. under nitrogen. After stirring at 5° C. for 1.5 h, (R)-(-)-2-amino-2-phenylethanol (0.33 g; 2.4 mmol) in dry DMF (6 ml) was added dropwise at 3°-5° C. The reaction was then stirred for 2 h in an ice bath and 16 h at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried with an. sodium sulfate and concentrated to dryness. The residue was purified by flash-chromatography on silica gel (ethyl acetate:methanol=98:2) to yield 2-acetylamino-4-(2-amino-5-chlorophenyl)-N-(2-hydroxy-1-phenyl-ethyl)-4-oxobutyramide as a yellow solid (0.18 g; 22%; m.p. 212°-215° C.) (pure diastereoisomer with Rf<).
Reaction SMILES: [CH2:1](N(CC)CC)C.[C:8](=[O:24])([O-])[O:9][C:10]1[CH:15]=C(Cl)C(Cl)=C(C(C)(C)C)[C:11]=1Cl.[CH3:25][C@H:26]1[CH2:30][CH2:29][NH:28][C@@H:27]1[C:31]([OH:33])=[O:32]>C(O)(C)(C)C.O>[C:10]([O:9][C:8]([N:28]1[CH2:29][CH2:30][C@H:26]([CH3:25])[C@H:27]1[C:31]([OH:33])=[O:32])=[O:24])([CH3:11])([CH3:15])[CH3:1]
Reactant: CC(C)(C)c1c(Cl)c(Cl)cc(OC(=O)[O-])c1Cl
Reactant: C[C@H]1CCN[C@@H]1C(=O)O
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O

Procedure:
Triethylamine (3.5 ml) and t-butyl-2,4,5-trichlorophenyl carbonate (3.5 g) were added to a solution of trans-3-methyl-L-proline (1.25 g) in t-butanol (12 ml) and water (8 ml). The mixture was heated to 60° for 2 hours, evaporated, the residue dissolved in 1 N sodium bicarbonate solution (50 ml) and the solution washed with ether. Excess solid citric acid was added, the product extracted into ethyl acetate, the combined extracts dried (Na2SO4) and evaporated giving a crude crystalline product (1.6 g). Recrystallisation from ethyl acetate/light petroleum (40°-60°) gave the desired product (1.33 g), m.p. 146°-150° [α]D20 - 60.1° (c, 1.0, chloroform)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:20])[C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:9]=2[C:17](=[O:19])[CH:18]=1.CO.[C:23](OC(=O)C)(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[C:23]([N:5]([C:6]1[C:7](=[O:20])[C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:9]=2[C:17](=[O:19])[CH:18]=1)[CH2:4][CH2:3][O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: COCCNC1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COCCN(C(C)=O)C1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Five drops of concentrated sulfuric acid was added to a solution of methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.2 g) in acetic anhydride (20 ml) and the mixture was stirred at room temperature for 1 hour. Methanol (20 ml) was gradually added to the reaction solution and then the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish brown powder.
Reaction SMILES: [CH3:1][N:2]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:14]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:14].[Cl:14][C:10]1[N:9]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN(c1ccncc1)n1cccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccncc1)n1cccc1Cl
Product: Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of N-Methyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (7.7 g) in 300 ml of anhydrous tetrahydrofuran cooled to 5° with an ice bath was added N-chlorosuccinimide (5.2 g). The reaction mixture was stirred sixty hours at ambient temperature, and thereafter additional NCS (0.9 g) was added. After stirring an additional sixteen hours at ambient temperature, the reaction mixture was stirred with an aqueous solution of sodium bisulfite and extracted with ether. The organic extract was washed with water and saturated sodium chloride and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 9.5 g of an oil. This oil was purified by HPLC (silica, ethyl acetate) to give 4.4 g of an oil. This oil was purified by column chromatography (alumina, ether) to give 2.4 g of the desired product as an oil. This oil was dissolved in 25 ml of isopropanol, filtered, and converted to the hydrochloride salt by the addition of ethereal hydrochloric acid. The solution was diluted with 25 ml of ether and cooled. The resultant precipitate was collected and dried to give 2.5 g of crystals, mp 230°-231° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2)#[CH:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]3)[CH:16]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1ccc2c(c1)CCC(=O)N2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CCc2cc(C#Cc3cccnc3)ccc2N1

Procedure:
A mixture of 11.6 mg of cuprous iodide, 86 mg of bis (triphenylphosphine)palladium(II)dichloride, 1.0 g of 6-ethynyl-3,4-dihydrocarbostyril and 3-bromopyridine were reacted as shown in Example 9, and the product isolated in a similar fashion, giving 6-[2-(3-pyridyl)ethynyl]-3,4-dihydrocarbostyril, m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:43])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([N:37]2CC[CH2:39][C:38]2=[O:42])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17](C)([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](NC1C=C(C=C(N2CCCC2=O)C=1)C(O)=O)(=O)[CH3:45].C12CC(CC1)CC2NC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC1C=CC=CC=1>>[C:38]([NH:37][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=1)[C:24]([NH:23][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH:17]2[CH2:18][CH:44]1[CH2:45][CH2:19]2)[CH3:12])=[O:43])(=[O:42])[CH3:39]
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: CC(=O)Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Product: CC(=O)Nc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E5, from 3-acetylamino-5-(2-oxopyrrolidin-1-yl)benzoic acid (D13) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).