Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:16][CH:15]=1)=[O:13].Cl.[CH3:38][NH:39][O:40][CH3:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[CH3:38][N:39]([O:40][CH3:41])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:30]=[C:29]([C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:18][CH:19]=2)=[O:13])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)-amino]benzoic acid (1.10 g, 2.32 mmol), N,O-dimethylhydroxylamine hydrochloride (226 mg, 2.32 mmol), and Hunig's base (1.62 mL, 9.30 mmol) in dimethylformamide (15 mL) were added HATU (882 mg, 2.32 mmol) and the mixture was stirred at rt for 2 h. The mixture was diluted with dichloromethane and washed with 2 N sodium hydroxide. The separated organic layer was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was purified by short flash column chromatography to give N,4-dimethyl-N-(methyloxy)-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzamide (1.16 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.80 (s, 1H), 8.19 (d, 2H), 8.00 (d, 2H), 7.90-7.79 (m, 5H), 7.67-7.63 (m, 4H), 7.44-7.40 (m, 2H), 7.35 (d, 1H), 3.59 (s, 3H), 3.27 (s, 3H), 2.31 (s, 3H). MS (EI) for C31H27N5O3: 518.3 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[C:3]1[S:2][CH3:1]
Reactant: CN(C)CCCCl
Reactant: CSc1[nH]c2ccccc2c1C(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1c(C(=O)Nc2ccccc2)c2ccccc2n1CCCN(C)C

Procedure:
A solution of 2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXV: R8 =H] (1.8 g, 6.4 mmol) in EtOH (400 mL) was treated with 3-(dimethylamino)propyl chloride hydrochloride (10.0 g, 64 mmol) and K2CO3 (13 g, 96 mmol) and heated under reflux for 3 hours. A further 10 equivalents of the reagents were then added, and the mixture was heated under reflux for a further 48 hours. EtOH was removed under reduced pressure, and the residue was diluted with water to give crude product. This was chromatographed on alumina, eluting with CH2Cl2 containing 0.2% MeOH, to give 1-[3-(dimethylamino)propyl] -2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXVI: R8 =H, R9 =(CH2)3NMe2 ] (0.49 g, 21%) as an oil.
Reaction SMILES: C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=O)C.C1(C)C(S)=CC=CC=1.B(F)(F)F.CCOCC.C(O[C@H:54]1[C@@H:67]([O:68][C:69](=[O:71])[CH3:70])[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]1[S:56][C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=O)C>C(Cl)Cl>[C:69]([O:68][C@H:67]1[C@H:66]([O:72][C:73](=[O:75])[CH3:74])[C@@H:65]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[O:64][C@@H:55]([S:56][C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[C@@H:54]1[NH:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])(=[O:71])[CH3:70]
Reactant: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccccc1S
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(C)cc2)[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 89 %

Procedure:
The tittle compound was prepared from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxylcarbonylamino)-β-D-glucopyranose (Boullanger, P. et al Carbohydr. Res. 1990, 202, 151) (11.8 g, 22.5 mmol), thiocresol (3.07 g, 24.75 mmol) and BF3-Et2O (10 mL) in dry CH2Cl2 (60 mL) by the procedure described above (see compound 1) The crude product was crystallization from ether to give 21 (11.8 g, 89%) as white crystals: m.p. 175-176° C.; [α]D22 +3° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 2.00 (s, 3H), 2.01 (s, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 3.71-3.73 (m, 1H), 4.11-4.25 (m, 2H), 4.73 (d, 1H, J=12.0 Hz), 4.79 (d, 1H, J=10.8 Hz), 5.01 (t, 1H, J=9.8 Hz), 5.26 (d, 1H, J=9.8 Hz), 5.31 (d, 1H, J=9.1 Hz), 7.11 (d, 2H, J=8.0 Hz), 7.41 (d, 2H, J=8.0 Hz); 13C-NMR (400 MHz, CDCl3); δ 20.56, 20.61, 20.73, 21.15, 54.93, 62.25, 68.44, 73.14, 74.47, 75.70, 86.65, 95.36, 127.84, 129.71, 133.62, 138.70, 153.85, 169.45, 170.61; HRMS for C22H26NO9SCl3Na (M+Na) calcd 610.0266, found 610.0286. Anal. Calcd for C22H26NO9SCl3: C, 45.03; H, 4.47; N, 2.39. Found: C, 45.46; H, 4.26; N, 2.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
m-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (300 ml.), and extracted with ether to remove the excess m-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the off-white solid that precipitates is filtered and air-dried. Several recrystallizations from n-butyl chloride yields 3.15 g. of material with m.p. 170°-172°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:30][CH2:31][N:32]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:33][CH2:34]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCNCC6)c5)cc4c3C2)nc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCN(S(C)(=O)=O)CC6)c5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
To a stirred solution of methyl-2-{8-[3-(piperazin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (800 mg, 1.65 mmol) in dry DCM (50 mL) was added 4-dimethylaminopyridine (1.012 g, 8.29 mmol), then methanesulfonyl chloride (0.155 mL, 1.99 mmol) was added at 0° C. and stirred for 10 min. The reaction mass was maintained at room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC and after completion the reaction mass was diluted with water and extracted with DCM. The DCM layer dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl-2-{8-[3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (900 mg, 95.40%) with HPLC purity 95.40%. 1HNMR (200 MHz, CD3OD) δ: 2.62 (t, 4H, 2×CH2), 2.85 (s, 3H, CH3) 3.0 (t, 2H, CH2), 3.22 (t, 4H, 2×CH2), 3.7 (s, 2H, CH2) 3.95 (s, 3H, OCH3), 4.4 (t, 2H, CH2), 5.18 (s, 2H, CH2), 7.2-7.8 (m, 7H, Ar—H), 8.9 (s, 2H, Pyrimidine-H); m/e=561 (M+1).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H]([N:31]5[CH:36]=[C:35]([C:37](N)=O)[CH2:34][CH:33]=[CH:32]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CS(C)=O.NC1[CH:51]=[C:52](C=CC=1)[C:53](N)=[O:54].C(N)(=[O:66])C1C=CC=NC=1>O>[C:36]1([OH:66])[C:35]2[CH:37]=[CH:51][CH:52]=[C:53]([OH:54])[C:34]=2[CH:33]=[CH:32][N:31]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: NC(=O)c1cccnc1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: O
Solvent: CS(C)=O
Product: Oc1cccc2c(O)nccc12
Reaction time: 1 h

Procedure:
Incorporation of radioactivity from labeled NAD into acid-precipitated protein is measured. The reaction mixture (volume 100 μL or 50 μL, in a test-tube or 96-well plate) contained 100 μg/mL calf thymus DNA (sonicated), 100 μg/mL histones, 100 mM Tris (pH 8.0), 1.0 mM DTT, 10 mM MgCl2, NAD (200 μm, 0.65 microcurie/mL), and varying amounts of enzyme. The reaction was incubated for 10 min at 37° C. or at room temperature for 60 min. The reaction was stopped and protein precipitated by addition of ice-cold trichloroacetic acid (TCA; 10% or 20% aqueous w/v). After brief storage in ice or at 4° C. for 2 hrs, the reaction mixture is filtered under vacuum through a glass fiber filter (2.5 cm disc, or 96-well filter plate). After washing with TCA and ethanol, the filter is dried and counted for tritium CPM after addition of scintillation fluid. 10 μL of a typical enzyme preparation of ˜20 mg/mL protein gave 10,000 to 20,000 CPM in the 100 μL assay using filter disc, counted with 6 mL of EcoLume (ICN). Insect cells infected with wild-type virus gave no activity. The Km for NAD is established to be 111 μM (literature 50 to 100 μM). The compounds of this invention which are tested for inhibition are dissolved in water or DMSO and added to the assay to give a range of concentrations. A few of the reference compounds tested gave the following results: 3-Aminobenzamide inhibited the reaction with an IC50 of 140 μM, nicotinamide gave IC50 ˜400 μM, and 1,5-isoquinolinediol gave IC50 of 1 μM. Another literature standard DPQ gave IC50 of 11 μM. The results obtained for the compounds of this invention are summarized in Table 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([CH2:18][O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[C:5]([CH3:24])[C:4]=1[CH3:25].[CH3:26][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:26][O:16][C:15](=[O:17])[C@H:14]([NH:13][S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:25])[C:5]=1[CH3:24])(=[O:12])=[O:11])[CH2:18][O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](COC(C)(C)C)C(=O)O)c(C)c1C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](COC(C)(C)C)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reaction time: 0.75 h

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-tert-butoxypropionic acid (2.79 g, 7.5 mmol) in 70% methanol/methylene chloride (50 mL) at 0° C. was added 1M trimethylsilyldiazomethane in hexanes (22.5 mL, 23 mmol). After 45 min., the reaction mixture was concentrated and chromatographed using preparative chromatography (9% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-tert-butoxypropionic acid methyl ester (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:27](=[O:28])[NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccccc2c1C(=O)C1=CNCCC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1nn2ccccc2c1C(=O)C1=CN(C(=O)Nc2ccc(Cl)cc2)CCC1

Procedure:
One g of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)-pyrazolo[1,5-a]pyridine was dissolved in 20 ml of methylene chloride and 1 g of p-chlorophenyl isocyanate was added dropwise whilst stirring to the solution. The mixture was stirred at room temperature for 2 hours, and after removal of solvent in vacuo, the residue was recrystallized from ethyl acetate to afford the title compound in yield of 1.2 g (73%), mp 198°-200° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:43])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (59 mg).
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH:17]=O.[OH2:19]>CS(C)=O>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:17]/[CH2:8][CH2:9][CH2:10][C:11]([O:4][CH2:2][CH3:5])=[O:19]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: O
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCC/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (2.14 g) was added gradually to a solution of 2-quinolinecarbaldehyde (2.0 g) and 1-(4-ethoxycarbonyl)butyltriphenylphosphonium bromide (9.0 g) in DMSO (18 ml), and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was poured into iced water and extracted with ether. The ether layer was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous sodium sulfate. The solvent was then distilled off and the crude residue was purified by silica gel column chromatography (hexane-ethyl acetate=10:1) to provide 0.65 g of ethyl (E)-6-(2-quinolyl)-5-hexenoate and 1.45 g of a mixture of (E) and (Z) compounds, both as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(CCO)C=CC=CC=1.O>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCc1ccccc1
Solvent: O
Product: O=C(O)c1cc2cc(-c3cccs3)ccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a sealed tube containing 2-[5-bromo-1-benzyl-1H-indole-2carboxylic acid (100 mg, 0.303 mmol) and 2-thiopheneboronic acid (116 mg, 0.909 mmol), (C6H5)4Pd (42 mg, 0.036 mmol), Na2CO3 (2,42 mmol) in a mixture of benzene-ethanol-H2O (5/1/2=v/v, 4.5 mL) was heated at 100° C. for 23 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column (15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[C:20]1(=[O:30])[N:24]([CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:8]([F:18])[CH:7]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C

Procedure:
The mixture of (N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline obtained in example 1, potassium phthalimide (40 gm) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to water (2 L) and filtered the solid obtained, and recrystallized from isopropyl alcohol to give 50 gm N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.Cl.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>C(O)C>[C:10]([NH:14]/[N:15]=[C:2](\[CH3:4])/[C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(C)=N/NC(C)(C)C
Yield: 71.3 %

Procedure:
To a solution of ethyl pyruvate (20.22 g, 174.1 mmol) in ethanol (150 mL) was added t-butyl hydrazine hydrochloride (21.7 g, 174 mmol) and N,N-diisopropylethyl amine (33.4 mL, 192 mmol). After stirring at reflux for 18 hours, the reaction was cooled and the volatiles were removed under reduced pressure. The resultant golden oil was taken up in 300 mL ethyl acetate and washed with 200 mL water and 300 mL saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to yield (E)-ethyl 2-(2-tert-butylhydrazono)propanoate (23.1 g) as a clear pale yellow oil. +APCI (M+H) 187.3; 1H NMR (400 MHz, CDCl3, δ): 5.51 (br. s., 1H), 4.25 (q, J=7.2 Hz, 2H), 1.89 (s, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.28 (s, 9H).
Reaction SMILES: C([S:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[SH:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)C(C)SC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(C)S
Temperature: -15 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Under nitrogen atmosphere, a mixture of 40.00 g (0.192 mol) of ethyl 3-acetylthio-2-methylbutyrate and 800 ml of ethanol was cooled to −15° C., 72.01 g (0.212 mol, 1.1 Eq) of a 20% solution of sodium ethoxide in ethanol was added dropwise thereto over 1 hour, and the mixture was stirred for 3 hours. The reaction mixture was neutralized with 15.00 g of acetic acid, and then ethanol was evaporated off under reduced pressure. After addition of an aqueous sodium chloride solution to the residue, extraction with diethyl ether was performed. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and brine (twice). The solvent in the organic layer was evaporated off, and vacuum distillation (35 to 36° C./2 torr) was performed to give 17.63 g of the objective compound (GC purity: 99.3%, yield: 56.1%, diastereomer ratio: 80.6/19.4).
Reaction SMILES: [CH2:1]([C@@:8]1([CH3:15])[NH:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH3:34]>>[CH2:1]([C@@:8]1([CH3:15])[NH:12][C:11](=[O:13])[C:10]([CH:16]([C:29]2[NH:30][C:31]3[C:27]([C:28]=2[CH3:34])=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: C[C@]1(Cc2ccccc2)NC(=O)C=C1O
Reactant: O=Cc1ccccc1
Product: Cc1c(C(C2=C(O)[C@@](C)(Cc3ccccc3)NC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, (R)-5-benzyl-4-hydroxy-5-methyl-1,5-dihydro-pyrrol-2-one (Example D) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a yellow solid. MS: 441.1 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][CH2:16][O:17][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCC1CN(Cc2ccccc2)CC1CO
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CN2CC3CCOCC3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
To a solution of 2-(1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl) ethanol (0.50 g) in toluene (30 mL) was added Et3N (0.8 mL), TsCl (0.75 g) and DMAP (10 mg). The mixture was stirred for 12 h at room temperature under N2, washed with water, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH) to give the title compound (0.18 g, 13.61%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 218.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][Si:22]([CH3:24])([CH3:23])[C:25]#[C:26][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-3-(propylsulfonyl)benzene (Intermediate 5; 23 g, 88 mmol) in THF (450 ml) was treated with Pd(dppf)Cl2 (3.9 g, 5.3 mmol), triethylamine (13.4 g, 132 mmol) and trimethylsilyl acetylene (8.64 g, 88 mmol). The reaction mixture was stirred at RT for 10 minutes, then cuprous iodide (1.0 g, 5.3 mmol) was added, the reaction mixture was heated at 60° C. for 24 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (98:2) as a eluent to afford the title compound as a brown oil.