Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]#[N:17])[CH:11]=[CH:12][C:13]=1[Cl:14].CO>C1(C)C=CC=CC=1>[ClH:7].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([NH2:2])=[NH:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.88 g (54 mmol) of ammonium chloride are suspended in 50 ml of toluene under an argon atmosphere and cooled to 0° C. After dropwise addition of 27 ml of a 2 M trimethylaluminium solution in toluene, the mixture is warmed to room temperature and then stirred for 1.5 h. 5 g (27 mmol) of 3,4-dichlorophenylacetonitrile are added, and the mixture is stirred at 80° C. overnight. After cooling to 0° C., 50 ml of methanol are added dropwise. The product is separated from the precipitated solid by filtration with suction, and the filter cake is washed several times with methanol. The combined filtrates are evaporated to dryness, and the residue is then suspended in dichloromethane/methanol 10:1 and again filtered with suction. Concentration of the filtrate results in 6.2 g (77% of theory) of the title compound.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[NH:4][C:5]1=[O:11].C1(=O)[NH:17][C:16](=O)[CH:15]=C1.O1C=CC=C1.BrCC#N>CC(C)=O.CN(C=O)C>[O:12]=[C:3]1[N:4]([CH2:15][C:16]#[N:17])[C:5](=[O:11])[CH:6]2[CH:2]1[CH:1]1[O:10][CH:7]2[CH2:8][CH2:9]1
Reactant: O=C1NC(=O)C2C3CCC(O3)C12
Reactant: O=C1C=CC(=O)N1
Agent: N#CCBr
Solvent: CC(C)=O
Solvent: c1ccoc1
Solvent: CN(C)C=O
Product: N#CCN1C(=O)C2C3CCC(O3)C2C1=O

Procedure:
Synthesis took place in analogy to Example VI a from 10-oxa-4-azatricyclo[5.2.1.02,6]decane-3,5-dione (obtainable from maleimide and furan from Diels-Alder reaction for example as described by Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T.; J Org Chem 1997, 62, 4088-4096 and subsequent hydrogenation as described by Ansell, M. F.; Caton, M. P. L.; North, P. C.; Tetrahedron Lett. 1982, 23, 2811) and bromoacetonitrile with the exception that acetone was used as solvent in place of DMF. The substance was employed as crude product in the next reaction.
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[OH:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[Br:6][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:19])[C:9]=1[OH:8]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: BrBr
Solvent: CC(C)(C)N
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(O)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a solution of tert-butylamine (1.6 mL, 15 mmol) in dichloromethane (100 mL) at −78° C. was added drop-wise over 30 minutes a solution of bromine (773 μl, 15 mmol in 15 mL of dichloromethane). The solution was stirred at −78° C. for 30 minutes. While maintaining the temperature at −78° C., a solution of methyl 3-hydroxy-2-methylbenzoate (2.5 g, 15 mmol in 15 mL of dichloromethane) was added to the reaction mixture drop-wise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The mixture was washed with 20% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 612 mg, 2.5 mmol (17%) of methyl 4-bromo-3-hydroxy-2-methylbenzoate as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 2H), 5.71 (s, 1H), 3.81 (s, 3H), 2.53 (s, 3H). MS (EI) for C9H9BrO3: 245 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:10][CH2:11][CH3:12])=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: CCCC#Cc1ccnc(F)c1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 75.3 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-4-pent-1-ynylpyridine (650 mg, 3.98 mmol) in acetonitrile (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.89 mL, 5.97 mmol) and 1-aminopyridinium iodide (974 mg, 4.38 mmol). The resultant dark solution was allowed to warm to room temperature and stirred vigorously. An additional equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1-aminopyridinium iodide were added after 18 and again after 36 hours. Water was added and the mixture concentrated in vacuo. The residue was partitioned between water and ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (4:1 to 3:1 hexane-ethyl acetate) provided 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (765 mg, 75%) as an off-white solid. 1H NMR (CDCl3) δ 8.48 (d, 1H), 8.30 (d, 1H), 7.64 (d, 1H), 7.32–7.23 (m, 2H), 7.04 (s, 1H), 6.86 (t, 1H), 2.95 (t, 2H), 1.82 (m, 2H), 1.03 (t, 3H); 19F NMR (CDCl3) δ −68.48; MS m/z 256 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:13])[C:10]([O:12][CH3:19])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@H](O)c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1cc(Cl)cc(Cl)c1

Procedure:
A solution of (R)-2-(3,5-dichlorophenyl)-2-hydroxyethanoic acid (19.10 g) in methanol (200 mL) containing concentrated sulfuric acid (1 mL) was stirred at reflux under nitrogen for 16.5 h. The solution was then concentrated under vacuum, and the resulting oil was dissolved in ethyl acetate (200 mL). This solution was washed with saturated aqueous sodium bicarbonate solution, followed by saturated aqueous sodium chloride solution (10 mL). After drying (magnesium sulfate), the ethyl acetate was removed, and the yellow oil was recrystallized from hexane (70 mL) to afford the title compound as a colorless crystalline solid (10.68 g). The mother liquor afforded additional product (3.61 g) upon concentration.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH2:30])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]>>[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=2[CH3:12])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2nc(C(F)(F)F)sc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction. The compound is purified on a silica gel column using ethyl acetate/methanol =9/1 as eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][C:37](OC)=[O:38].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.CCCCCC.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CC(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
To a solution of methyl 2-(2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)acetate (500 mg, 0.884 mmol) in THF (6 mL) at 0° C. was added 3.5M lithium aluminum hydride/THF (0.20 mL, 0.71 mmol). After stirring for 45 minutes at 0° C. aqueous work-up followed by flash chromatography (silica gel, hexane/EtOAc) afforded the title compound in 65% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (dd, J=7.82, 5.47 Hz, 1H) 7.70 (s, 0H) 7.40 (s, 1H) 7.15-7.25 (m, 2H) 6.61-6.73 (m, 1H) 5.78 (br. s., 0H) 3.89 (t, J=5.96 Hz, 1H) 3.18 (s, 2H) 3.10-3.24 (m, 3H) 3.00 (d, J=4.89 Hz, 1H) 2.76 (t, J=5.86 Hz, 1H) 2.29 (br. s., 0H) 0.99 (br. s., 2H). LCMS (m/z, ES+)=538 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[NH:4]1.[C:17](=[S:19])=[S:18].[CH2:20](N(CC)CC)C.CI>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([CH3:16])[N:4]1[C:17]([S:19][CH3:20])=[S:18]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Solvent: CS(C)=O
Solvent: CI
Product: CSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
(1RS, 3RS)-cis-3-Hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (4.326 g) is dissolved in dimethylsulfoxide (20 ml), and thereto are added CS2 (2.4 ml) and triethylamine (5.6 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise methyl iodide (2.5 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice-water, and the mixture is extracted with ethyl acetate. The extract is washed with water, 5% HCl and water in order, dried over sodium sulfate and then distilled to remove the solvent. The residue is recrystallized from aqueous ethanol to give the title compound (5.5 g, 90%) as colorless needles, m.p. 164°-166° C., NMR (CDCl3, δ): 1.68 (d, J=6.8 Hz, 3H, C1 --CH3), 2.73 (s, 3H, CSSCH3); Mass m/e: 306 (M+), 258 (M+ --CH 3 SH).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 3-trifluoromethyl-phenylamine (4 g, 24.8 mmol), acetic anhydride (10.1 g, 99.3 mmol), DMAP (0.9 g, 7.4 mmol) and triethyl amine (2.5 g, 24.8 mmol) was heated to reflux 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 30% ethylacetate in hexane to get the title compound as off-white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][CH2:19][NH:20]4)[N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH3:33][C:30]1([CH3:34])[O:29][CH2:28][C:27]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH2:25][N:20]2[C:21]3[C:16](=[C:15]([C:12]4[N:11]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=5)[O:14][N:13]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19]2)[CH2:32][O:31]1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4)no2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a mixture of the product of Step D (0.0334 g; 0.1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (3×0.03 g; 0.33 mmol) and NaBH(OAc)3 (3×0.07 g; 0.93 mmol) in 1,2-dichloroethane (1.5 ml) AcOH (3×0.01 ml) was added portion wise over a period of 3 days with stirring at room temperature. The mixture was then diluted to 15 ml with EtOAc, washed with 10% NaOH, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, hexane:EtOAc, 9:1), to give the title compound (0.03 g; 51%) as colourless foam. 1H-NMR (CDCl3) 0.95 (tr, 3H, J=7.4 Hz); 1.44 (m, 15H); 1.61-1.72 (m, 2H); 1.89-1.97 (m, 2H); 2.66 (tr, 2H, J=7.8 Hz); 3.06 (tr, 2H; J=6.5 Hz); 3.34 (tr, 2H, J=5.4 Hz); 3.77 (s, 2H); 3.95 (s, 4H); 4.7 (broad s, 1H); 7.02 (d, 1H, J=7.6 Hz); 7.14 (tr, 1H, J=7.6 Hz); 7.22-7.25 (m, 1H+CDCl3); 7.33 (d, 2H, J=8.3 Hz); 8.09 (d, 2H, J=8.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)C.OS(O)(=O)=O>CO>[CH3:1][O:3][C:4](=[O:19])[C:5](=[O:18])[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1

Procedure:
A solution of (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 33.39 g, 0.12 mol) and conc H2SO4 (0.5 mL) was stirred at reflux for 6 h in methyl alcohol (MeOH, 400 mL). Upon cooling and solvent concentration, (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid methyl ester (6; 22.7 g, 71%) was collected as yellow crystals: mp 135-136° C.; 1H NMR (400 MHz, CDCl3) δ 14.74 (s, 1H), 7.67 (d, J=15.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.61 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 3.92 (s, 3H); HRMS-ESI (m/z): calcd for C13H11ClO4, 266.034. found, 266.034.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[S:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[S:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
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: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h

Procedure:
To a solution of #32 (321 mg, 0.881 mmol, 1 eq.) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #39 (484 mg, ≦0.769 mmol, 0.9 eq.), HATU (353 mg, 0.881 mmol, 1 eq.) and diisopropylethylamine (463 μL, 2.64 mmol, 3 eq.). After stirring for 18 hours, the mixture was diluted with dichloromethane, washed with water and with brine, dried over magnesium sulfate, filtered, and concentrated onto silica in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #43 (574 mg, 68% over two steps) as a white solid. LC-MS: m/z 956.6 [M+H+], retention time=4.49 minutes; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.80 (d, J=7.5 Hz, 2H), 7.64-7.72 (m, 2H), 7.16-7.35 (m, 7H), [5.43 (dd, J=11, 4.5 Hz) and 5.58 (dd, J=11.5, 4 Hz), total 1H], 3.72 and 3.75 (2 s, total 3H), 3.34 and 3.35 (2 s, total 3H), 3.26 and 3.29 (2 s, total 3H), 3.05 and 3.11 (2 br s, total 3H), 1.39 and 1.40 (2 s, total 3H), [1.24 (d, J=6.7 Hz) and 1.29 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[N+:11]([O-])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].[CH2:16]([N:18](CC)CC)C.C[Si](C#N)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[C:16]([C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][C:12]=2[N:11]=1)#[N:18]
Reactant: COC(=O)C1CCc2c(ccc[n+]2[O-])C1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)C1CCc2nc(C#N)ccc2C1
Temperature: 130 °C
Yield: 23.4 %

Procedure:
A 150 mL pressure vessel was charged with 6-(methoxycarbonyl)-5,6,7,8-tetrahydroquinoline 1-oxide (13.58 g, 65.52 mmol), triethylamine (18 mL, 130 mmol), trimethylsilyl cyanide (26.2 mL, 196 mmol) and acetonitrile (33 mL), and the mixture was heated at 130° C. for 21 h. Slowly quenched reaction into 2M Na2CO3 (250 mL) then diluted with DCM (500 mL). The mixture was filtered through celite and the filter cake washed with DCM (2×200 mL) and water (100 mL). The aqueous layer was extracted with additional DCM (100 mL×2). The combined organics was washed with 1M Na2CO3 (200 mL) and 1 M NaH2PO4 (150 mL×2), dried (Na2SO4), filtered and evaporated. The residue was purified by silica chromatography (100% hexanes to 100% DCM to 20% MeOH in DCM). Additional purification by silica chromatography (0-100% EtOAc in hexanes) yielded a pale yellow solid (3.32 g, 23%). m/z=217.5 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 3.74 (s, 3H), 3.18-2.94 (m, 4H), 2.88-2.78 (m, 1H), 2.35-2.26 (m, 1H), 2.09-1.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2=[N:15][N:16]([CH3:18])[CH2:17][N:13]2[C:12]2[S:19](=[O:22])[CH2:20][CH2:21][C:11]=2[CH2:10][N:9]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.CCOCC>[CH3:25][CH:20]1[S:19](=[O:22])[C:12]2[N:13]3[CH2:17][N:16]([CH3:18])[N:15]=[C:14]3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]=2[CH2:21]1
Reactant: CN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1CC2=C(N3CN(C)N=C3C(c3ccccc3Cl)=NC2)S1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1 g of 6-o-chlorophenyl-8-methyl-1,2-dihydro-4H-s-triazolo[3,4-c]-thieno[2,3-e][1,4]diazepin-1-one is dissolved in 25 ml of dimethylformamide, and 0.09 g of sodium hydride (50% in mineral oil) is added, and the resulting mixture is heated at 60° C on a water bath with stirring for 30 minutes. After cooling to room temperature, a solution of 0.6 g of methyl iodide in 5 ml of ether is added dropwise, and the whole mixture is stirred at room temperature for 7 hours. Then the reaction mixture is poured into ice water, the precipitated crystals are filtered off, and the filtrate is extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate, and the chloroform is removed under reduced pressure. The residue is recrystallized from a mixture of ligroin and ethanol to give the title compound as white crystals, melting at 199°-200° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][C:19]#[N:20].[OH-].[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[C:18]1[C:19]([NH2:20])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Nc1ccncc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccncc2cc1-c1c(Cl)cccc1Cl
Temperature: 65 °C
Yield: 84.4 %

Procedure:
4-Aminonicotinaldehyde (100 mg, 0.78 millimole (hereinafter “mmol”)), 2,6-dichlorophenylacetonitrile (217 mg, 1.2 mmol), 10% aqueous NaOH (0.101 mL, 0.25 mmol) and 700 uL of absolute ethanol are combined and heated at 65° C. for 24 hours (hereinafter “h”). The reaction mixture is cooled to ambient temperature and the solvents are evaporated under reduced pressure. The residue is diluted with 700 uL of DMSO filtered and purified with preparative reverse phase chromatography to afford the title compound as a yellow solid (191 mg, 84% yield). MS ES+ m/z=290.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(benzyloxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.2 Hz, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.28-7.47 (m, 7H), 6.98-7.00 (m, 2H), 5.10 (s, 2H), 3.75-3.83 (m, 4H), 3.58-3.60 (m, 2H), 3.07-3.13 (m, 4H); MS (ESI−) M/Z 469 (M−H)−.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:7]1)(=[O:3])[NH2:2].CO.O1CCCC1.O.[OH-].[Li+]>O>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Cc2cn(CCC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Reaction time: 12 h
Yield: 79.2 %

Procedure:
A solution of methyl 4-[1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (0.13 g) in a combination of methanol (2 ml), tetrahydrofuran (2 ml), and water (1 ml) was treated with lithium hydroxide monohydrate (0.07 g). The mixture was stirred for 12 hours and then concentrated to remove the organic solvents. The resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The white precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.10 g, 79%) as a white powder, mp 129°-131° C.