Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21]([NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:22])[CH3:25]
Reactant: CC(N)C(=O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(C)C(=O)c1ccccc1
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of triethylamine (15 g) in chloroform (15 ml) was added dropwise to a stirred mixture of 2-aminopropiophenone hydrochloride (12 g) and chloroform (65 ml) at ice bath temperature in 10 minutes. To the stirred mixture was added dropwise a solution of ethyl chloroformate (8 g) in chloroform (20 ml) under the same conditions and then stirring was continued for 4 hours at ice bath temperature. The solution was evaporated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, water, 5% hydrochloric acid, and water, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil containing the object compound. The above obtained product was purified by column chromatography on silica gel (200 g) using a mixture of diisopropyl ether and chloroform (1:4) as an eluent to give an oil of 2-ethoxycarbonylaminopropiophenone (10.48 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]([CH3:24])([C:21](O)=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:54][C:55]1[C:63]([NH2:64])=[CH:62][CH:61]=[CH:60][C:56]=1[C:57]([NH2:59])=[O:58]>CN(C=O)C>[NH2:54][C:55]1[C:56]([C:57](=[O:58])[NH2:59])=[CH:60][CH:61]=[CH:62][C:63]=1[NH:64][C:21]([C:20]1([CH3:24])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:22]
Reactant: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C(=O)Nc2cccc(C(N)=O)c2N)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-4: To a solution of 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (620 mg, 1.91 mmol) in anhydrous DMF (5 ml) was added EDC.HCl (1.098 mg, 5.73 mmol), HOAt (390 mg, 2.87 mmol) and triethylamine (0.4 ml, 2.87 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (346 mg, 2.29 mmol) was added and heated to 55° C. for 3 days. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum and purified by preparative TLC using ethyl acetate as eluent to afford benzyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 481.2 [M+Na]+
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>CO>[F:27][C:28]([F:35])([F:34])[C:29]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:30]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)C(F)(F)F)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
4′-C-Aminomethylthymidine (4) (1.5 mmol) was dissolved in methanol (10 mL) and triethylamine (1.5 mL) at ambient temperature. The solution was then treated with neat ethyl trifluoroacetate (1 mL) and the resulting solution stirred for 18 hours at ambient temperature with exclusion of moisture. The solvents and reagents were then removed under vacuum to give the crude product. Purification by flash column chromatography (9:1 dichloromethane:methanol) afforded the title compound (7) as a white foam (0.37 g, 66%). δH(300 MHz, CD3OD) 8.77(1H, t, br, N3—H), 7.73(1H, s, H-6), 6.24(1H, dd, H-1′), 4.56(1H, dd, H-3′), 3.6(3H, s, H-5′, obs d, 4′-C—CH2), 3.53(1H, d, 4′-C—CH2), 2.35(2H, m, H-2′), 1.81(3H, s, 5-CH3); δC(75.45 MHz, CD3OD), 166.24, 160.08–158.62(q, CF3CO), 152.21, 138.11, 123.01–111.51(q, CF3CO), 111.51, 88.93, 85.69, 72.79, 64.23, 41.70, 40.81, 12.40; ES +ve m/z 368 (M+H)+, 390(M+Na)+; ν cm−1 1684. For an alternative synthesis of this compound see Wang et al, Tetrahedron Letters 1996, 37, 6515–6518.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C)nc3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M218) (260 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (137 mg, 66%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH3:5].[OH-].[Li+]>CO.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
2-(4-Tert-butylphenyl)propionic acid methyl ester (946 mg, 4.29 mmol) was dissolved in MeOH (10 ml) and mixed with a solution of lithium hydroxide (154 mg, 6.44 mmol) in water (5 ml). The reaction mixture was stirred for 18 h at RT. The solvent was removed under vacuum and the aqueous residue mixed with diethyl ether (30 ml). The phases were separated. The aqueous phase was reextracted with diethyl ether (20 ml). The aqueous phase was adjusted to a pH of 3 using 1 N hydrochloric acid solution. There formed a clouding or precipitation which was extracted from the aqueous phase by the addition of EtOAc (2×20 ml). The organic phase was washed with sat. NaCl solution (20 ml), dried and concentrated. 2-(4-Tert-butylphenyl)propionic acid was obtained as a colourless solid in a yield of 83% (735 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC#N)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 250 mL flask, 4-isopropylphenylacetonitrile 8.00 g (50.2 mmol) was dissolved in tetrahydrofuran (150 mL) under a nitrogen atmosphere. The solution was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 52.8 mL (52.8 mmol) added. The resulting mixture was stirred at −78° C. for 1 hour. To this reaction mixture was added iodomethane 3.29 mL (52.8 mmol). The resulting mixture was slowly allowed to warm to ambient temperature over 16 hours then quenched with 0.2M hydrochloric acid and extracted twice with diethyl ether. The organic fractions were combined, dried (MgSO4) and concentrated under vacuo. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 6.32 g (73%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:14][C:15]1([CH3:23])[CH2:21][CH2:20][C:19](=[O:22])[O:18][C:16]1=[O:17]>C1C=CC=CC=1>[C:16]([C:15]([CH3:23])([CH3:14])[CH2:21][CH2:20][C:19]([N:2]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:1])=[O:22])([OH:18])=[O:17]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: CNCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CN(CCc1c[nH]c2ccccc12)C(=O)CCC(C)(C)C(=O)O
Reaction time: 8 h

Procedure:
6.97 g of 3-(2-methylaminoethyl)-indole, 100 ml of dry benzene and 5.69 g of 2,2-dimethylglutaric anhydride are introduced at ambient temperature into a 250 ml round-bottomed flask provided with a condenser, a CaCl2 drying tube and a magnetic stirrer. The reaction mixture is heated slowly at the reflux temperature for 1 hour 30 minutes with stirring. It is then left to cool and to stand overnight at ambient temperature.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3noc(C4CC4)n3)ccn2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (235 mg) obtained in Example 56-1) was dissolved in pyridine (1 mL), then cyclopropanecarbonyl chloride (0.065 mL) was added thereto and heated under reflux for 90 minutes. The reaction liquid was diluted with ethyl acetate, washed with water, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 187 mg of the entitled compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11]1[CH2:15][CH2:14][CH2:13][C:12]=1[C:16]#[N:17]
Reactant: N#CC1CCCC1=O
Reactant: Nc1ccc(F)cc1F
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2F)CCC1

Procedure:
2,4-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone (Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under reflux for 19 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C., 0.25 mmHg) gave the product as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[N:22]1([C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[O:5])[CH2:23][CH2:24]1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CC2)ccc1Cl
Temperature: 100 °C
Yield: 17 %

Procedure:
2-Chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.15 g), cesium carbonate (0.192 g) and acetonitrile (3 ml) were combined and heated in a sealed tube at 100° C. for 24 hours. The cooled reaction mixture was poured into water (50 ml) and the product extracted into ethyl acetate, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by NPHPLC eluting with 0-5% ethanol in dichloromethane to give the title compound as a white solid (0.023 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH2:24][C:25]#[N:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:24][C:25]#[N:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC#N)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-t-butyldimethylsilyloxypyrrolidine (88 g) in methanol (450 ml), 6N hydrochloric acid (45 ml) was added, and the resultant mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-(1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.93 (s, 1H), 7.72-6.68 (m, 12H), 5.06-4.98 (m, 1H), 3.66-3.50 (m, br, 2H), 3.02-2.82 (m, br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.02-1.76 (m, br, 6H), 1.64-1.48 (m, br, 1H), 1.48-1.36 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C33H41Cl2FN2O2.0.5EtOAc: C, 66.55; H, 7.18; N, 4.43; Found: C, 66.35; H, 6.86; N, 4.46. ESMS m/e: 550.8 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=[CH:19][CH:20]=1.O>CN1C(=O)CCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[NH2:21])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (4 g, 21.5 mmol) and 3-fluoronitrobenzene (2.3 ml, 21.5 mmol) in anhydrous NMP (5 ml) was heated to 120° C. for 3 days. After cooling water (25 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography using successively petroleum ether and a mixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluents. Yield of t-butyl 4-(3-nitrophenyl)-1-piperazinecarboxylate: 1.34 g (20%). This intermediate was quantitatively hydrogenated to 2g in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
2-chloro-3-nitrobenzoic acid (543.6 g, 2.7 mol) was suspended in methanol (3425.0 ml), and concentrated sulfuric acid (108.5 ml) was added thereto. The mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature, and then the solvent was concentrated under reduced pressure. The concentration residue was added into a saturated aqueous solution of sodium bicarbonate. A solid that precipitated was filtered, and washed with water. The solid thus obtained was dissolved in ethyl acetate, washed with saturated saline, and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, the filtrate was concentrated and dried to solid under reduced pressure, and the resultant solid was washed with n-hexane. As a result, 542.6 g (yield: 93%) of the indicated compound was obtained
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC1(C)CC(=O)Nc2ccccc2N1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 9 h
Yield: 10.9 %

Procedure:
To a solution of 4,4-dimethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.0 g) in N,N-dimethylaniline (20 ml) was added 4-nitrobenzoyl chloride (0.98 g) at ambient temperature. The mixture was stirred at 150° C. for 9 hours. The resulting mixture was diluted with chloroform and the organic layer was washed successively with 1N hydrochloric acid and saturated aqueous sodium bicarbonate. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (1% methanol in chloroform) to give 4,4-dimethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (195 mg) as a slightly yellow solid.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27](OC)=[O:28])=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:43])/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCO>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:28][N:43]=[C:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reactant: N/C(=N\O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(-c5ccccc5)no4)c3)cc12
Yield: 14.3 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)—N′-hydroxybenzimidamide (51 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (8.7 mg, 14%). 1H NMR (400 MHz, DMSO-d6) d ppm 8.49-8.56 (1H, m), 8.44-8.49 (1H, m), 8.19-8.25 (1H, m), 8.13-8.18 (2H, m), 8.07-8.12 (1H, m), 8.00-8.07 (2H, m), 7.98 (1H, s), 7.76-7.86 (3H, m), 7.59-7.68 (3H, m), 7.41 (2H, t, J=8.91 Hz), 2.88 (3H, d, J=4.77 Hz). LC-MS retention time: 1.94 min; m/z (MH+): 490. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=17.39 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=14.58 min, purity=98%.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:16]1([NH:15][C:2]2[C:11]3[CH:12]=[CH:13][S:14][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc2ccccc2c2sccc12
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: c1ccc(Nc2nc3ccccc3c3sccc23)cc1
Temperature: 120 °C

Procedure:
4-chlorothieno[3,2-c]quinoline (23 mg) was mixed with aniline (0.1 ml) and NMP (0.1 ml) and the mixture was heated in a microwave oven at 120° C. for 10 min. NMP (0.8 ml) was added and the compound purified by preparative HPLC. Genevac evaporation afforded N-phenylthieno[3,2-c]quinolin-4-amine as a pinky solid (31 mg, quant.). LCMS (ES): 95% pure, m/z 277 [M+1]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Li]CCCC.C[Si](Cl)(C)C.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1>O1CCCC1.O>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of cis-2,6-dimethyl piperazine (247 mg) in tetrahydrofuran (5 mL) was added n-BuLi (2.67 M hexane solution, 1.62 mL) at −78° C. The mixture was stirred at room temperature for 30 minutes, and trimethyl silyl chloride (0.27 mL) was added thereto. After stirring for 40 minutes, a solution of 2-chloro-6-trifluoromethyl benzothiazole (500 mg) in tetrahydrofuran (2 mL) was added thereto and the mixture was stirred for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. The residue was purified by column chromatograph on silica gel to give the title compound (367 mg). Yield: 54%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13]Cl)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:12]=1
Reactant: ClCc1cncc(Br)c1
Reactant: c1nc[nH]n1
Product: Brc1cncc(Cn2cncn2)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], 1H-1,2,4-triazole has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 238.9, 241.3 (M+H+).