Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=CC=1[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:15][CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[N+:18]([C:17]1[CH:16]=[N:15][C:7]2[C:6]([CH:4]=1)=[CH:14][C:13]1[CH2:12][CH2:11][CH2:10][C:9]=1[CH:8]=2)([O-:20])=[O:19]
Reactant: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1cnc2cc3c(cc2c1)CCC3
Temperature: 90 °C

Procedure:
6-(2-Chlorobenzoyl)-5-(2-nitroethenylamino)indan (4.8 g) was added in small portions to a solution of DBU (4.8 g) in benzene (50 ml) with heating at 90° C. The mixture was refluxed for 30 minutes and, then, washed with 2N HCl and water and dried (MgSO4). The solvent was then distilled off to give crystals of 4-2-chlorophenyl)-7,8-dihydro-3-nitro-6H -cyclopenta[g]quinoline. The crystals were collected by filtration and washed with methanol (4.50 g, 99.1%). Recrystallization from ethanol gave light brown prisms, mp. 175°-176° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[F:12][C:13]1[C:14]([NH2:20])=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1.[ClH:21].Cl.[C:23](=N)(OCC)[CH2:24][C:25](=N)OCC.C(O)(=O)C>Cl>[ClH:21].[ClH:21].[F:12][C:13]1[C:14]2[N:20]=[C:23]([CH2:24][C:25]3[NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=4[N:11]=3)[NH:19][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=N)CC(=N)OCC
Reactant: Nc1cccc(F)c1N
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cccc2[nH]c(Cc3nc4c(F)cccc4[nH]3)nc12
Yield: 32.6 %

Procedure:
The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles), 3-fluoro-1,2-phenylenediamine (0.41 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (25 to 75% acetonitrile (with 0.1% TFA) over 50 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.208 g of pure 2-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-1H-benzimidazol-4-ylamine dihydrochloride in 18% yield. It had MS: m/z=282.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (12.99 minutes using the JWTFACN gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)[O:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:27])[CH:3]=1.C(N(CC)CC)C.CN1C(=O)N(C)CC1>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)[O:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:27])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Nc4ccc(Cl)cc4F)ncnc3o2)cc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: Nc1ccc(-c2cc3c(Nc4ccc(Cl)cc4F)ncnc3o2)cc1

Procedure:
0.95 g (2.5 mmols) of 4-(4-chloro-2-fluoranilino)-6-(4-nitrophenyl)furo[2,3-d]pyrimidine suspended in ca. 50 ml of THF, 2 ml of triethylamine and 2 ml of DMEU, mixed with a spatula tip of catalyst suspension (ethanolic Raney nickel) and shaken over night under H2 at normal pressure. The suspension is filtered by suction through Celite, concentrated by evaporation, mixed with H2O, set at pH 10 with 5% NaOH solution, filtered by suction, and the residue washed with a lot of H2O. The product is worked up by column chromatography (dissolved in acetone and added to the column as a silica gel adsorbate, silica gel, pentane:ethyl acetate=3:2, m.p.: 229-232° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.Cl[C:13](C(O[Na])=O)([F:15])[F:14].C1OCCOCCOCCOCCOCCOC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]\[C:9](=[O:11])[CH3:10])/[N:6]([CH:13]([F:15])[F:14])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: O=C(O[Na])C(F)(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Product: CC(=O)/N=c1\ccc(Br)cn1C(F)F

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-yl)-acetamide (1 g, 4.6 mmol) in 30 ml CH3CN was added ClCF2COONa (848 mg, 5.58 mmol), followed by 18-Crown-6 (244 mg, 0.93 mmol). The reaction mixture was heated to reflux for 12 hrs. Then the reaction mixture was cooled down and the solvent was removed under reduced pressure. To this was added methylene dichloride and washed with water. Organic layer was dried over anhy sodium sulphate and concentrated under reduced pressure to furnish the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide. This was carried to the next step without purification.
Reaction SMILES: [Na+:1].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]=1[S:24]([O-:27])(=[O:26])=[O:25])=[O:8].[C:31](=[O:34])([O-])[O-].[Na+].[Na+].[CH2:37]([OH:39])[CH3:38]>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[NH:3]([C:4]1[CH:30]=[CH:29][CH:28]=[C:38]([C:37]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:16]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]=2[S:24]([O-:27])(=[O:26])=[O:25])=[O:39])[CH:5]=1)[C:31]([NH:3][C:4]1[CH:30]=[CH:29][CH:28]=[C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:16]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]=2[S:24]([O-:27])(=[O:26])=[O:25])=[O:8])[CH:5]=1)=[O:34]
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cccc3c2S(=O)(=O)[O-])c1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cccc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cccc3c2S(=O)(=O)[O-])c1)Nc1cccc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cccc3c2S(=O)(=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 10.0 g of 2-(m-aminobenzamido)-1,5-naphthalenedisulfonic acid disodium salt prepared as in Example 2) and 22.4 g of anhydrous sodium carbonate in 250 ml of water is bubbled in phosgene at room temperature for 35 minutes before a thick translucent gel is formed. The gas diffuser is removed and stirring speed is increased considerably. The resulting mixture is changed to a white solid after about 20 minutes of stirring (at this point the mixture is not acid to Congo Red). The gas diffuser is reinserted and phosgenation is continued for an additional hour at room temperature then the acid mixture is neutralized with 12 ml of 3N sodium hydroxide. The mixture is then filtered over a 48 hour period to obtain a moist paste which is slurried with about 125-150 ml of 80% ethyl alcohol then is filtered and is oven dried at 120° C. overnight to give the product of the example.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[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])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[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[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (203 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (290 mg, 71%).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20])=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41][CH:42]([CH3:44])[CH3:43])(=O)=O>CN(C=O)C.O>[C:17]([NH:16][C:13]1[CH:14]=[C:15]2[C:6]3[CH:5]=[CH:4][C:3]([O:20][CH2:39][C@@H:40]([NH:45][C:46](=[O:47])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:41][CH:42]([CH3:43])[CH3:44])=[C:2]([F:1])[C:7]=3[O:8][CH2:9][C:10]2=[CH:11][N:12]=1)(=[O:19])[CH3:18]
Reactant: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1F
Temperature: 90 °C
Yield: 37 %

Procedure:
To a stirred solution of N-(7-fluoro-8-hydroxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, TFA (70 mg, 0.170 mmol) and potassium carbonate (97 mg, 0.704 mmol) in DMF (4 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (52.0 mg, 0.176 mmol) at room temperature and the reaction mixture was heated to 90° C. for 1 h. After completion of reaction, the volatiles were removed under reduced pressure to afford a brown residue. To this residue water (15 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (30 mL), brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to afford (S)-tert-butyl (1-((2-acetamido-7-fluoro-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (90 mg, 0.066 mmol, 37% yield) as a brown oil. The product was carried forward without further purification. LCMS (ESI) m/e 472.2 [(M−H)−, calcd for C25H31FN3O5 472.2]; LC/MS retention time (Method E): tR=1.99 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:9]([O:4][CH2:3][CH2:2][Br:1])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH2Cl2 (50 mL) was added t-butyldimethylchlorosilane (63.4 g, 0.42 mol), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirring overnight the reaction mixture was washed 3× with water. The organic fraction was dried with Na2SO4, filtered, and concentrated in vacuo to provide 85 g of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][C:19]#[N:20])[N:3]=1
Reactant: [C-]#N
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature, mp. 249°-251° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[F:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:9]=[CH:10][CH:11]=1>CN(C=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:3])[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(F)c1)c1cccc(I)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc(I)c1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Sodium hydride (1.11 g of 60% NaH in mineral oil) was added to a solution of CH3I (4.53 g) and N-(3-fluorophenyl)-3-iodobenzamide (7.26 g) in DMF (120 mL) at 0° C. under nitrogen. After being stirred at 0° C. for another 5 minutes, the reaction was stirred at room temperature under nitrogen for 4 h. The reaction was quenched by slow addition of saturated aqueous NH4Cl (120 mL), followed by addition of water (100 mL). The mixture was extracted with diethyl ether (300 mL×2). The combined ether layers were washed by water (150 mL×4) and brine (150 mL×1), dried by Na2SO4 and concentrated to give crude product (7.56 g), which was purified by column chromatography to afford N-(3-fluoro-phenyl)-3-iodo-N-methylbenzamide (5.88 g; 78%). 1H NMR (600 MHz, DMSO-d6) δ 7.64 (m, 2H), 7.28 (m, 1H), 7.24 (d, 1H, J=7.5 Hz), 7.19 (m, 1H), 7.04-6.99 (m, 3.33 (s, 3H).
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=NOC)[C:10]([NH:12]C)=[O:11].[H-].[Na+].CC(C)CC1(C2C=NC(S(C)(=O)=O)=C(C)C=2)OCCO1.O>CS(C)=O>[C:4]1([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: Cc1cc(C2(CC(C)C)OCCO2)cnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 132.2 %

Procedure:
2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (0.46 g, 2.07 mmol) was dissolved with stirring in anhydrous dimethyl sulphoxide (20 mL) and 60% sodium hydride (0.10 g, 2.5 mmol) added. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 2-(2,2-dimethylethyl)-2-(5-methyl-6-methylsulphonyl-3-pyridinyl)-1,3-dioxolane (0.62 g, 2.07 mmol) in anhydrous dimethyl sulphoxide (5 mL) added. The reaction mixture was heated to 45° C. and stirred overnight. It was then cooled to room temperature and poured into water. This was extracted with ethyl acetate (2×40 mL), the organic extracts combined and washed with water and brine, and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10-50% ethyl acetate:pentane) gave the desired product (0.37 g, 40%) as a clear gum.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:12]Br>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cc(Cl)cc(CBr)c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(Cl)cc(C=O)c1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of sodium metal (52 mg, 2.3 mmol) in ethanol was added 2-nitropropane (0.23 g, 2.4 mmole) followed by the addition of 3-chloro-5-methybenzylbromide (0.5 g, 2.3 mmol). The reaction was allowed to stir for 3 hours and the precipitate formed was filtered off. The filtrate was concentrated under reduced pressure, redissolved in diethylether and washed with 1N sodium hydroxide (twice), water, and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography using 10% dichloromethane and 90% petroleum ether, to give 0.15 g of 3-chloro-5-methylbenzaldehyde (42%). 1H-NMR (CDCl3): 2.46 (s, 3H) 7.43(s, 1H) 7.56 (s, 1H) 7.68(s, 1H), 9.92 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:22][NH2:23]>CCO>[Br:18][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][C:15]=1[CH3:17])[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:22][N:23]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Br)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.192 g, 0.536 mmol) in EtOH (3 mL) was added anhydrous hydrazine hydrate (0.107 g, 2.144 mmol) and the mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to give 6-bromo-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as white solid (0.15 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 7.46 (s, 1H), 7.02 (s, 1H), 4.86 (q, J=6.8 Hz, 1H), 4.60 (dd, J=12.8 Hz, 2H), 2.26 (s, 3H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:25])=[O:24])=[CH:21][CH:20]=1>>[ClH:25].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: Cl
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc(F)cc1

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 2.00 g (0.00869 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 2.81 g 0.01738 mol) of p-fluorobenzoyl chloride with the exception that separation of the aqueous and organic layers provided an aqueous slurry containing the desired product. This slurry was filtered and the solid obtained thereby was washed with ethyl acetate to provide 1.17 g of a solid. The filtrate was then reduced to dryness under reduced pressure to provide an additional 2.0 g of a solid. The solids were combined and then dissolved in methanol containing diethyl ether and hydrochloric acid and the resulting solution was reduced to dryness under reduced pressure. The final product was purified by crystallization from a cyanomethane/methanol solution followed by recrystallization from an ethanol/diethyl ether solution to provide 2.75 g of the desired titled compound (m.p. 209°-210° C.). Analysis for C19H17FN4O2.HCl: Calc.: C, 58.69; H, 4.67; N, 14.41; Found: C, 58.60; H, 4.80; N, 14.18.
Reaction SMILES: Br.Br.[N:3]1([CH2:9][CH:10]2[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37](Cl)=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]>C(Cl)(Cl)Cl>[ClH:28].[N:3]1([CH2:9][C:10]2([C:37](=[O:38])[CH2:36][C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1cccc2c1CCNC2CN1CCCCC1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCCC2)NCCc2c(O)cccc21

Procedure:
Prepared as Ex. No. 34, from 1.65 g (4.06 mmoles) of 1-(piperidin-1-yl)methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 2.6 ml (18.50 mmoles) of Et3N and 2.2 g (9.84 mmoles) of 3,4-dichlorophenyl acetyl chloride in 50 ml of dry chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](Cl)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccn2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.42 mL) and tetrahydrofuran (15 mL) was added pyridine-2-carbonylchloride hydrochloride (214 mg) with stirring at room temperature. The mixture was stirred at room temperature for 30 min and at 50° C. overnight. Triethylamine (0.42 mL) and pyridine-2-carbonylchloride hydrochloride (214 mg) were added to the reaction mixture. 2 hr later, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine (5 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (10 mL) and 2M aqueous sodium hydroxide solution (3.0 mL) were added to the residue, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was neutralized with 6M hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (300 mg) of the title compound as a pale-orange solid.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:32])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>CS(C)=O>[CH3:20][CH:21]([N:32]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1
Reactant: CC(N)Cc1ccc2c(c1)OCO2
Reactant: O
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Solvent: CS(C)=O
Product: CC(Cc1ccc2c(c1)OCO2)N=C(OCc1ccccc1)C(=O)c1ccccc1

Procedure:
5.2 g of 2-benzyloxyphenylglyoxal hydrate (crude oil) are dissolved in 15 ml of dimethylsulfoxide, and 3.54 g of α-methyl-3,4-methylenedioxyphenethylamine are added thereto. The mixture is treated in the same manner as described in Example 1-(2), whereby a solution of α-(α-methyl-3,4-methylenedioxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH2:33]([OH:35])[CH3:34]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:31])[C:28]([O:35][CH2:33][CH3:34])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Yield: 71 %

Procedure:
Ethyl {1-benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-5-[4-(tert-butyl)phenyl]-1H-indole (0.732 g, 2.16 mmol), oxalyl chloride (0.75 mL, 8.6 mmol), and ethanol (6 mL) according to the procedure described in Step 3 of Example 1. Purification by flash chromatography (Biotage apparatus) using 5-10% ethyl acetate in hexane as an eluant afforded the title compound as a light yellow solid (0.671 g, 71%). 1HNMR (200 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.4 (s, 1H), 7.45-7.7 (m, 6H), 7.35 (s, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=6.7 Hz), and 1.3-1.45 ppm (m, 12H).