Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.ClC(Cl)(Cl)C1C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH:22]=1.[NH4+].[Cl-]>CCOCC.BrBr>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][C:27]([CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])([C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)[OH:28]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)CCC(=O)c1cccnc1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)c1ccccc1
Product: CC(C)(C)CCC(O)(Cc1ccc(Cl)cc1Cl)c1cccnc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A solution of 66.2 g of 2,4-dichlorobenzyl chloride in 150 ml of ether was added dropwise to 8.2 g of Mg in 100 ml of diethyl ether. After 20% of the amount of dichlorobenzyl chloride had been added, the reaction was started by adding a few drops of bromine. After completion of the dropwise addition of the 2,4-dichlorobenzyl chloride solution, the mixture was refluxed for 1/2 an hour. It was then added dropwise to a solution of 55 g of 3,3-dimethylbutyl pyridin-3-yl ketone in 100 ml of ether. After it had been refluxed for a further two hours, the reaction mixture was hydrolyzed by dropwise addition of saturated aqueous NH4Cl solution (until the pH was 8), while being cooled with ice. The mixture was stirred for 15 hours at room temperature (20° C.) and extracted with diethyl ether, and the ether phase was washed with water, dried over Na2SO4, concentrated and distilled. 52 g of 3,3-dimethylbutyl-2,4-dichlorobenzyl-pyridin-3 -yl-carbinol (active ingredient No. 36) were obtained; boiling point 196°-202° C./0.5 mbar.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[N:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:27]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][CH:32]([NH2:36])[CH2:33]2)=[N:28]1.[BH4-].[Na+]>CO.O>[CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH2:12][NH:36][CH:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][N:27]([C:20]4[C:19]5[C:24](=[CH:25][CH:26]=[C:17]([O:16][CH3:15])[N:18]=5)[N:23]=[CH:22][CH:21]=4)[N:28]=3)[CH2:33]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: CN(C)c1ccc(C=O)c(F)c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc(N(C)C)c(C#N)c3F)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg, 0.36 mmol) in CH3OH (7 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (19 mg, 0.50 mmol) was then added and the suspension was stirred for 30 min at RT. The reaction mixture was diluted with a few drops of H2O, and the solvents were removed under reduced pressure. The crude material was purified by basic reverse phase to provide 70 mg (44%) of the title compound. MS (ESI): exact mass calculated for C26H26FN7O, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t, J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:50]([C@@H:53]2[CH2:58][CH2:57][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[C:49]2[C:44]=1[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]2>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:42][C:43]3[CH:52]=[CH:51][C:50]([C@@H:53]4[CH2:54][CH2:55][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:57][CH2:58]4)=[C:49]4[C:44]=3[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]4)[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (94.83 mg, 0.18 mmol) and ethyl cis-4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Compound 304B, 70.0 mg, 0.213 mmol). 1H NMR (400 MHz, MeOD) δ ppm 8.57 (br. s., 1H), 8.32 (s, 1H), 7.82-7.88 (m, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.96 (dt, J=8.1, 2.2 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.05-4.13 (m, 4H), 3.91 (s, 3H), 3.35 (s, 1H), 3.33 (br. s., 1H), 2.92-3.03 (m, 1H), 2.51 (td, J=11.7, 3.4 Hz, 1H), 2.44-2.56 (m, 1H), 2.17 (br. s., 5H), 1.98 (d, J=10.1 Hz, 2H), 1.63-1.83 (m, 4H), 1.25-1.33 (m, 9H). MS (ES+): m/z: 746.20/747.19 (100/40) [MH+]. HPLC: tR=4.44 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][N:15]([CH3:21])[C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NCCN1c1nc(-c2ccc(Br)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(Br)cc3)cs2)C1=O
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
1-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]imidazolidin-2-one (0.155 g, 0.480 mmol), prepared in step 2 of Example 4, was dissolved in 2.4 mL of anhydrous tetrahydrofuran and sodium hydride (60% suspension in mineral oil, 20 mg, 0.53 mmol) was added. The mixture was stirred for 20 min and then methyl iodide (0.03 mL, 0.48 mmol) was added and stirring was continued for 4 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. The mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) afforded the title compound (146 mg, 90%) as a white solid. HRMS: calcd for C13H12BrN3OS+H+, 337.99572; found (ESI, [M+H]+), 337.9954. Analytical HPLC: retention time 10.1 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40 C 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]Br.C(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:11][C:9]1[C:2]([CH3:1])=[C:3]([C:6]([CH3:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(C)c1C#N
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c(C)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dimethylbenzonitrile (5.0 g, 38.0 mmol), bromine (1.9 ml, 38.0 mmol) and chloroform (10 ml) is stirred at room temperature for 24 hours and subsequently heated to 60° C. for 6 hours. Upon cooling down to 0° C., 10 g of AlCl3 are added and the mixture is stirred for 4 hours at 0° C. The reaction mixture is poured into water and extracted with toluene. The organic phase is separated and concentrated and the residue is purified by column chromatography yielding the pure product as brown crystals, 6.2 g, mp. 60° C.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH:15]=[CH2:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33]OS(C)(=O)=O)[CH2:28]1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C@@:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH:15]=[CH2:16])[C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:28]1)=[O:26]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: C=Cn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide (0.70 g, 1.40 mmol), 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine (0.61 g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) and acetonitrile (18 mL) under argon for 48 hours. Cool and concentrate in vacuo. Thin layer analysis (silica gel, 10% methanol/0.1% ammonium hydroxide solution in acetonitrile) indicates a mixture with a major component Rf=0.40. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (50 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions to afford a tan solid. Purify the solid (in three separate injections of 110 mg, 250 mg and 250 mg) by reverse phase chromatography (PrepPak 40×100 mm μBondapak C18, 10 μm, 125 A°, Waters 037684, flow rate 35 mL/minute using the following gradients: 5 minutes with 10% acetonitrile/90% water with 0.1% trifluoroacetic acid, increase over 30 minutes to 50/50 water/acetonitrile, hold 5 minutes at 50/50 water/acetonitrile, increase over 5 minutes to 100% acetonitrile, hold 15 minutes at 100% acetonitrile). Combine the desired fractions to afford 0.17 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)NCc2c[nH]c(=S)n2[C@H]2CCc3c(F)cc(F)cc3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.30 g, I mmol), prepared as in Example 31, and 4-butylbenzoyl chloride (0.21 mL, 1.1 mmol) in 10 mL of dry pyridine was stirred under argon at approximately 0° C. for 1 hour and then at approximately 25° C. for an additional 2 hours. The mixture was concentrated and the residue was treated with water. The mixture was extracted with ethyl acetate (3x) and the combined extracts were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to give (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]-4-butylbenzamide (0.25 g, 0.55 mmol), m.p. 242°-243° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (170 mg, 0.641 mmol) in NMP (2 mL) was added cyclopropanamine (110 mg, 1.924 mmol) dropwise. The mixture was stirred at RT for 3 hours. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol, 96% yield), which was used for the next step without any purification. LC-MS (M+H)+=286.1
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1cccs1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1cccs1
Yield: 86 %

Procedure:
29.7 g of methyl α-isocyanoacetate, 120 g of triethylamine, 450 ml of tetrahydrofuran and 48.4 g of 2-thienylcarbonyl chloride are treated in the same manner as described in Preparation 1-(1). 53.9 g of 5-(2-thienyl)-4-methoxycarbonyloxazole are thereby obtained.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:13][C:6]1[C:5]([C:4](=[O:14])[N:3]([O:2][CH3:1])[CH3:15])=[CH:10][C:9]([NH:11][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[C:8]([F:12])[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CON(C)C(=O)c1cc(N)c(F)cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(C(=O)N(C)OC)c(Cl)cc1F
Temperature: 0 °C

Procedure:
55.6 g of N-methoxy-N-methyl-5-amino-2-chloro-4-fluorobenzamide are dissolved in 200 ml of pyridine and the solution is cooled to 0° C. 30.4 g of ethyl chloroformate are added dropwise at 0° C. while stirring and thereafter the reaction mixture is stirred for 14 hours. The mixture is poured into 1 liter of ice-water, the aqueous mixture is extracted three times with 250 ml of ethyl acetate each time, the combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and the solvent is evaporated off. The product is crystallized from diethyl ether. In this manner there is obtained ethyl 4-chloro-2-fluoro-5-(N-methoxy-N-methylcarbamoyl)-carbanilate, m.p. 121° C., used as the starting material in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16](=[O:24])[CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[C:4]=2[CH:3]=1.O.C([O-])(O)=[O:27].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16](=[O:24])[CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(CCn1ccnc1)N1c2ccccc2Sc2ccc(Cl)cc21
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A solution of 14 g of SO2Cl2 in 65 ml of CH2Cl2 is added dropwise over the course of 1 hour and at 10° to a mixture of 35.6 g of 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine, 8.2 g of silica gel, 8.2 ml of water and 850 ml of CH2Cl2. Stirring is continued for 2 hours at 10°; 100 ml of water is added dropwise and the mixture is rendered alkaline by adding NaHCO3. Working up in the customary manner gives 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, melting point 148°-149°.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[O:13])=[CH:7][CH:6]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([NH:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:19])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)N
Reactant: NN=Cc1ccc(NC(=O)C2CC2C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC(C)NC(=O)C1CC1C(=O)Nc1ccc(C=NN)cc1
Reaction time: 8 h

Procedure:
To 1.0 g (0.0035 mol) 2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl-carboxylic acid hydrochloride in 100 mL dry DMF was added 0.36 g (0.39 mL, 0.0035 mol) N-methylmorpholine and 0.48 g (0.46 mL, 0.0035 mol) isobutylchloroformate. The reaction was allowed to proceed for ten minutes at room temperature then 0.515 g (0.576 mL , 0.0035 mol) ethyl 3-aminobutyrate was added. The reaction was allowed to proceed overnight. The volatiles were removed under vacuum at 55° C. until a viscous oil remained. The residue was dissolved in water (60 mL) and purified by preparative RPHPLC. Two diastereomers were obtained and separated by HPLC. The faster eluting diastereoisomer, isomer 1, was collected and lyophilized to 0.9 g of a white solid: 1H NMR (300 MHz) d6 -DMSO δ 1.17 (m, 8H), 2.07 (m, 1H), 2.38 (m, 1H), 4.04 (m, 3 H), 7.77 (s, 4H), 8.28 (d, J=7.9), 8.80 (bs, 2H), 9.16 (bs , 2H), 10.78 (s , 1H); MS (FAB) 361.3 (MH+).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=1>O.ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:36]([C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1-hydroxybenzotriazole (0.53 g, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.67 g, 3.5 mmol) and 2,2,2-trifluoroethyl amine (0.51 ml. 6.35 mmol) were added to a dichloromethane solution (5 ml) of 4-chloropyridine-2-carboxylic acid (0.5 g, 3.17 mmol) and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=11:1→5:1). The purified product was concentrated to dryness under reduced pressure to obtain N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide (435 mg) as white powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][C:12]([N:14]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:15]1[C:20]([S:21](O)(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:38]>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][C:12]([N:14]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[C:15]1[C:20]([S:21]([Cl:38])(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13]
Reactant: COCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2ccccc2)cccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2ccccc2)cccc1S(=O)(=O)Cl

Procedure:
To a solution of 3.8 g (7 mmol) of the N,N-diethylethanamine salt of 2-[(3-methoxy-1-oxopropyl)(trifluoroacetyl)amino][1,1'-biphenyl]-3-sulphonic acid in 14 ml of dichloromethane are added 1.75 g (8.4 mmol) of phosphorus pentachloride, the mixture is heated for 3 hours at the reflux temperature and is then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (46.4 mg, 41%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCOCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 73.4 %

Procedure:
To a suspension of 1.00 g of 4-hydroxy-2-pyridone in 50 ml of dried dioxane were added 3.78 ml of triethylamine and a solution of 2.17 g of 4-nitrobenzoyl chloride in 30 ml of dried dioxane, and the mixture was refluxed for 6 hours. After the dioxane was distilled off, the residue was washed with water and then with a 1:1 mixture of methanol-acetone to obtain the title compound in an amount of 1.72 g (yield: 73.4%)
Reaction SMILES: NC1C=C(C)C2C(=CC3C(C=2)=CC=CC=3)C=1C#N.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])#[N:20].C[O:40]C1C(C(Cl)=O)=CC=CC=1>N1C=CC=CC=1>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[NH:20][C:19](=[O:40])[C:21]2[C:22](=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:28]=1
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Reactant: COc1ccccc1C(=O)Cl
Agent: Cc1cc(N)c(C#N)c2cc3ccccc3cc12
Solvent: c1ccncc1
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide 2-Amino-4-methyl anthronitrile (50.0 g, 378.3 mmol) was dissolved in 1 L dry pyridine and cooled to 0° C. O-Anisoyl chloride (63.0 ml, 453.96 mmol) was added dropwise over a 40 minute period and the reaction was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 16 hours. The reaction was poured over 2 L of ice and the product formed a precipitate. The product was collected by vacuum filtration and dried for 3 days to produce the desired product a fluffy tan solid. Recovered 92.0 g 91% yield. LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.