Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(N)[C:6](F)=[C:5](F)[C:4](F)=[C:3]([NH2:10])[C:2]=1F.Cl.Cl.[NH3:15].N[C:17]1[C:18](C)=[C:19]([OH:24])[C:20](C)=[CH:21][CH:22]=1.OO>O>[CH:17]1[C:22](=[N:10][C:3]2[CH:4]=[CH:5][C:6]([NH2:15])=[CH:1][CH:2]=2)[CH:21]=[CH:20][C:19](=[O:24])[CH:18]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cc1ccc(N)c(C)c1O
Reactant: N
Agent: Cl
Agent: OO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 4 h

Procedure:
0.01 mole (2.11 g) methoxyparaphenylenediamine dihydrochloride is dissolved in 100 cc water and the pH thereof is adjusted to 8 by addition of ammonia. This solution is immediately added to 0.01 mole (1.37 g) 3-amino 2,6-dimethyl phenol, preliminarily dissolved in 100 cc water. There are added to this resulting mixture 30 cc ammonia 22° Be and 130 cc hydrogen peroxide to make 20 volumes, and the mixture is allowed to stand at room temperature for four hours. On filtering the reaction mixture on a suction filter there are obtained 1.8 g of the above indoaniline in crystalline form which melts at 217°. After a recrystallization from a mixture of dimethylformamide and water, the said indoaniline exhibited the same melting point.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:5].[CH3:18][Mg]Br.O>C1COCC1.C(OCC)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:6]([C:4](=[O:5])[CH3:18])=[CH:7][N:8]=2)[CH:12]=1
Reactant: CON(C)C(=O)c1cnc(-c2cccnc2)s1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Yield: 98 %

Procedure:
A solution of N-methoxy-N-methyl-2-(3-pyridyl)thiazole-5-carboxamide (5.6 g, 21.9 mmol) in 150 ml of THF was cooled to 0° C. and treated with methyl magnesium bromide (8.4 ml of a 3M solution in diethyl ether, 24.1 mmol). The reaction was stirred at 0° C. and shown to be complete by LC/MS and TLC after 1 Hr. The mixture was hydrolyzed with 5 ml water and evaporated. The residue was taken up in 200 ml of ethyl acetate and washed with 2×80 ml water and 1×80 ml brine. The organic phase were dried over Na2SO4, filtrated and concentrated in vacuo to give the title compound (4.4 g, 98%) as orange crystals which were pure enough for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:8]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred suspension of compound 2 (0.600 g, 3.40 mmol, 1.00 equiv) in dry DMSO (15 mL) was added 4-fluorobenzylamine (1.20 g, 10.0 mmol, 3.00 equiv) followed by Et3N (0.500 mL, 4.10 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:3) to afford compound 3 (0.550 g, 52.0%) as yellow solid. TLC: 70% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.54 (m, 2H), 7.38-7.32 (m, 4H), 7.17 (t, J=8.8 Hz, 2H), 5.92 (d, J=8.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.59 (99.4% purity).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:23])=[C:4]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[CH3:29].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[N:23]=[C:30]([CH3:31])[N:24]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]=2[C:3]=1[CH3:29]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1NC(C)(C)C
Product: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Reaction time: 2 h

Procedure:
6-Chloro-5-methyl-N4 -(1,1-dimethylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine was combined with an excess of triethyl orthoacetate and heated first on a steam bath for about 16 hours and then in an oil bath at 130° C. for 2 hours. The excess triethylorthoacetate was distilled off under vacuum. The resulting residue was diluted with methylene chloride, washed with water and sodium bicarbonate solution, dried over magnesium sulfate then filtered through a layer of silica gel eluting with additional methylene chloride. The filtrate was concentrated under vacuum to provide a mixture which was carried on to thenext step.
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.CN[CH2:39][CH2:40]CC.[CH2:43]([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])C>>[ClH:31].[CH2:46]([N:45]([CH3:43])[CH2:48][CH2:49][C:9]1[CH:10]=[C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)[CH:12]=[CH:13][CH:8]=1)[CH2:47][CH2:39][CH3:40]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: CCN(CC)CC
Reactant: CCCCNC
Product: CCCCN(C)CCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)c1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 6 to afford the desired product as hydrochloride salt. M.p.=162-166° C. 1H NMR (DMSO) 400 MHz δ 10.24 (bs, 1H), 9.63 (s, 1H), 8.34-8.29 (m, 2H), 7.79 (bs, 1H), 7.68-7.65 (m, 1H), 7.56-7.45 (m, 3H), 7.43-7.41 (m, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.04-7.00 (m, 1H), 6.87 (d, J=8 Hz, 1H), 4.46 (t, J=6.4 Hz, 1H), 3.34-3.10 (m, 5H), 3.06-2.96 (m, 3H), 2.79 (t, J=4.8 Hz, 3H) 1.68-1.59 (m, 2H), 1.32-1.24 (m, 2H), 0.87 (t, J=7.6 Hz, 3H). LCMS m/e 531 [M+H]. Calc. for C31H32Cl2N4.1.93 Hydrochloric acid.0.30 Water.0.17 Ethyl Acetate: C, 61.15; H, 5.81; N, 9.00. Found C, 61.15; H, 5.82; N, 9.00.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([C@@H:11]([CH2:19][CH3:20])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([NH2:18])=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[N+:1]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:11]([CH2:19][CH3:20])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([NH2:18])=[N:14]2)=[CH:10][CH:9]=1)([O-:4])=[O:2]
Reactant: CC[C@@H](C[C@H]1COC(N)=N1)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H](C[C@H]1COC(N)=N1)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
To stirred nitric acid (9.5 ml, 65% conc.) at room temperature was added (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine (1.5 g, CAS 1043495-96-0) and the mixture was then heated at 60° C. for 3 hours. The mixture was then cooled in an ice-bath before being made basic by careful addition of 30% aq. sodium hydroxide solution. The resulting mixture was diluted with ethyl acetate/THF (1:1) and the phases were separated. The organic phase was washed with saturated brine, dried over sodium sulphate and concentrated in vacuo to give (S)-4-[(S)-2-(4-nitro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine (1.89 g, quant.) as a yellow solid. MS (ISP): 264.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[Cl:32][C:33]1[C:34]([F:42])=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[C:34]=3[F:42])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cccc(Cl)c1F
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(Cl)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 248. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.59 (s, 1H), 8.30-8.21 (m, 1H), 7.86-7.77 (m, 2H), 7.52-7.43 (m, 1H), 5.05-4.77 (m, 2H), 4.16 (ddd, J=24.7, 13.6, 4.7 Hz, 1H), 3.99 (ddd, J=17.9, 13.5, 4.8 Hz, 1H), 3.77 (s, 3H), 3.27-3.22 (m, 1H), 2.18-2.09 (m, 1H), 1.88-1.78 (m, 2H), 1.71-1.60 (m, 3H). LCMS (ES+) m/z 468 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1(C)[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=O)C.[CH3:24][Mg]Cl.O.[CH2:28]1[CH2:32][O:31]CC1>>[O:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14][CH:13]1[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C:6]([C:32]([OH:31])([CH3:28])[CH3:24])([CH3:4])[CH2:7]1
Reactant: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: C1CCOC1
Reactant: C[Mg]Cl
Solvent: O
Product: CC(C)(O)C1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a solution of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (1.13 g, 3.53 mmol) in dry THF (50 ml) under nitrogen at 0° C. a solution of methyl magnesium chloride in THF (3.53 ml, 3.0 M) was added dropwise. The resulting solution was refluxed for 2.5 h. Water was then slowly added under cooling and the product was extracted with DCM and purified by column chromatography (DCM/MeOH, 95:5) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+].ClCCl.CO>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccnc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC1(c2cccnc2)CNC(=O)C1
Reaction time: 18 h

Procedure:
Combine 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethyl ester (50 g, 172 mmol) and cobalt(II)chloride hexahydrate (81.8 g, 344 mmol) in methanol (500 mL). While maintaining the temperature at or below 20° C. with an ice-bath, add portionwise sodium borohydride (65.1 g, 1.72 mol). After the addition is complete, allow the reaction mixture to stand at ambient temperature. After 18 hours, evaporate the reaction mixture in vacuo to obtain a residue. Quench the reaction mixture by adding ammonium chloride and 0.5 M aqueous sodium hydroxide solution. Adjust the pH of the quenched reaction mixture to about 8 using 1 M aqueous hydrochloric acid solution. Filter through celite and extract the aqueous filtrate twice with dichloromethane. Combine the organic layers, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol 10/1 to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:12][C:13](=[O:43])[CH2:14][N:15]([S:25]([C:28]1[CH:37]=[C:36]2[C:31]([C:32]([Cl:42])=[CH:33][N:34]=[C:35]2[NH:38][C:39]([NH2:41])=[NH:40])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:42][C:32]1[C:31]2[C:36](=[CH:37][C:28]([S:25]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:14][C:13]([OH:43])=[O:12])(=[O:26])=[O:27])=[CH:29][CH:30]=2)[C:35]([NH:38][C:39]([NH2:41])=[NH:40])=[N:34][CH:33]=1
Reactant: COc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methoxybenzyl)glycine t-butyl ester trifluoroacetate (150 mg, 0.231 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 40 min. The mixture was diluted with PhMe, concentrated in vacuo, azeotroping with PhMe, and the residue triturated with i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methoxybenzyl)glycine trifluoroacetate (122 mg, 0.206 mmol) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:14](=[O:15])[CH:13]([CH2:16][CH:17]=[CH:18][CH3:19])[C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>N1C=CC=CC=1>[C:1]1([N:7]2[C:14](=[O:15])[C:13]([CH2:16][CH:17]=[CH:18][CH3:19])([C:20](=[O:23])[CH2:21][CH3:22])[C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=CCC1C(=O)NC(=O)N(c2ccccc2)C1=O
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CC=CCC1(C(=O)CC)C(=O)NC(=O)N(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A quantity of 1.29 g of 1-phenyl-3-methylallyl-barbituric acid prepared as described in Example Ia) is dissolved in 10 ml of pyridine. 0.52 ml of propionyl chloride is added dropwise to this solution which is cooled at 0° C. The reaction mixture is stirred at approximately 0° C. for 30 minutes and then at room temperature for 3 hours, and is then poured on 50 ml of ice water. After stirring with active carbon and filtering, the filtrate is acidified with conc. hydrochloric acid and extracted with methylene chloride. The organic layer is separated, washed with water, dried and evaporated. The final product is purified by means of column chromatography: silica gel/methylene chloride. The title compound is obtained in a yield of 0.65 g; melting-point 76°-80° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([C:17]#[N:18])=[N:11]2.CO.O1CCCC1.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([C:17]#[N:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1)=[C:8]2[CH3:30]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C#N)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(C#N)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-2-cyano-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.056 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (2.0 mL) and lithium hydroxide (0.60 g) was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a white solid, 0.015 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:15]1[CH2:23][CH2:24][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Product: N#CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1

Procedure:
Prepare by the method of example 76.1 using 4-chlorophenyl-acetonitrile (1.0 g, 6.6 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (1.5 g, 6.6 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1>C(O)C.C(O)(=O)C>[O:21]=[C:18]1[CH2:19][CH2:20][C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[CH:17]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C1CCC(=O)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC2=CC(=O)CC2)cc1
Yield: 33.8 %

Procedure:
0.51 g of 4,5-dihydro-6-(4-aminophenyl)-5-methyl-3(2H)-pyridazinone and 0.25 g of cyclopentane-1,3-dione were suspended in a mixture of 5 ml of ethanol and 5 ml of acetic acid and the resulting suspension was refluxed for 7 hours. After cooled, deposited crude crystal was collected by filtrating and recrystallized from DMF-heptane-CHCl3 to give 0.24 g of the title compound. m.p. >300° C. NMR (solvent DMSO-d6 -CDCl3) δ 1.20 (d, 3H), 2.32-3.32 (m, 7H), 5.60 (S, 1H), 7.56 (dd, 4H), 9.82 (S, 1H), 10.80 (S, 1H).
Reaction SMILES: [O:1]=[V:2].Cl.Cl.Cl.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[OH:14])=[CH:9][CH:8]=1>>[O-2:14].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=2)[O:14][V+2:2]([O:14][Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=2)[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[O:1][Si:13]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: O[Si](c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=[V]
Agent: Cl
Product: Brc1ccc([Si](O[V+2](O[Si](c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)O[Si](c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Product: [O-2]

Procedure:
vanadium oxytrichloride is reacted with tri-(p-bromophenyl)-silanol [m.p.: 120°- 121° C.] to produce tris-[tri-(p-bromophenyl)-siloxy]-vanadium oxide [m.p.: 175° C];
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](=[NH:22])[NH2:21])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[CH2:27]([N:31]1[CH2:36][CH2:35]N[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:31]1[CH2:36][CH2:35][N:22]([C:20](=[NH:21])[C:19]2[CH:18]=[C:17]([NH:16][C:15](=[O:26])[NH:14][C:11]3[CH:10]=[CH:9][C:8]([S:5]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:6])=[O:7])=[CH:13][CH:12]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN1CCNCC1
Reactant: CCCNS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C(=N)N)c2)cc1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCCC)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 3-(3-(4-(N-propylsulfamoyl)phenyl)ureido)benzimidamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[CH:22]=O)/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[NH:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][OH:40].C(O)(=O)C>ClCCl.CO>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=2[CH2:22][N:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[CH2:39][OH:40])/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2C=O)s1
Reactant: OC[C@@H]1CCCN1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2CN2CCC[C@H]2CO)s1
Yield: 38 %

Procedure:
In a vial (5 mL), a mixture of Example 375C (88 mg, 0.200 mmol), support-bound cyanoborohydride resin (0.256 g, 0.599 mmol), (S)-pyrrolidin-2-ylmethanol (60 mg, 0.593 mmol), and acetic acid (18 mg, 0.300 mmol) in dichloromethane (1 mL) and methyl alcohol (1 mL) was shaken on an orbit shaker for 2 hr. The reaction was filtered, concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) in 38% yield as TFA salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 1.72-1.81 (m, 1H) 1.88-1.99 (m, 2H) 2.05-2.20 (m, 3H) 2.27-2.41 (m, 1H) 3.34-3.42 (m, 1H) 3.52-3.66 (m, 1H) 3.67-3.82 (m, 4H) 3.85-3.96 (m, 1H) 4.36-4.46 (m, 3H) 4.57 (d, J=12.69 Hz, 1H) 4.86-4.93 (m, 2H) 7.28 (s, 1H) 7.76-7.82 (m, 1H) 7.87-7.94 (m, 1H) 8.73-8.75 (m, 1H); MS (DCI/NH3) m/z 526 (M+H)+. Anal. calcd calcd C26H34F3N3O3S.1.9 CF3CO2H: C, 48.22; H, 4.87; N, 5.66. Found: C, 48.28; H, 4.63; N, 5.67.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11]Br)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=[O:17])C.[K+].CO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][OH:17])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: Fc1cc(Br)c2occ(CBr)c2c1F
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: OCc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
The compound (1.47 g, 4.51 mmol) obtained in Step 1 was dissolved in acetonitrile (50 mL), and potassium acetate (660 mg, 6.76 mmol) was added thereto, and stirred at 60° C. for 3 hours. After cooling, the solvent was distilled away, and to the resulting residue, methanol (20 mL) and potassium carbonate (1.56 g, 11.28 mmol) were added, and stirred at room temperature for 2 hours. The solvent was distilled away. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.