Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][NH:6][C:7]([C:9]1[N:17]=[C:16]2[N:11]([N:12]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:14]=[CH:15]2)[N:10]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:13]3[CH:14]=[CH:15][C:16]4[N:11]([N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:42])=[O:3])=[O:8])[N:17]=4)[N:12]=3)[CH2:27][CH2:26]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
928 mg of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]glycine ethyl ester was dissolved in 7 ml of ethanol; 2.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water; 1 N hydrochloric acid was added to bring the mixture to pH 4.5. The crystal obtained was collected by filtration, washed with water, acetone and ethyl acetate and dried to yield 443 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10](OC1C=CC=CC=1)(=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>C(O)C>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[C:10]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: Cc1ccc(O)c(N)c1
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3O)nc2c1
Temperature: 200 °C

Procedure:
A mixture of 2-amino-p-cresol (10.0 g, 0.081 mole) and phenyl salicylate (17.4 g, 0.08 mole) was heated under nitrogen atmosphere in an oil bath at 200° C. for 1½ h. To the cooled reaction mixture ethanol was added and the product filtered off under suction. The product was dried under vacuum at 75° C., and then purified by column chromatography (dichloromethane). The eluent containing the product was concentrated and ethanol added to the residue to give a bright white crystalline solid. The product was suction filtered and dried under vacuum at 75° C. Yield 7.4 g (40%). M.p 138° C. (DSC, onset). Elemental analysis: Found, C 74.62, H 4.86 and N 6.32%. C14H11NO2 requires C 74.65, H 4.92 and N 6.22%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]I.Cl>C(OCC)C>[O:1]([CH2:8][CH2:9][CH:10]([OH:11])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCOc1ccccc1
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)CCOc1ccccc1
Yield: 67 %

Procedure:
24.9 g of methyl iodide was reacted with 7.26 g of magnesium in 150 ml of anhydrous diethyl ether to obtain methylmagnesium iodide by Grignard reaction. To a solution consisting of 20 g of 3-phenoxypropionaldehyde and 200 ml of anhydrous diethyl ether was added dropwise the methylmagnesium while maintaining a temperature of not more than 20° C. To the reaction solution was added 25 ml of concentrated hydrochloric acid and the solution was separated into two phases, which phases were then separated from each other. The ether layer was washed with an aqueous sodium bicarbonate solution, washed with water, dried with anhydrous sodium sulfate and then condensed under reduced pressure to obtain 15.0 g of 4-phenoxy-2-butanol having a boiling point of 61° C. to 62° C. at 3 mmHg in a yield of 67%.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([NH:33][C:34]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=S)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[C:40]([O:39][C:37](=[O:38])[NH:36]/[C:34](=[N:33]\[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Mercuric chloride (41 mg, 0.15 mmol) was added to a mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol), bis-N-Boc thiourea (38 mg, 0.14 mmol) and triethylamine (0.45 mmol) in DMF (5 mL) at 0° C. After 1 h of stirring at 0° C., ethyl acetate was added. The resulting mixture filtered and the filtrate washed sequentially with water and brine then dried (Na2SO4) and concentrated. The resulting residue was purified by reverse-phase chromatography to yield Z-tert-butyl(((tert-butoxycarbonyl)imino)(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)methyl)carbamate (74 mg, MS m/z=587 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[OH-].[Na+]>CCOC(C)=O>[Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(Br)c(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(Br)cc1N
Temperature: 75 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of 4,5-dibromo-2-nitroaniline (3.35 g, 11.32 mmol) in EtOAc (150 mL) was added stannous chloride dihydrate (12.8 g, 56.74 mmol), the mixture was stirred at 75° C. for 16 h, then allowed to cool to room temperature and poured into ice-water (about 150 mL). To the mixture was added 1N aq NaOH with vigorous stirring to take the pH to 9 (pH paper). The resulting thick yellow white emulsion was extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine (2×50 mL), dried (over Na2SO4) and evaporated to dryness. The residual solid was dried under 1 mmHg at 40° C. for 14 h giving 2.92 g (97%) of 4,5-dibromo-1,2-phenylenediamine as a yellowish powder. Mp 149°-50° C. IR (KBr) 3400, 1623, 1489, 1394, 1271, 868 cm-1. 1H NMR (DMSO-d6) 6.754 (s, 2H), 4.867 (s, 4H).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15]>C(O)(=O)C.[BH3-]C#N.[Na+]>[CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13]
Reactant: CON=CCCc1c(Cl)cc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONCCCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
To a stirred solution of 3-(2,4,6-trichloro-phenyl)-propionaldehyde O-methyl-oxime in acetic acid, NaCNBH3 was added at 0° C.-10° C. The reaction mass was then stirred at ambient temperature for 6 hours. When the TLC confirmed completion of the reaction, acetic acid was removed by azeotropic distillation. The residue was basified with 10% NaOH solution and aqueous solution was extracted with ethyl acetate (3×30 ml). The combined organic layer was washed with water and brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 3% ethyl acetate in hexane) to afford O-methyl-N-[3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.4 g, 88%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[C:3]([C:2]1([CH2:1][CH2:8][CH2:7][CH2:6][CH3:11])[CH2:4][C:9]2[C:10]([CH3:10])([CH3:2])[CH2:11][CH2:6][C:7]([CH3:1])([CH3:9])[C:8]=2[CH2:3]1)#[CH:4]
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1(CCCCC)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.6 g of this dibromide were dissolved in 10 ml of THF, cooled to −78° C. and treated dropwise with 1.8 ml of a 1.6 molar solution of butyl lithium in hexane. After stirring at −78° C. for 1 hour and at room temperature for 1 hour, the reaction mixture was poured on ice/saturated aqueous ammonium chloride solution and extracted with hexane. The organic phase was dried (Na2SO4) and the solvent evaporated to yield 0.4 g of 2-ethynyl-4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene as yellowish oil.
Reaction SMILES: [CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)Cl>[Br:34][C:13]1[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]2[C:11]([N:12]=1)=[C:10]([C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)[N:9]=[C:8]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:7]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Solvent: ClC(Cl)Cl
Product: CCC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of 5-(9-sec-Butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (200 mg, 0.57 mmol) in 15 ml of chloroform, was added slowly NBS, (120 mg, 0.68 mmol) at a temperature of 5° C. The reaction was continued for 2 hours at this temperature. After simple work-up, the product 5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine was purified by flash column (solvent system: 50% ethyl acetate in hexane) to deliver the desired compound in a yield of 49% (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:18](=[O:21])[NH:17][C:16](=[O:22])[NH:15][C:14]=2[N:13]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:11])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:18](=[O:21])[NH:17][C:16](=[O:22])[NH:15][C:14]=2[N:13]=1
Reactant: COc1cc(C(N)=O)ccc1-c1nc2[nH]c(=O)[nH]c(=O)c2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1-c1nc2[nH]c(=O)[nH]c(=O)c2[nH]1

Procedure:
Prepared by boiling 0.7 gm of 8-(2-methoxy-4-aminocarbonylphenyl)-1H,3H-purin-2,6-dione in 10 ml of phosphorus oxychloride for 24 hours. The compound crystallizes as the hemihydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:15][O:16][C:17]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:13]
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3cccc(OC)c3OC)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 21.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31].CCCCCC.C(OCC)(=[O:44])C>ClCCl>[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[O-:31][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:44])=[O:32]
Reactant: CCOC(C)=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At room temperature, triethylamine (1.0 mL, 7.2 mmol, 1.2 equiv.) was added to a solution prepared by dissolving estrone (1.62 g, 6.0 mmol) in 10 mL of dichloromethane. The mixture was cooled to 0° C., and then trifluoromethanesulfonyl chloride (760 pt, 7.2 mmol, 1.2 equiv.) was added to the mixture over 3 minutes or more with stirring to effect a reaction. After 6 hours, the reaction was quenched by adding a saturated sodium hydrogen carbonate aqueous solution (10 mL) to the reaction mixture, and the reaction mixture was separated into two layers. The organic layer (dichloromethane solution) was isolated preparatively, and 20 mL of dichloromethane was added to the aqueous layer to extract the product. The above operation was repeated twice. An excess amount of anhydrous magnesium sulfate was added to the collected organic layer (dichloromethane solution), and the mixture was filtered. The solvent was evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=5/1) to obtain estrone triflate (Rf=0.36, white solid, 1.98 g) (see below). The yield thereof was 82%.
Reaction SMILES: [CH:1]1(CCCCCCCCCCCCN)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:25]([N:43]=[C:44]=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH:1]1([N:43]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:44]([NH:43][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCCNC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 42, starting from 7.0 g of the compound of Example 1 and 5.9 g of octadecyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:8]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
86.00 g (0.39 mol) of 5-chloro-2-nitro-benzoyl chloride was dissolved in 300 ml of toluene, a solution of 62.00 g (0.35 mol) of 4-aminobenzenesulfonyl fluoride was added dropwise, and the mixture was heated under reflux for 4 h. Subsequently it was cooled, concentrated in vacuo to half of its volume, cooled, and the precipitated solid was filtered off with suction. 121.60 g (86%) of the title compound having a melting point of 182-184° C. were obtained.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[Sn:16](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:25]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[C:7]1([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:9]=[CH:10][O:6]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1coc(-c2ccco2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(c2ccco2)CC=CO1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of n-BuLi (7.7 mL, of 2.5M in hexanes, 19.2 mmol, 1.3 equivalents) was added dropwise to a solution of bifuran (2 g, 14.9 mmol) in dry THF (100 mL) at −78° C. under N2. The mixture was allowed to come to room temperature and stirred for 1 h. To the white suspension was added dropwise Bu3SnCl (4 mL, 14.9 mmol) at 0° C. and the reaction was allowed to reach room temperature and stirred for 2 h. The mixture was extracted with hexane, dried (MgSO4) and evaporated. Seperation by chromatography using bacified silica (Et3N) and hexane gave 1 (3.8 g, 60% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.85-0.91 (t, J=7.3 Hz, 9H), 1.03-1.13 (m, 6H), 1.26-1.39 (m, 6H), 1.48-1.63 (m, 6H), 6.40-6.42 (m, 1H), 6.50 (d, J=3.3 Hz, 1H), 6.57 (dd, J=3.3, 6.0 Hz, 2H), 7.34 (dd, J=0.7, 1.8 Hz, 1H) ppm. 13C NMR (300 MHz, CDCl3): δ 10.2, 13.7, 27.2, 28.9, 104.6, 105.0, 111.3, 123.0, 141.4, 147.5, 151.0, 160.9 ppm
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCCCCC>[CH3:14][N:15]([CH3:17])[CH:16]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9](=[O:11])[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccc(F)cc1
Solvent: CCCCCC
Product: CC(=O)C(=CN(C)C)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-propanone (10.0 g) and N,N-dimethylformamide dimethylacetal (8.00 g) was stirred at 120° C. for 2 hrs. The reaction mixture was cooled, and hexane was added to the precipitated solids, which were collected by filtration to give 4-(dimethylamino)-3-(4-fluorophenyl)but-3-en-2-one (11.3 g, yield 83%) as a pale-yellow solid.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:20]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=1)([CH3:19])[CH3:18])C1C=CC=CC=1.N>C1COCC1>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([CH3:19])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: CC(C)(NCCCc1nccn1Cc1ccccc1)c1ccc(Cl)cc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(NCCCc1ncc[nH]1)c1ccccc1
Temperature: -35 °C

Procedure:
A solution of the final product from Example 86 (200 mg) in dry THF (5 ml) was added to liquid ammonia (15 ml) (purified by treating the liquid ammonia with sodium and distilling the ammonia into another flask). The mixture was cooled in a dry ice acetone bath at -35° C., in a flask fitted with an acetone dry ice condenser, and small pieces of sodium were added until the blue colour persisted. After 15 minutes ammonium chloride (0.1 g) was added and the ammonia allowed to evaporate. Ethanol (10 ml) was added to the mixture followed by water (10 ml) and the solvent largely removed under reduced pressure. The residue was diluted with water and extracted with dichloromethane to give a residue which was purified by flash column chromatography on silica using methanol/ethyl acetate (1:1) as the mobile phase to give 3-(imidazol-2-yl)-N-(1-methyl-1-phenylethyl)propylamine as an oil.
Reaction SMILES: [CH2:1]([Mg]Br)C.[F:5][C:6]1[CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[F:12].CCCCCC.CCOC(C)=O>C(OCC)C>[F:5][C:6]1[CH:7]=[C:8]([C:13]([OH:15])([CH3:1])[CH3:14])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethylmagnesium bromide in ether (38.0 mL, 38.0 mmol) at 0° C., was added a solution of 3′,4′-difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether (35 mL). The reaction mixture was stirred at 0° C. for 1 h when TLC analysis indicated that the reaction was complete (Rf=0.3, 3:1 hexane/EtOAc). The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2×30 mL), washed with Rochelle's salt followed by brine and the organic layer was dried over Na2SO4. The solvent was removed in vacuo after filtration and 2-(3,4-difluorophenyl)propan-2-ol was obtained as a colorless oil (crude wt.=5.4 g, 97%) which looked >90% pure by NMR. It was used in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:18])[CH:4]=1)#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:18])[CH:4]=1
Reactant: N#Cc1ccc(C(=O)NC2CCCCC2)c(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(C(=O)NC2CCCCC2)c(F)c1
Yield: 95.9 %

Procedure:
Dissolve 4-cyano-N-cyclohexyl-2-fluoro-benzamide (620 mg, 2.5 mmol) in 7N ammonia in methanol (150 mL) and hydrogenate at 500 psi pressure in the presence of Raney® nickel (500 mg) for 16 h at 60° C. Filter the mixture and concentrate in vacuo. Purify by SCX chromatography to give the title compound as a white solid (600 mg, 94%). MS (ES−) m/z: 251 (M−H)−.
Reaction SMILES: [BrH:1].N[NH:3][C:4]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=[NH:5].ClC1C=CC(C=O)=CC=1>>[BrH:1].[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH:8]=[N:7][NH:6][C:4](=[NH:3])[NH2:5]
Reactant: N=C(NN)NN=Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: O=Cc1ccc(Cl)cc1
Product: N=C(N)NN=Cc1ccc(Cl)c(Cl)c1

Procedure:
In a similar manner the reaction of 1-amino-3-(4-bromobenzylideneamino)guanidine methosulfate with 4-chlorobenzaldehyde gives the methosulfate salt of the subject compound. The reaction of 1-amino-3-(4-cyanobenzylideneamino)guanidine hydroiodide with 4-chlorobenzaldehyde gives 1-(4-chlorobenzylideneamino)-3-(4-cyanobenzylideneamino)guanidine hydroiodide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidine hydrochloride with 4-cyanobenzaldehyde affords the corresponding hydrochloride salt which melts at 297°-298°C. The reaction of 1-amino-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide and 4-chlorobenzaldehyde gives 1-94-chlorobenzylideneamino)-3-(3,4-dichlorobenzylidenamino)guanidine hydrobromide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidine hydrochloride with 3,4-dichlorobenzaldehyde gives the corresponding hydrochloride salt which melts at 288°C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[C:16]([CH3:30])[CH:15]=3)[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[CH:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([NH2:45])[CH:36]=1)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[CH:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:45][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH:8]=3)=[CH:15][C:16]=2[CH3:30])=[O:22])[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Nc1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1cc(NC(C)C)cc(C(F)(F)F)c1
Yield: 54.2 %

Procedure:
Dissolve phenyl N-[4-[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]oxy-2-methyl-phenyl]carbamate (343 mg, 1.57 mmol), N1-isopropyl-5-(trifluoromethyl)benzene-1,3-diamine (700 mg, 1.73 mmol) and DIEA (608 mg, 4.72 mmol) in THF (4 mL), heat the reaction at 80° C. for 3 hrs. After the reaction is complete, remove the volatiles under reduced pressure. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (450 mg, 83%). MS: (M+1): 529.3.