Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[C:8](/[CH3:15])\[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:4][CH3:5])[CH3:2]>O1CCCC1>[CH2:1]([N:3](/[CH:6]=[CH:7]/[C@H:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C/C=C(/C)CCC=C(C)C
Solvent: C1CCOC1
Product: CCN(/C=C/[C@H](C)CCC=C(C)C)CC
Yield: 104.1 %

Procedure:
1.14 g (5.0 mmol) of (Z)-N,N-diethyl-3,7-dimethyl-2,6-octadienylamine, 5 ml of tetrahydrofuran and 16 mg (0.0192 mmol) of [η4 -bicyclo[2.2.1]hepta-2,5-diene][(R)-(6,6'-dimethyl-2,2'-biphenylylene)-bis(diphenylphosphine)]rhodium (I) tetrafluoroborate were placed in a Pyrex bomb tube under nitrogen. After degasifying the mixture, the tube was sealed and heated in a bomb tube oven at 85° C. to 90° C. for 19 hours. The brownish-red mixture was evaporated and the residue was distilled in a bulb-tube at about 120° C./0.05 mmHg. There were obtained 1.09 g of (1E,3R)-N,N-diethyl-3,7-dimethyl-1,6-octadienylamine as a colourless distillate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCC(=O)c1cccc(Cl)c1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
3′-Chloro-2′-hydroxypropiophenone (10 g, 54.3 mmol) and potassium carbonate (17.5 g) in 70 ml of acetone are admixed with 7 ml of dimethyl sulphate. The reaction mixture is boiled at reflux for three hours. After it has cooled to room temperature, the batch is subjected to suction filtration through Celite and the filter cake is washed with diethyl ether. After the solvent has been removed on a rotary evaporator, the yellow oil which remains is diluted with 200 ml of diethyl ether and the organic phase is washed with 0.2 M aqueous sodium hydroxide solution (100 ml) and brine (100 ml). The organic phase is dried over sodium sulphate and the solvent is removed on a rotary evaporator. This leaves the desired title compound as a colourless oil (98% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:25]2[CH2:26][CH2:27][CH:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:23][CH2:24]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccnn2Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (6.3 g) in acetic acid (70 mL) was added 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (12.0 g) was added, and the mixture was stirred for 18 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.27 g, 9%).
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:1](=[O:11])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH2:3])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: C=C(C(=O)O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: C=C(C(=O)NC1CCCCC1)c1ccccc1
Yield: 28.9 %

Procedure:
This compound was made from atropic acid (10.48 g, 70.8 mmol), N-methylmorpholine (7.8 ml, 70.9 mmol), iso-butyl chloroformate (9.2 ml, 70.9 mmol), and cyclohexylamine (8.1 ml, 70.7 mmol) using the procedure described in Example 3. The crude product was purified by recrystallisation from cyclohexane to give the product (4.69 g), as white crystals, m.p. 131°-133°. (Found: C, 78.7; H, 8.8; N, 5.95. C15H19NO requires C, 78.6; H, 8.35; N, 6.1%.)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].I[C:22]1C=C(C=C(I)[C:30]=1OC1C=CC(OC)=CC=1)C(Cl)=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([O:7][CH2:22][CH3:30])=[O:6]
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Reactant: COc1ccc(Oc2c(I)cc(C(=O)O)cc2I)cc1
Product: CCOC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1
Temperature: 70 °C

Procedure:
Ethyl 3,5-diiodo-4-(4′-methoxyphenoxy)benzoate (Compound 5) was synthesized by way of 3,5-diiodo-4-(4′-20 methoxyphenoxy) benzoyl chloride, the latter having been described in Borrows et al., supra. Thus, in a 10 ml flask 3,5-diiodo-4-(4′methoxyphenoxy)benzoic acid (99.2 mg, 0.200 mmole) was converted to 3,5-diiodo-4-(4′-methoxyphenoxy) benzoyl chloride. After removal of excess thionyl chloride under vacuum, anhydrous ethanol (5.0 ml) was added with stirring and the mixture heated to 70° C. for 5 minutes. Excess ethanol was removed and the dry residue dissolved in hot 95% ethanol (4.0 ml), from which the product ester crystallized in the refrigerator (3° C.). Yield: 55.8 mg (53%) of buff-colored crystals. Melting point: 96-98° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:35]([N:15]3[C:16]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([CH3:27])[C:17]([C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)([CH3:19])[N:18]=[C:14]3[C:8]3[C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][CH:7]=3)=[O:36])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperidino-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H48N6O2Cl2 [(M+H)+] 691.3289, observed 691.3291.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].C1(C)C=CC=CC=1>Cl.C1(C)C=CC=CC=1.O>[CH3:19][C:17]1[C:11]([CH3:10])=[C:12]([OH:13])[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][CH:7]=2)[N:5]=1
Reactant: COc1ccccc1N
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c(O)c(C)c(C)nc12
Temperature: 200 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
12.3 g of 2-methoxyaniline, 14.2 g of ethyl 2-methylacetoacetate and 3 drops of 1N HCl are introduced into a 250 ml three-necked flask fitted with Dean-Stark apparatus and a condenser. The mixture is stirred overnight. 100 ml of toluene are added and the mixture is refluxed until distillation of the toluene/water azeotrope is complete. The toluene is then evaporated off and 100 ml of diphenyl ether are added. The mixture is heated at 200° C. for 1 h. 50 ml of diphenyl ether are evaporated off and the mixture is cooled to room temperature. 20 ml of petroleum ether are added and the product which crystallizes is filtered off. 2.1 g (yield: 10%) of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline are obtained—m.p.: >290° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[F:16][C:15]([F:17])([F:18])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 390 g. of 4-trifluoromethylphenyl benzyl ether in 3580 ml. of ethanol was placed in a low pressure hydrogenation vessel along with 30 g. of 5 percent palladium-on-carbon. An initial hydrogen pressure of 60 psi was used and the solution was hydrogenated at room temperature until the theoretical uptake of hydrogen had been achieved--about 2 hours. The catalyst was removed by filtration. Concentration of the filtrate yielded 4-trifluoromethylphenol, distilling in the range 51°-54° C. at 6 torr. Yield=212 gms. (84.5 percent).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>C(NCC)C.O.C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:32][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[CH:31][C:22]=2[N:21]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:2]([F:20])([F:19])[F:1])[OH:18])[N:27]=1
Reactant: O=C(c1ccccc1)C(O)(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: CCNCC
Solvent: O
Product: Cc1ccc2c(N=C(c3ccccc3)C(O)(c3ccccc3)C(F)(F)F)cccc2n1
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
484 mg (2 mmol) Diethyl(phenyloxomethyl)phosphonate and 2,2,2-trifluoroacetophenone are stirred in 3 ml DMF together with 14 mg (0.22 mmol) potassium cyanide for 3 hours (Demir et al. J. Org. Chem. 2005, 70, 10584-87). Direct chromatographic purification on silica gel (ethyl acetate in hexane 33%) yields 580 mg phosphoric acid (1-benzoyl-2,2,2-trifluoro-1-phenylethyl)diethyl ester. 250 mg (0.6 mmol) of the phosphoric acid ester are stirred for 18 hours in 10 ml diethyl amine and 1 ml water. Evaporation and flash chromatography on silica gel (ethyl acetate in hexane 33%) yield 80 mg 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one. 80 mg (0.29 mmol) 3,3,3-trifluoro-2-hydroxy-1,2-diphenylpropan-1-one, 0.2 ml tetra t.-butyl othotitanate and 45 mg (0.29 mmol) 5-amino-2-methylquinolin are refluxed for 18 hours in 3 ml toluene and 0.1 ml acetic acid. The reaction mixture is poured into water after cooling and filtrated through a path of cellites after stirring for 15 minutes and diluting with ethyl acetate. The phases were separated and the aqueous layer was extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 90 mg of raw β-[(2-methylquinolin-5-yl)imino]-α-phenyl-α-(trifluoromethyl)benzeneethanol. To 30 mg of the raw imine in 2 ml methanol and 0.5 ml THF are added 20 mg sodium borohydride in two portions. The mixture is stirred over 2 hours, after that period quenched by addition of acetone and saturated ammonium chloride solution and diluted with ethyl acetate. The phases are separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Preparative thin layer chromatography on silica gel (ethyl acetate in hexane 50%) yields 2 mg of the title compound and 8 mg of the starting material.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](=[O:14])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:12]1[CH:13]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[C:10]([Br:15])[C:11]1=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]cc(Cc2ccccc2)cc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(Cc2ccccc2)cn1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 5-benzyl-3-bromopyridin-2(1H)-one 4 (3.5 g, 13.5 mmol) in dry DMF (100 mL) was added NaH 60% suspension in mineral oil (0.5 g, 16.2 mmol) and stirred for 30 min, followed by the addition of benzyl bromide (0.1.36 g, 7.9 mmol) and mixture further stirred for 1 h at RT. DMF was distilled off and the residue redissolved in EtOAc (250 mL), washed with brine solution (2×100 mL), dried over anhydrous Na2SO4 and EtOAc distilled off to give a yellow syrup, which was purified by column chromatography on silica gel (EtOAc:Hexane, 4:6) to give 5. Yield 3.8 g (83%), yellow solid, mp 89-90° C. 1H NMR (CDCl3, 500 MHz): δ 3.69 (s, 2H, CH2), 5.18 (s, 2H, CH2), 7.11 (d, 1H, CH, J=2 Hz), 7.12-7.39 (m, 10H, Ar—H), 7.60 (d, 1H, CH, J=2 Hz), 13C NMR (CDCl3, 125 MHz): δ 37.4, 53.5, 117.1, 119.1, 126.9, 128.2, 128.2, 128.3, 128.3, 128.6, 128.8, 128.8, 128.9, 128.9, 134.6, 135.8, 138.7, 143.0, 158.3. HRMS (M+H)+ calcd for C19H17BrNO 354.0494, found 354.0455.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH2:19])=[O:8]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Nc1ccccc1N
Product: NCc1cccc(C(=O)Nc2ccccc2N)c1
Yield: 29 %

Procedure:
The title compound (140 mg, 58% yield) was prepared as a grey solid from 3-cyano-benzoic acid (294 mg, 2 mmol) and o-phenylenediamine (432 mg, 4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 242 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C)C=O.O>[NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19]
Reactant: N#C[S-]
Reactant: Nc1cc(=O)nc(SCc2ccccc2)[nH]1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
6-Amino-2-[(phenylmethyl)thio]-4-(1H)-pyrimidinone (10.5 g) (prepared as described in WO 96/35678) and potassium thiocyanate (25 g) in dimethylformamide (200 mL) were heated together at 65° C. Pyridine (6.3 mL) was added and the solution cooled to 5° C. Bromine (2.2 mL) was added slowly and the reaction mixture stirred for 2 hours at 5-10° C. The reaction mixture was poured onto ice and water, stirred for 1 hour and the solid was filtered off. After washing with water and ether a pure sample was obtained after tituration with hot methanol.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH:35]([CH3:39])[C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:25]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:27])[CH:6]=1)[C:36](=[O:37])[CH:35]([O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:39])[CH3:26]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(Oc1ccccc1)C(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)Oc1ccccc1

Procedure:
(2′-{[Ethyl-(2-phenoxy-propionyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-45) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-phenoxypropionyl chloride.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].CS[C:16]#[N:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:5][C:6]1[C:7]([CH3:13])=[CH:8][C:9]([OH:12])=[C:10]([CH:11]=1)[C:16]#[N:17]
Reactant: CSC#N
Reactant: Cc1cc(O)ccc1F
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(O)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a IM solution of boron trichloride in dichloromethane (48 ml, 48 mmol) was added, in sequence, a solution of 4-fluoro-3-methylphenol (4.44 ml, 40 mmol) in dichloromethane (40 ml), methyl thiocyanate (3.3 ml, 48 mmol) and anhydrous aluminium chloride (5.4 g, 40 mmol) at 0° C. with stirring. The reaction mixture was heated under reflux for 3 h, and stirred at room temperature overnight. The solvent was evaporated, replaced by dichloroethane and added to ice and 4N sodium hydroxide (132 ml). The mixture was heated at reflux for 0.5 h with stirring, cooled to room temperature, the organic layer separated, and the aqueous layer further washed with dichloroethane. The aqueous layer was acidified with 2M hydrochloric acid and the solid that had precipitated collected by filtration, and washed well with water. The solid was dissolved in ethyl acetate, dried over magnesium sulphate, evaporated and the residue triturated with isohexane with ice cooling to give 3.5 g (58%) of the sub title compound as a colourless solid.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:16])[NH:12][CH:13]1[CH2:15][CH2:14]1.C[O-].[Na+]>CO>[CH:13]1([N:12]2[C:11](=[O:16])[C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:4][C:3]2=[O:2])[CH2:15][CH2:14]1
Reactant: COC(=O)Nc1ccccc1C(=O)NC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Yield: 53 %

Procedure:
A solution of (2-cyclopropylcarbamoyl-phenyl)-carbamic acid methyl ester was dissolved in MeOH (100 ml) and treated with NaOMe (0.5 M, 5 ml, 2.5 mmol) and the mixture heated to reflux for 12 h. The mixture was cooled and filtered to give 4.05 g (53%) of 3-cyclopropyl-1H-quinazoline-2,4-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)cc1
Yield: 86 %

Procedure:
Compound 46 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.[C:22](#N)[CH3:23].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH2:21]([O:20][C:3]1[CH:4]=[C:5]([Cl:19])[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][C:2]=1[Br:1])[CH:22]=[CH2:23]
Reactant: CCOc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Reactant: CC#N
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Temperature: 0 °C

Procedure:
To a stirred −10° C. solution of (5-Bromo-2-chloro-4-methoxyphenyl)(4-ethoxyphenyl)methanone (54.3 mmol) from Step 4 in dichloromethane (150 mL)/acetonitrile (150 mL) was added triethylsilane (20 mL, 109 mmol) followed by boron trifluoride diethyl etherate (16 mL, 109 mmol) at −10° C. The solution was allowed to warm to 0° C. over 2 h prior to quenching with saturated sodium carbonate solution. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with water prior to drying over magnesium sulfate. Filtration and concentration under reduced pressure yielded the title compound as a yellowish solid which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].[Cl:32][CH2:33][CH2:34][CH2:35][S:36](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:38])=[O:37]>>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([NH:8][CH2:7][CH:6]([O:5][C:3](=[O:4])[NH:2][CH3:1])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropylamine IVc2 is allowed to react and worked up by the same procedure as described in (4). m.p. 102°-104° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11]([NH2:13])=[O:12].S(=O)(=O)(O)O>>[Cl:1][CH2:2][C:3]1[N:13]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([F:17])=[C:8]([F:7])[CH:9]=2)[O:12][CH:5]=1
Reactant: NC(=O)c1ccc(F)c(F)c1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Product: Fc1ccc(-c2nc(CCl)co2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With stirring, 500 mg (3.94 mmol) of 1,3-dichloroacetone and 619 mg (3.94 mmol) of 3,4-difluorobenzamide are heated at +135° C. for 1 h. After cooling to RT, the mixture is allowed to stand at this temperature for 90 min 1.0 ml of conc. sulphuric acid is then added, and the mixture is stirred at RT for a further 15 min. The entire mixture is then poured onto 50 ml of ice. Initially, a viscous oil is formed. The mixture is stirred for 60 min, during which time a precipitate is formed which is filtered off with suction, dried under high vacuum and then purified chromatographically on silica gel 60 (mobile phase: isohexane/ethyl acetate 10:1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[N:14]1([C:20]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a stirred solution of tert-butyl 1-piperazinecarboxylate (2.50 g, 13.42 mmol) in CH2Cl2 (75 mL) cooled in an ice-water bath was added 4-morpholinecarbonyl chloride (1.57 mL, 13.42 mmol) followed by Et3N (3.74 mL, 26.84 mmol), and the reaction mixture was allowed to warm to room temperature. After 15 h, the reaction mixture was washed with 1.0 N HCl (50 mL), saturated NaHCO3 (75 mL), and brie (50 mL), dried, and concentrated to give the title compound (3.80 g, 95%) as a white solid. Mp: 171-173° C. 1H NMR: δ3.69 (t, J=4.9 Hz, 4H, CH2OCH2), 3.46-3.40 (m, 4H, CH2NCH2), 3.28 (t, J=4.9 Hz, 4H, CH2NCH2), 3.25-3.20 (m, 4H, CH2CH2), 1.47 (s, 9H, t-Bu). MS (DCI/CH4): m/z (rel itensity) 300 (MH+, 73), 272 (28), 244 (100), 200 (73). Anal. (C14H25N3O4): C, H, N.