Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:25]([NH2:27])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:25]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an N2 atmosphere 39 μL (0.5 mmol) methanesulphonic acid chloride are added to a solution of 100 mg (0.24 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine and 161 μL (2 mmol) pyridine in 10 mL DCM and the reaction mixture is stirred for 2 h at RT. To complete the reaction a further 160 μL pyridine and 39 μL methanesulphonic acid chloride are added and the mixture is stirred overnight. It is combined with 10% Na2CO3 solution, the organic phase is separated off and the solvent is eliminated i.vac. The residue is purified by HPLC.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N1C=CC=CC=1.[FH:14].[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:30]=[C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)SCCCS2)[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1>ClCCl>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:30]=[C:29]([C:31]([F:1])([F:14])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccccc3)SCCCS2)c1
Reactant: F
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(F)(F)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Chill a solution of nitrosonium tetrafluoroborate (0.074 g, 0.63 mmol), hydrogen fluoride-pyridine (0.250 mL) in dichloromethane (2 mL) in aplastic bottle. Add a solution of N-methyl-5-(2-phenyl-[1,3]dithian-2-yl)-N-propyl-isophthalamic acid methyl ester (0.123 g, 0.286 mmol) in dichloromethane (1 mL) to the bottle and stir at room temperature for 2 h. Dilute the solution with dichloromethane (5 mL) and filter though a pad of magnesium sulfate and aluminum oxide. Wash solid with ethyl acetate (50 mL), concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36]([Cl:39])(=[O:38])=[O:37].[ClH:40]>C(Cl)(Cl)Cl>[ClH:39].[ClH:40].[CH3:35][S:36]([NH:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Reaction time: 1 h

Procedure:
To a solution of 1-(6-aminopyridin-2-ylmethyl)-4-benzhydrylpiperazine (3.58 g) and triethylamine (1.01 g) in chloroform (20 ml) was dropwise added methanesulfonylchloride (1.15 g) at 5° to 10° C. under cooling with stirring, which was continued at the same temperature for 1 hour. To the resultant mixture, additional triethylamine (0.51 g) and methanesulfonyl chloride (0.57 g) were added successively. The mixture was stirred for 1.5 hours. The reaction mixture was washed with water, dried and evaporated in vacuo. The resulting oily product was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired compound were combined and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to give 1-(6-methanesulfonylaminopyridin-2-ylmethyl)-4-benzhydrylpiperazine dihydrochloride (0.97 g). mp: 201°-202° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC1=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Reaction time: 35 h
Yield: 8.1 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 546 mg of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 2-(3), and 200 mg of Lipase B was added thereto, followed by stirring at room temeprature for 35 hours. Any insoluble matter was removed by filtration and washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by short silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 35 mg (yield: 83%) of (S)-1,4-dihydro 2,6-dimethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: B.[Na].[F:3][C:4]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:5]=1[C:6](O)=[O:7].B(F)(F)F.CCOCC>O1CCCC1>[F:14][C:9]1[C:10]([F:13])=[CH:11][CH:12]=[C:4]([F:3])[C:5]=1[CH2:6][OH:7]
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: B
Agent: FB(F)F
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1c(F)ccc(F)c1F
Temperature: 0 °C
Yield: 102 %

Procedure:
To a solution of sodium boron hydride (51.6 g) in tetrahydrofuran (500 ml) is added dropwise a solution of 2,5,6-trifluorobenzoic acid (120 g) in tetrahydrofuran (200 ml) with stirring at below 10° C., and thereto is further added dropwise a solution of BF3.(C2H5)2O (232 ml) in tetrahydrofuran (500 ml) under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water (1.5 liter) and is extracted with diethyl ether. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 g), as pale yellow oil, b.p. 112° C. (30 mmHg).
Reaction SMILES: C(OC1C(OC(=O)C)C(OC(=O)C)C(COC(=O)C)OC1[C:24]1[C:32]2[C:28](=[N:29][C:30](=[O:33])[N:31]=2)[CH:27]=[CH:26][C:25]=1[C:34]([O-])=O)(=O)C.[OH-:37].[Na+]>C(O)C>[OH:37][C:26]1[C:25]([CH3:34])=[CH:24][C:32]2=[N:31][C:30](=[O:33])[N:29]=[C:28]2[CH:27]=1
Reactant: CC(=O)OCC1OC(c2c(C(=O)[O-])ccc3c2=NC(=O)N=3)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1O)=NC(=O)N=2
Yield: 92 %

Procedure:
A solution of (16) (0.30 g, 1.32 mmol) in 10% sodium hydroxide (5 ml) and ethanol (5 ml) was heated under reflux for 1.5 h. When cooled to room temperature the ethanol was removed in vacuo and the mixture was filtered to give (18) as a white solid (0.20 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-])=O)[CH:20]=2)=[CH:4][CH:3]=1.CC(O)=O>C(O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[NH2:26])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(-c3ccc(F)cc3)n2n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(-c3ccc(F)cc3)n2n1
Temperature: 80 °C
Yield: 942.3 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.075 g, 0.0198 mmol) in ethanol (6 mL) and water (2 mL) containing AcOH (1.18 mmol) is added iron (0.055 g, 0.991 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (50 mL) is added. The mixture is extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 0.065 g (95%) of the title compound as a yellow solid: Rf 0.36 (95:5 CH2Cl2:MeOH); LCMS (m/z)=349.4 [M+H]+, tR=2.31 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:26](OCC)[O:27]CC)=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:26]=[O:27])=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1OC
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1OC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (447.5 mg) in acetone (7.5 ml) was added 6N-hydrochloric acid (0.2 ml) and stirred at room temperature for an hour. The resultant mixture was treated in a similar manner to Example 2-4), to give reddish yellow crystals of diethyl 2-methyl-4-(2-methoxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (373.2 mg). The product was recrystallized from a mixture of diethyl ether and n-hexane to give the pure product, m.p. 111° to 112° C.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)C(Cl)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:41]([NH:48][CH3:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([N:48]([CH3:49])[C:22]([C@@H:12]1[CH2:11][C:10](=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][N:13]1[C:15](=[O:17])[CH:31]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:24])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Product: CN(Cc1ccccc1)C(=O)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N-benzyl-N-methylamine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=532.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
To a solution of 1-(4-bromo-phenyl)-piperazine (1.47 g, 6.10 mmol) and acetic acid (0.42 mL, 7.4 mmol) in methanol (25 mL) was added 37% formaldehyde in water/methanol (56.7:37:6.3, water:formaldehyde:methanol, 5.6 mL, 180 mmol). The mixture was stirred at room temperature for 18 hours. The suspension was cooled to 5° C. in an ice/water bath and Sodium cyanoborohydride (4.98 g, 79.2 mmol) was added in small portions. The mixture was stirred and warmed to room temperature for 18 hours. The mixture was slowly poured into saturated aqueous ammonium chloride (200 mL) and stirred for 1 hour. The mixture was extracted with dichloromethane (3×75 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an oily solid. The material was placed under high vacuum for 18 hours to yield a white solid (1.54 g). 1-(4-Bromo-phenyl)-4-methyl-piperazine was isolated as a white solid (1.54 g, 99%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.36-7.31 (m, 2H), 6.82-6.76 (m, 2H), 3.20-3.15 (m, 4H), 2.60-2.55 (m, 4H), 2.36 (s, 3H). MS=255, 257 (MH)+. 32b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as pale yellow solid (0.022 g, 18%). MP=242-244° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.95 (m, 2H), 6.67 (s, 1H), 3.20-3.15 (m, 4H), 3.10 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:1]1([C:7]2([C:17]3[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2ccccc2)CCCCC1
Reactant: Oc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A mixture of 5 g (28.4 mmol) of 1-phenyl-1-cyclohexanol, 5.35 g (56.8 mmol) of phenol and 250 mg (1.32 mmol) of toluenesulfonic acid monohydrate was stirred at 85° C. under nitrogen atmosphere for 4 hours. The material was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine. The resulting solution was dried (Na2SO4), filtered and concentrated to a white solid which was heated under high vacuum to remove residual phenol. The resulting residue was purified by flash chromatography on silica gel, eluting with methanol/dichloromethane to provide 5.64 g (22.4 mmol) of 4-(1′-(phenyl)cyclohexyl)phenol.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(O)(=O)[C@H](CC(O)=O)O.C(N(CC)CC)C.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C(O)C[C@H](O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@H](CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol), which was derived from L-malic acid by means known in the art, in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0-2%) as eluent gave 4.90 g (99%) of the title material as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C[O-].[Na+].CO.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>C1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(O)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 3.05 g of 3,4-dimethylphenol, 1.19 g of sodium methoxide, 40 ml of methanol and 10 ml of benzene is added 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate. The mixture is refluxed for 24 hours and the solvent removed under reduced pressure. The residue is chromatographed over silica gel with dichloromethane as eluent. The product is obtained as a viscous oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[N:15]/[CH:12]2[CH2:14][CH2:13]2)=[CH:2]1
Reactant: NC1CC1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Product: C(=N/C1CC1)\c1c[nH]c2ncccc12
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (1.46 g) in ethanol (30 mL) was added cyclopropylamine (1.41 mL), and the mixture was stirred at 50° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and then treated azeotropically with toluene. The resulting residue was triturated with isopropyl ether/n-hexane (3:1) to give N-[(1E)-1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene]cyclopropylamine [REx(28-1)] (1.75 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:22]([O-])=O)=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>CO.O.C(Cl)(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:5]=2[C:4]=1[NH2:22]
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (6,7-dimethoxy-5-nitro-quinazolin-4-yl)-phenyl-amine (1.0 g, 3.14 mmol) (from Example 1, Step B, supra), NH4Cl (1.7 g, 31.4 mmol) in MeOH, H2O and CHCl3 (40 mL, 2:1:1) was added Zn powder (2.0 g, 31.4 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 (1:1) as eluent to give the desired 6,7-dimethoxy-N 4-phenyl-quinazoline-4,5-diamine as a yellow gum. (Yield 0.5 g, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2cccc(C#N)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2cccc(C#N)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C

Procedure:
To a solution of 358 mg of 4-[4-(3-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DMF (1.5 mL) 135 mg of potassium carbonate and 101 μL of methyl iodide are added. The mixture is stirred during the night at room temperature, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)#[N:3].Cl.C(OC(=[NH:37])C1C=CC(C=CC2C=CC=CC=2)=CC=1)C.C(=N)([O-])C1C=CC=CC=1.N>CO.C(O)C.C1C=CC=CC=1>[ClH:1].[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]([NH2:37])=[NH:3])=[CH:5][CH:6]=1)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=N)c1ccc(C=Cc2ccccc2)cc1
Reactant: N#Cc1ccc(C=Cc2ccccc2)cc1
Agent: Cl
Agent: N
Agent: N=C([O-])c1ccccc1
Solvent: c1ccccc1
Solvent: CO
Solvent: CCO
Product: N=C(N)c1ccc(C=Cc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Hydrogen chloride is bubbled through a mixture of 4-cyanostilbene (13.5 g., 0.065 mole), obtained according to the method of Belgian Pat. No. 641,415 (Chem. Abs. 63: 3092g (1965)), in 35 ml. of dry benzene and 17.5 ml. of absolute ethanol at 0° to 5° C. for a period of 3 hr. The reaction is maintained at 0° to 5° C. for 48 hr. and the solvent and excess hydrogen chloride removed under reduced pressure. The residue stirred with 50 ml. of dry benzene and collected provides 13.0 g. of ethyl-4-styrylbenzimidate hydrochloride. A methanol solution of the benzimidate salt is cooled to 5° to 10° C., saturated with ammonia and heated at a temperature of 100° C. for a period of 3 hr. in an enclosed container. Concentration of the reaction mixture provides 4-styrylbenzamidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>C1COCC1>[C:7]([N:6]1[C:4](=[O:5])[C:3]2[C:2](=[C:14]([CH3:15])[CH:13]=[CH:12][CH:11]=2)[NH:1][C:21]1=[O:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(C(=O)NC(C)(C)C)c1N
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)n(C(C)(C)C)c(=O)[nH]c12

Procedure:
The compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2-amino-3-methylbenzoic acid with triphosgene in THF produced 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, which was treated with tert-butylamine and DMAP in DMF to produce 2-amino-N-tert-butyl-3-methylbenzamide. Reaction of the benzamide with CDI in THF produced 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione, which was reacted with methyl 3-(bromomethyl)benzoate and MeONa in DMF, followed by treatment with hydrochloric acid aqueous solution, to produce 8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 8-methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.