Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[ClH:1].[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([CH:40]5[CH2:42][CH2:41]5)[CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(C2CC2)C1
Reaction time: 6 h

Procedure:
To a solution of 250 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride in 10 ml of methanol were added 157 μl of triethylamine, 300 mg of Molecular Sieves 3A, 323 μl of acetic acid, 1.53 ml of [(1-ethoxy cyclopropyl)oxy](trimethyl)silane, and 146 mg of sodium cyanoborohydride under ice-cooling, followed by stirring for 6 hours under heating to reflux. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the obtained residue were added saturated aqueous sodium bicarbonate and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To a mixture of the obtained purified product, ethyl acetate, and methanol was added a 4 M hydrogen chloride/ethyl acetate solution under ice-cooling, and the solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 136 mg of 8-(cyclohexylmethoxy)-N-[(3S)-1-cyclopropylpiperidin-3-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[O-:22].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17]([CH3:18])=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [O-]Cl
Reactant: CCOC(=O)C(C)(SC)C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)S(C)=O

Procedure:
Ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylthio-3-oxopropanoate, prepared in Example XC (Compound 261), was reacted with aqueous sodium hypochlorite in a water-methylene chloride mixture in a manner similar to that described in Example XCIII to give ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylsulfinyl-3-oxopropanoate having a melting point of 124° C.-127° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]([CH3:25])[C:15]=2[CH:26]([O:29][Si](C)(C)C)[C:27]#N)[CH:10]=[CH:11][C:12]=1[F:13].[CH3:34][OH:35]>>[CH3:34][O:35][C:27](=[O:1])[CH:26]([C:15]1[N:16]([CH3:25])[C:17](=[O:24])[C:18]2[C:23]([C:14]=1[C:9]1[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:29]
Reactant: CO
Reactant: O=S(=O)(O)O
Reactant: Cn1c(C(C#N)O[Si](C)(C)C)c(-c2ccc(F)c(F)c2)c2ccccc2c1=O
Product: COC(=O)C(O)c1c(-c2ccc(F)c(F)c2)c2ccccc2c(=O)n1C
Yield: 79 %

Procedure:
To a mixture of conc. H2SO4 (2.5 ml) and methanol (7.5 ml) was added [4-(3,4-Difluoro-phenyl)-2-methyl-1-oxo-1,2-dihydro-isoquinolin-3-y]-trimethylsilanyloxy-acetonitrile (580 mg, 1.45 mmol), after addition, the resultant mixture was stirred at reflux overnight under N2. TLC showed SM was consumed, diluted with EA, adjusted with saturated NaHCO3 to pH=8˜9, extracted with EA, the organic layers was dried over Na2SO4 and concentrated to dryness to afford crude product. (m=430 mg, yield=79%). LCMS: (10-80 AB—2MIN-E.M): Rt=1.021, purity=64%, M+1=360.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:32][CH3:33])[CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:33])[C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNc1cc(C)cc(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)nc(N(C)C(=O)CCN(C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (550 mg, 4.04 mmol) in dichloromethane (5 mL) was cooled to 0° C., triethylamine (1.12 mL, 8.08 mmol) was added followed, after 5 min, by (4,6-dimethyl-pyridin-2-yl)-methyl-amine (1.14 g, 4.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min then partitioned between water and dichloromethane. The organic phase was separated, washed with saturated bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate in hexane as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide (600 mg, 43%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N+:17]([O-:19])=[O:18])([CH2:15][OH:16])[CH2:13][OH:14])[CH:6]=[CH:5]2.C(Cl)Cl.CO[C:25](OC)([CH3:27])[CH3:26].B(F)(F)F>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([N+:17]([O-:19])=[O:18])[CH2:15][O:16][C:25]([CH3:27])([CH3:26])[O:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: COC(C)(C)OC
Reactant: O=[N+]([O-])C(CO)(CO)c1ccc2cc(Br)ccc2c1
Agent: FB(F)F
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OCC(c2ccc3cc(Br)ccc3c2)([N+](=O)[O-])CO1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
2-(6-Bromo-naphthalen-2-yl)-2-nitro-propane-1,3-diol (32.6 g, 0.100 mol) was dissolved in methylene chloride (150 mL, 2.3 mol; Acros, anhydrous) and 2,2-dimethoxypropane (180 mL, 1.5 mol; Aldrich), cooled with an ice bath. Boron trifluoride is etherate (10.1 mL, 0.0800 mol; Aldrich) was added slowly. The mixture was stirred for 15 min and large amount of solid precipitated. The cooling bath was removed and the mixture was stirred at r.t. for 4 hours. The mixture was quenched with aqueous saturated NaHCO3 (˜600 mL) to pH˜8, extracted with EtOAc (600 mL, 300 mL, 2×100 mL). The EtOAc layer was washed with water, brine, dried over Na2SO4, filtered. The solvent was evaporated to 100 mL. The resulted solid product was collected by filtration and the mother liquid was concentrated further to afford the second crop of product. Rf of product=0.4 (EtOAc/hexane=1/4). Total product weighed 30.0 g (yield 82%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+].CCOC(C)=O>CCO.C1COCC1>[C:10]([NH:9][CH:5]([CH2:6][CH:7]=[CH2:8])[C:4]([OH:15])=[O:3])(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: C=CCC(NC(=O)C(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)C)C(=O)O
Reaction time: 2.5 h
Yield: 63.5 %

Procedure:
11.70 g of the above prepared 2-isobutyrylamino-pent-4-enoic acid ethyl ester (67.55 mmol) were dissolved in 110 ml of a 1:1 mixture of EtOH and THF and treated under cooling with an ice bath with 33.80 ml of 2N NaOH (2 eq.). After 2.5 h, the reaction mixture was poured onto crashed ice/AcOEt/HCl, the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane afforded 7.95 g of the title product as white solid.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[Sn]>O>[C:11]([O-:16])(=[O:17])/[CH:12]=[CH:13]\[C:14]([O-:10])=[O:15].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCC[Sn](=O)CCCC
Agent: [Sn]
Solvent: O
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 50 °C

Procedure:
The foregoing procedure was repeated using 124.35 g. (0.5 mole) of di-n-butyltin oxide and 24.5 g. (0.25 mole) of maleic anhydride with 100 cc. water as the reaction medium. In this instance the water and maleic anhydride were combined and heated to 50° C. to dissolve the anhydride. The solution was then cooled to 30° C., at which time the di-n-butyltin oxide was added. The resultant mixture was then heated to the boiling point (98° C.) and maintained at that temperature for 2 hours with stirring. The liquid phase was decanted and the solid washed with 200 cc. of water. The dried solid weighed 148.85 g. (98.5% of theoretical yield) and was found to contain 33.3% by weight of tin. The theoretical tin content for the reaction product of di-n-butyltin oxide and maleic anhydride in a 2:1 molar ratio, respectively is 34.0% by weight.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][C:19]2[C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21][N:22]([CH3:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:37].[Na+].C1CCCCC1>C(Cl)(Cl)Cl>[CH3:30][N:22]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])=[O:37])[C:20]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: Cn1nc(-c2ccccc2)c(Sc2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Product: Cn1nc(-c2ccccc2)c(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Temperature: 9 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
At a temperature of 9° C a solution of m-chloroperbenzoic acid (10.15 g, 85%, 0.05 mole) in dry chloroform (50 ml) is added to a solution of 4-(phenylthio)-1-methyl-3,5-diphenylpyrazole (6.84 g, 0.02 mole) in dry chloroform (50 ml). The reaction mixture is stirred for 3 hours at 9° C and then overnight at room temperature. A heavy precipitate forms. The mixture is treated with 2% aqueous sodium hydroxide and extracted with chloroform. The chloroform layer is separated and stripped in vacuo to give an oil. Trituration of the oil with cyclohexane affords crystals 6.8 g (91%), m.p. 135° C to 141° C. Recrystallization from a mixture of benzene and pentane gave white crystals, m.p. 149° C to 150° C.
Reaction SMILES: [Li][CH:2](CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[C:25]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])([CH3:23])[CH3:22].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[C:25]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([CH3:2])[C:26]=1[C:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[O:28])([CH3:23])[CH3:22]
Reactant: CCN(CC)C(=O)c1cccc(F)c1[Si](C)(C)C(C)(C)C
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CI
Product: CCN(CC)C(=O)c1c(C)ccc(F)c1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
1.3M s-BuLi in cyclohexane (1.8 mL, 2.3 mmol) was added dropwise with stirring to THF (20 mL) and TMEDA (0.32 g, 2.76 mmol), cooled to -78° C. under nitrogen. To this mixture was added dropwise the compound of Example 9 (0.6 g, 2 mmol), dissolved in a minimum amount of THF. After stirring for 10 min, MeI (0.98 g, 6.9 mmol) was injected. The mixture was stirred for 1 h; 15 mL of 25% citric acid was added and the mixture extracted with ether 3 times. The ether extracts were combined and washed twice with water, dried (MgSO4), and concentrated. The crude product was purified by RC, eluting with 3:7 ethyl acetate/hexanes. The title compound was obtained as a light yellow oil in a 31% yield.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[N:11])C1C1C=CC=CC=1)#[N:2].NCCN1CCN(CCN)C1C1C=CC=CC=1>>[NH2:2][CH2:1][CH2:3][NH:4][CH2:8][CH2:7][NH:6][CH2:9][CH2:10][NH2:11]
Reactant: N#CCN1CCN(CC#N)C1c1ccccc1
Agent: NCCN1CCN(CCN)C1c1ccccc1
Product: NCCNCCNCCN

Procedure:
This Example demonstrates the reduction of (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile (5) to intermediate 2-[3-(2-Amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine (8). As shown in Scheme 9, intermediate (8) is treated with an acid to form a triethylenetetramine salt. The reduction is effected by LiAlH4, the acid used is hydrochloric acid and the tetrahydrochloride salt of triethylenetetramine is produced.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[C:9]([F:16])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:31][C:32]1[C:40]([NH2:41])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH2:36])=[O:35]>N1C=CC=CC=1.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([NH2:36])=[O:35])[C:32]=3[N:31]=2)=[C:9]([F:16])[CH:8]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(C2OCCCO2)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4OCCCO4)cc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A solution of EXAMPLE 22B (770 mg, 3.4 mmol) in pyridine (5 mL) and N,N′-dimethylformamide (10 mL) was treated with 1,1′-carbonyldiimidazole (763 mg, 3.4 mmol) at 40° C. for 30 minutes. 2,3-Diaminobenzamide dihydrochloride (826 mg, 5.1 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue refluxed overnight in 20 mL of xylene and 2 mL of acetic acid. After cooling and concentration, the residue was purified by flash chromatography on silica gel using ethyl acetate to give the title compound (550 mg, 50%). MS (DCI/NH3) m/z 342 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CCO.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][OH:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2CO)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: OC[C@@H]1CCCN1C1CCNCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A solution of 3.00 g (10.5 mmol) of 4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (intermediate 3A) in 70 ml of EtOH was treated at RT with 5.27 ml (21.1 mmol) of hydrochloric acid in 1,4-dioxane (4 molar) and the mixture was heated up to 100° C. After two hours, the solvents were evaporated and the residue was re-crystallized from MeOH/MeCN and Et2O to give 2.21 g (82%) of the title compound as colorless solid. MS: 185.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1)[CH2:38][CH3:39]
Reactant: CCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -30 °C
Yield: 62.4 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (301 mg, 0.9 mmol) in CH2Cl2 (10 ml) was stirred under an N2 atmosphere. Triethylamine (0.25 mL, 1.8 mmol) was added, and the solution was cooled to −30° C. A 1 M propyl chloroformate solution (0.1 mL in 0.9 mL CH2Cl2, 0.9 mmol) was added, and the reaction mixture was allowed to warm to room temperature over a period of 30 minutes. After adding CH2Cl2 to the reaction mixture, it was washed 2 times with water, before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (236 mg, 62%). LC/MS: m/z 421 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.09-3.86 (m, 6H), 3.78-3.73 (m, 1H), 3.21-3.09 (m, 2H), 2.49 (s, 3H), 2.15-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.62-1.48 (m, 2H), 0.89-0.86 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16][CH3:17])[N:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])[CH3:3].C1C=C([O:29]O)C(C(O)=O)=C(C(O)=O)C=1>C(O)C.O>[CH3:19][C:18]([C:7]1[CH:8]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16]([CH3:17])=[O:29])[N:15]=2)[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CSc1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Solvent: CCO
Solvent: O
Product: CS(=O)c1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A 50° C. solution of 1.0 g (3.13 mmol) of the methylthiotriazole (Example 43) in 50 ml of 95% ethanol is treated dropwise with a solution of 0.92 g (2.98 mmol) of 80% monoperoxyphthalic acid, magnesium salt (MMPP) in 4.5 ml of water over 20 minutes. The resulting reaction mixture is stirred at 40° to 50° C. for two hours and concentrated in vacuo. The residue is dissolved in ethyl acetate, extracted with saturated aqueous NaHCO3 (three times), water and brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, 5% methanol-chloroform, 26×6.5 cm) followed by recrystallization from acetone-water gives 0.30 g (1.05 g theor., 29%) of the sulfoxide as a white solid, mp 135°-145° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:32].[Na].[Na].C(OC(=O)CC(OCC)=O)C.[I-].[K+]>C(Cl)(Cl)Cl.C(O)C>[CH2:31]([O:33][C:34](=[O:41])[CH:35]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH:15]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[C:24]([NH2:26])=[O:25])=[CH:17][CH:18]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1)C(=O)OCC

Procedure:
A solution of 3.7 gm (10 m mol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzyl chloride [m.p.: 123°-125° C.; prepared from the alcohol described in Example 25 by means of thionyl chloride in chloroform] in 35 ml of absolute ethanol was added dropwise to a solution of sodium malonic acid diethyl ester [prepared from 0.7 gm (30 m mol) of sodium in 25 ml of absolute ethanol and 4.8 gm (30 m mol) of malonic acid diethyl ester]. A catalytic amount of potassium iodide was added, and the mixture was refluxed for 16 hours. After evaporation in vacuo, the evaporation residue was adjusted neutral by means of hydrochloric acid and extracted with methylene chloride. The organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=6:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10].N1C=CC=CC=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:2]=1[NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
To 0.30 g (1.4 mmol) of the material from Step B in 5 mL of chloroform was added 0.28 ml (3.5 mmol) of pyridine and 0.27 mL (1.7 mmol) of 4-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirred overnight at room temperature and then heated at reflux for 5 hours. After cooling to room temperature the reaction mixture was washed with 1N HCl, dried (sodium sulfate) and filtered. The volatiles were removed with a rotary evaporator. The residue was purified by MPLC (5–25% ethyl acetate in hexanes as eluant) to afford 0.10 g of the title compound, a compound of the invention, as a white solid melting at 104–107° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([Cl:17])[C:12]([F:18])=[CH:11][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].[CH:19](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([Cl:17])[C:12]([F:18])=[CH:11][C:3]=1[C:4]([C:6](=[CH:19][NH:39][CH:36]1[CH2:38][CH2:37]1)[C:7]([O:9][CH3:10])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: NC1CC1
Reactant: COC(=O)CC(=O)c1cc(F)c(Cl)c(OC)c1Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)c(OC)c1Cl
Reaction time: 2 h
Yield: 72.8 %

Procedure:
73.8 g of methyl 2,4-dichloro-5-fluoro-3-methoxybenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution and the reaction was then carried out for 2 hours. The resulting mixture was filtered under suction. The residue was re-crystallized from a mixture of petroleum ether and cyclohexane to yield 66.0 g (0.182 mol) of methyl 2-(2,4-dichloro-5-fluoro-3-methoxybenzoyl)-3-cyclopropylaminoacrylate in 72.9% yield.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C=C.[CH3:20][CH2:21][O:22][CH2:23]C.[OH-:25].[Na+]>O>[CH3:23][O:22][CH2:21][CH2:20][O:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOCC
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: C=C
Agent: [Na+]
Solvent: O
Product: COCCOc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
54 g of 2-chloro-5-trifluoromethyl-1,3-dinitrobenzene are heated to 60° C. together with 64 g of ethylene glycolmonomethyl ether, and 23.5 g of 50 percent strength aqueous sodium hydroxide solution are added dropwise in the course of 30 minutes. The mixture is subsequently stirred at 60° C. for one hour, a further 5 g of sodium hydroxide solution are added and the mixture is subsequently stirred again at 60° C. for a further 1.5 hours. The mixture is then cooled, 50 ml of water are added and the product which has precipitated is filtered off and dried.