Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:41][C:38]5([C:35]6[N:36]=[CH:37][C:32]([F:31])=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform:Methanol 9.5:0.5 200 ml. Yield: 32 mg (55%). 1H NMR (400 MHz, CD3OD): δ 8.58 (d, J=0.5 Hz, 2H), 8.05-7.93 (m, 2H), 7.89-7.79 (m, 2H), 7.68 (s, 2H), 7.49-7.36 (m, 2H), 7.34-7.23 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.38 (m, 2H). LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([SH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([Si:12]([Cl:15])([Cl:14])[Cl:13])=[CH2:11]>N(C(C)(C)C#N)=NC(C)(C)C#N>[Si:12]([CH2:10][CH2:11][S:9][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])([Cl:15])([Cl:14])[Cl:13]
Reactant: CC(S)c1ccccc1
Reactant: C=C[Si](Cl)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC(SCC[Si](Cl)(Cl)Cl)c1ccccc1
Reaction time: 6 h

Procedure:
Into a 500 ml. three-necked flask were charged 108 g. (0.78 mole) 1-phenyl-ethanethiol, 126 g. (0.78 mole) vinyltrichlorosilane and 1.2 g. (0.5 weight percent) azobisisobutyronitrile catalyst. The contents were heated and stirred for 6 hours at 80°-90°C. Fractional distillation of the reaction mixture gave the product fraction, Cl3SiCH2CH2SCH(CH3)C6H5, b.p. 110°/0.53 mm Hg. Vapor phase chromatographic analysis of the distilled product (120 g.) showed it contained a mixture of alpha and beta isomers. Yield of (1-phenylethylthio)ethyltrichlorosilane was 85 percent, based on ViSiCl3 reacted.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSCCC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Yield: 108.9 %

Procedure:
To a stirred solution of intermediate 21, ethyl 3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (97 mg, 0.2 mmol) in 3 mL tetrahydrofuran was added lithium hydroxide (15 mg, 0.6 mmol) in 3 mL water. After 20 min the reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The extract was dried over MgSO4, filtered and concentrated to give 82 mg of the title compound (88% yield). LC/MS m/e 377.
Reaction SMILES: [C:1]([N:8]([CH3:16])[C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12])[CH3:16])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
20.0 g Boc-MeVal-OH (86.5 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 130 ml 1M BH3-THF (0.13 mol; Fluka) were added at 0° C. over 1 h and the clear, colo reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 75 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 150 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 17.4 g (94%) product as colorless oil. 1H-NMR:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10](=[O:18])[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10](=[O:18])[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]2=3)=[CH:27][CH:26]=1
Reactant: O=S1Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CS(=O)c3ccccc32)cc1
Yield: 19.4 %

Procedure:
A mixture of (2S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine-10-oxide (see Preparation 19) (180 mg), 4-methoxyphenethyl bromide (140 mg) and sodium carbonate (70 mg) in acetonitrile (20 ml) was heated under reflux for 18 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (5 g), performing a gradient elution initially using dichloromethane as eluant and changing to dichloromethane/methanol (98:2). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (50 mg, 19%).
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:3]([C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C=Cc2cccnc2CC(O)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CCc2cccnc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethenyl]benzoate (0.463 g, 1.29 mmol) was dissolved in ethanol (15 ml), acetic acid (3 drops) and 10% palladium on carbon (0.05 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CO>[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:37][CH:38]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(O)cc2)n1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Oc3nnc(-c4ccccc4)c4ccccc34)cc2)n1

Procedure:
A mixture of 1-chloro-4-phenylphthalazine (0.0900 g, 0.374 mmol), 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol (0.110 g, 0.374 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in 1 mL DMSO was heated in a sealed tube for 1 h. Upon cooling, a white precipitate formed. The material was partitioned between water and DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude solid, which was suspended in MeOH, sonicated, filtered and dried to give N-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=499 [M+H]+. Calc'd for C30H22N6O2: 498.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=4)(=[O:26])=[O:25])=[CH:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccc(C)cc4s3)cc2)cc1

Procedure:
To 2-(4-aminophenyl)-6-methylbenzothiazole (5 g, 20.8 mmol) in pyridine (60 mL) was added para-toluenesulphonyl chloride (5.953 g, 31.2 mmol, 1.5 eq.) in pyridine (40 mL). The reaction mixture was heated at reflux for 10 mins, then cooled and water (100 mL) added. The white precipitate formed was collected on a filter, washed with water and dried under vacuum to give N-[4-(6-methylbenzothiazol-2-yl)phenyl]-4-methylbenzenesulfonamide as a white solid. The yield was 8.091 g (99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)c1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of crude (4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester (8.2 g 27 mmol) and Et3N (4.2 g, 40 mmol) in dichloromethane (250 mL) was added dropwise MsCl (3.2 g, 27 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min and was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to dryness. The residue was recrystallized with DCM/pet ether (1:3) to give [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (7.5 g, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.23-7.41 (m, 5H), 6.57 (s, 1H), 4.65-4.77 (m, 1H), 4.35 (d, J=6 Hz, 2H), 2.90 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:11]=1
Reactant: CSc1nc(Cc2ccc(Cl)c(Cl)c2)[nH]c(=O)c1C#N
Reactant: C1CCNCC1
Product: N#Cc1c(N2CCCCC2)nc(Cc2ccc(Cl)c(Cl)c2)[nH]c1=O

Procedure:
100 mg (0.34 mmol) of 2-(3,4-dichlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are stirred with 261 mg (3.07 mmol) of piperidine at 85° C. for 16 h. After removal of the volatile constituents in vacuo, the residue is purified by preparative HPLC. 42 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2.C([O-])(=O)C.[Na+].Cl.[CH3:37][O:38][NH2:39].O>C(O)C>[CH3:37][O:38][N:39]=[C:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])=[CH:21][C:20]=3[Cl:30])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: CON
Reactant: O=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21

Procedure:
1.24 g of 6-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-3,4-dihydro-2H-naphthalen-1-one, 0.23 g of sodium acetate and 0.23 g of O-methylhydroxylamine hydrochloride are stirred in 10 ml of ethanol at 50° C. for 18 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained. M.p. 75-77° C.
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=[O:22])[CH2:9][N:10]([S:12]([C:15]1[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:11])(C)(C)C.[C:23]([OH:27])#[C:24][CH2:25][CH3:26]>O>[CH2:23]([O:27][C:18]1[N:17]=[CH:16][C:15]([S:12]([N:10]([CH2:9][C:8]([OH:7])=[O:22])[CH3:11])(=[O:13])=[O:14])=[CH:20][CH:19]=1)[C:24]#[C:25][CH3:26]
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Reactant: CCC#CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)O)cn1
Yield: 45 %

Procedure:
To a solution of 0.77 mL (19.3 mmol) of 2-butynl-ol and 0.18 g (4.37 mmol) of sodium hydroxide were heated at 100° C. for one hour. [(6-chloro-pyridine-3-sulfonyl)-methyl-amino]-acetic acid tert-butyl ester (1.0 g, 3.12 mmol) was added to this solution. Additional butynol was added to facilitate stirring, and the reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 2N HCl, and extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over MgSO4, concentrated to solids which were slurried in 1:1:1 dichloromethane:hexane:ethyl acetate to afford 0.41 g (45%) of [(6-but-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-acetic acid as an off-white solid. Electrospray Mass Spec 299.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].[CH:35]1([NH:38][CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:35]1([NH:38][CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:37][CH2:36]1
Reactant: C1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.5 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (225 mg, 0.43 mmol), cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (91 mg, 0.64 mmol), HOBt (91 mg, 0.67 mmol), EDAC (130 mg, 0.68 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give 211 mg (76%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[NH:6]3.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:27]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2C
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To 1.45 g (4.7 mmol) of the compound (155) obtained in Example 33, 10 ml (109 mmol) of dimethyl sulfate was added, and the solution was heated 3.5 hours at 120° C. After air-cooling, to 90 ml of ice/water containing 15 g (109 mmol) of anhydrous potassium carbonate, the solution was added, and the solution was stirred overnight. The solution was extracted with 50 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel 8 g, eluent solvent; chloroform:methanol=100:1) to obtain 830 mg of the subject compound (156) in a 57% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc(C)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (250 mg, 1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43 mmol) by a procedure similar to example 1b and was isolated as white powder (210 mg, 84%). 1H NMR (CDCl3): 8.69 (d, J=8.4 Hz, 1H), 7.75 (dd, J=8.1 and 7.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][CH:11]([O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][CH:11]([O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(Cl)c(NC(OC(=O)c2ccccc2)C(=O)OCc2ccccc2)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(NC(OC(=O)c2ccccc2)C(=O)O)c1Cl

Procedure:
20 grams of ester IV (0.045 mol) obtained as in Example 1 were dissolved in 200 ml of ethyl acetate and, after adding 2 g of 10% palladium on carbon, were treated with hydrogen at ambient temperature and pressure. At the end of the reaction the catalyst was filtered on Celite, washing the filter with a little ethyl acetate, and the solvent was then evaporated in vacuo and the residue was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([CH2:10][OH:11])[C:5]1=[O:12])[C:2]#[CH:3].[CH3:13][C:14]1([CH3:25])[C@H:16]([CH:17]=[C:18]2[CH2:21][CH2:20][CH2:19]2)[C@H:15]1[C:22](O)=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][C:14]1([CH3:25])[C@H:16]([CH:17]=[C:18]2[CH2:19][CH2:20][CH2:21]2)[C@H:15]1[C:22]([O:11][CH2:10][N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH2:1][C:2]#[CH:3])[C:5]1=[O:12])=[O:23]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](C=C3CCC3)C2(C)C)C1=O
Yield: 17 %

Procedure:
A solution of 3.6 g of (1-propargyl-2,4-dioxo-imidazolidin-3-yl)-methanol in 10 ml of methylene chloride was added at 20° C. to a mixture of 4 g of (1R,trans)2,2-dimethyl-3-(cyclobutylidenemethyl)-cyclopropane-1-carboxylic acid, 4.6 g of dicyclohexylcarbodiimide, 20 ml of methylene chloride and a catalytic amount of 4-dimethylamino-pyridine and the mixture was stirred at 20° C. for 17 hours and was vacuum filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl actate mixture and then a 95-5 benzene-ethyl acetate mixture yielded 1.2 g of (1-propargyl-2,4-dioxo-imidazolidin-3-yl)-methyl(1R,trans)2,2-dimethyl-3-(cyclobutylidenemethyl)-cyclopropane-1-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)=[CH:16][S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[NH:37][CH2:38][CH3:39])[C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[CH:16][S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[NH:37][CH2:38][CH3:39])[C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2SC=C(c3ccccc3OC)N2C)C(=O)N1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC=C(c3ccccc3O)N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 192 was treated with boron tribromide in DCM at 25° C. After 15 min the product mixture was quenched with brine, concentrated and chromatographed (silica gel, 0–10% MeOH/DCM) to yield the title compound. MS(ESI): 540 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>ClCCl>[CH3:19][Si:20]([CH3:22])([CH3:21])[N:1]([CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: CO[Si](CCCN)(OC)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[Si](CCCN([Si](C)(C)C)[Si](C)(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Aminopropyltrimethoxysilane (0.398 mol) and triethylamine (100 mL) were dissolved in dichloromethane (200 mL) in a round-bottom flask and trimethylsilyl chloride (0.800 mol) was added in a dropwise manner. After the addition was completed, the mixture was stirred at room temperature for 24 hours. Upon completion of reaction, N,N-bis(trimethylsilyl)aminopropyltrimethoxysilane (yield: 89%) was obtained through concentration under reduced pressure and fractional distillation. 1H and 13C NMR spectroscopic data of the purified N,N-bis(trimethylsilyl)aminopropyltrimethoxysilane are as follows.