Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)=O>>[F:27][C:26]([F:28])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OC(F)(F)F)c3)cs2)c1
Yield: 86.3 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (213 mg, 1.00 mmol) obtained in Example 1b and 2-bromo-1-[3-(trifluoromethoxy)phenyl]ethanone (283 mg, 1.00 mmol), the title compound (343 mg, 86%) was obtained as colorless crystals.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: CN(C)CCS
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(SCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 2-(dimethylamino)ethanethiol hydrochloride was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-{[2-(dimethylamino)ethyl]thio}-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.20 (s, 6H), 2.30 (s, 3H), 2.57 (m, 2H), 2.83 (m, 1H), 3.28 (m, 2H), 7.31 (d, 1H), 7.59 (m, 3H), 7.93 (s, 1H), 8.08 (d, 1H), 8.38 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 443.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1([Cl:15])[CH2:11][CH:10]1[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:8][C:9]1([Cl:15])[CH2:11][CH:10]1[C:12]([NH:14]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:13]
Reactant: CCC(=O)C(=O)O
Reactant: NC(=O)C1CC1(Cl)Cl
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(Cl)Cl)C(=O)O
Yield: 17.8 %

Procedure:
A mixture of 1.53 g (15 mmoles) of 2-ketobutyric acid, 1.54 g (10 mmoles) of 2,2-dichlorocyclopropanecarboxamide and 10 ml of toluene was heated under reflux for 12 hrs. with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). An additional 0.7 g of 2-ketobutyric acid was added and the reaction mixture was heated under reflux for an additional 12 hrs. The mixture was cooled, diluted with 20 ml of toluene and extracted with saturated sodium bicaronate (3×10 ml). The extracts were combined, washed with ether and acidified to pH 3 (pH meter) with concentrated hydrochloric acid. A gum precipitated which soon solidified. It was filtered, washed with water, dried and recrystallized from nitromethane to give 423 mg of Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-butenoic acid, m.p. 188°-189.5° C. The NMR spectrum was in accord with the desired structure.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[N:23]=[CH:22][CH:21]=1>O.[Cu]>[CH2:25]([N:24]1[C:20]([NH:19][C:8]2[C:9](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:21][CH:22]=[N:23]1)[CH3:26]
Reactant: CCn1nccc1N
Reactant: COc1ccc(C(=O)O)c(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
K2CO3 (13.94 g, 0.101 mol) was dissolved in water (67 ml) and then 2-iodo-4-methoxybenzoic acid (25.3 g, 0.091 mol) was added, followed by 5-amino-1-ethylpyrazole (11.2 g, 0.101 mol) and finally copper (2.7 g). The reaction mixture was refluxed for 20 hours, cooled to room temperature and then water (350 ml) was added and the mixture was refluxed for 0.75 hours. The reaction mixture was cooled, and the product was collected by filtration, recrystallized from ethanol, and dried in an oven at 40° C. to afford 13.37 g (56%) of N-(1-ethylpyrazol-5-yl)-4-methoxyanthranilic acid, m.p. 130°-135° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:17]([CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(CN=[N+]=[N-])ccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 6chloromethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (10 g, 42.2 mmol, 1.00 mmol equiv.) in DMF (84 mL) is added sodium azide (13.7 g, 211.2 mmol, 5.00 mmol equiv.) at room temperature and the reaction contents are stirred overnight. The reaction is checked by TLC (5% ethyl acetate in hexanes). The reaction is terminated by pouring the reaction contents into water and extracting with ethyl acetate. The organic solvents are removed in vacuo and the crude product filtered through a plug of silica gel (ratio of 10:1) and eluted with hexanes. The solvent is removed in vacuo and stored under vacuo to afford 10 grams of the desired product 6-azidomethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (97% yield).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH2:28])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][N:28]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
An aqueous solution of 1.26 g. (0.006 mole) of diethyl oxalacetate sodium salt was acidified with hydrochloric acid and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to dryness in vacuo. The resulting oil in 30 ml. of methanol under N2 was mixed with 0.812 g. (0.003 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and allowed to stand at room temperature for 1.5 hours. The solution was evaporated in vacuo, dissolved in methylene chloride, washed with dilute sodium hydroxide and dried over magnesium sulfate. After filtration the solution was evaporated in vacuo giving 7-chloro-2-[[1,2-bis-(ethoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oil. Nmr confirmed the structure. Nmr (CDCl3) δ 1.20 and 1.22 (2 t's, 6, CH2CH3), 4.13 (q, 6, CH2CH3), 4.48 (broad s, 2, 3--CH2), between 6.93 and 7.83 (m's, 8, arom H's).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].[C:24]1([C:30]2[C:31]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:32][N:33]3[C:38]=2[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:32]3[N:33]4[C:38]([CH:37]=[CH:36][CH:35]=[CH:34]4)=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:21])[O:22]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: c1ccc(-c2cn3ccccc3c2-c2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)c(-c4ccccc4)c4ccccn34)OC(=O)c3cccnc32)c2ccccc21

Procedure:
A mixture of 1.6 grams of (1-ethyl-2-methylindol-3-yl) (3-carboxypyridin-2-yl)ketone, 1.85 grams of 1,2-diphenylindolizine and 10 ml. of acetic anhydride was heated at about 40° C. for 104 minutes and then cooled in an ice bath. The reaction mixture was filtered and the product was repeatedly recrystallized from a toluene-petroleum ether mixture until a constant melting point of 206.5°-207.5° C. was obtained. A chloroform solution of the final product produced a blue color when applied to a record sheet material coated with a zinc-modified phenolic resin.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:18]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1>[C:1]([N:5]1[C:9]([Cl:18])=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)n1cc(C(=O)O)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(=O)O)c1Cl
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
tert-butyl-1H-pyrazole-4-carboxylic acid (5 g, 29.73 mmol) was dissolved in tetrahydrofuran (50 ml) at room temp. In a separate flask was added n-butyllithium (2.5M solution in hexane, 29.73 ml, 74.33 mmol) and was cooled to −15° C. The 1-tert-butyl-1H-pyrazole-4-carboxylic acid solution was added dropwise to the n-Butyllithium solution, maintaining internal temperature below −10° C. The total addition time lasted 30 min. The resulting brownish suspension was stirred and maintained between −10° C. and −15° C. for 40 min. The reaction was then cooled to −15° C. to −20° C. A solution of hexachloroethane (14.08 g, 59.46 mmol) in tetrahydrofuran (50 ml) was added dropwise, maintaining internal temperature below −10° C. The total addition time lasted 20 min. After the addition, the resulting dark brownish solution was stirred at −10° C. to −15° C. for 30 min and was warmed up to room temp. over 1 h. The reaction mixture was then cooled to 15° C. and water (50 ml) was added slowly, maintaining internal temperature below 20° C. 120 ml of organic solvents were distilled under reduced pressure at 25° C. water bath leading to a suspension. Heptane (50 ml) was added leading to a clear brownish biphasic solution. After stirring at room temp. for 15 min, the aqueous layer (pH=11.8) was separated. The organic layer was extracted once with NaOH (1N, 20 ml). The combined aqueous phase was washed with heptane (25 ml) and was cooled in an ice-bath. Hydrochloric acid (6N) was added to adjust pH=2, maintaining internal temperature below 20° C. The suspension was stirred in the ice-bath at 0-5° C. for 1 h and the solid was filtered and washed with water (40 ml). After drying in vacuo at 60° C. for 18 h, 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5.28 g) was obtained as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:5]2[N:6]([C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 g of ethyl 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 18A; 115 mmol, 1 equivalent) were dissolved in 550 ml of THF and 700 ml of methanol, 13.8 g of lithium hydroxide (dissolved in 150 ml of water; 577 mmol, 5 equivalents) were added and the mixture was stirred at RT overnight. 1 N aqueous hydrochloric acid was added and the mixture was concentrated under reduced pressure. The solid obtained was filtered off and washed with water. This gave 34 g of the title compound (84% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][C:65]=1[CH3:66]>ClCCl>[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[CH3:66]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(C)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (50 mL), and HBTU (0.758 g, 2.000 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.400 g, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion formed, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (1.073 g, 1.635 mmol, 82% yield) as a white solid. LC-MS m/z 647.4 (M+H)+, 0.98 min (ret time); mp 117-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:22])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:11].[CH3:23]N(C(OC)OC)C>CC#N>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:23]=[N:22][C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12][C:10]1=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)NC(=N)NCc1ccccn1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: Cc1cccc(C)c1-n1cnc(NCc2ccccn2)nc1=O

Procedure:
To a suspension of 10.2 g. (28.0 mmol) of 1-(2',6'-dimethylphenyl)-3-[(2-pyridyl)methyl]amidinourea in CH3CN (100 ml) is added 10.0 g. (84.0 mmol) of DMF-DMA and the reaction mixture heated at reflux for two hours. The solvent is removed under vacuum and the residue diluted with H2O and made basic with 10% aqueous NaOH (pH 10). The aqueous layer is extracted with CHCl3 (2×100 ml.) and the extracts dried (MgSO4) and concentrated under vacuum to an orange oil, which by NMR looks to be a mixture of starting material and product. The oil is layered out with H2O and Et2O. The oil solidifies. This solid is filtered and washed with H2O and Et2O and air dried. The solid is then crystallized (2×) from EtoAc to give 3.2 g. (37%) of a tan crystalline solid, melting point 165°-6° C.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([O:13][CH3:14])(Cl)Cl.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH:9]([SiH2:10][O:13][CH3:14])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CO[Si](C)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CO[SiH2]C(C1CCCCC1)C1CCCCC1
Yield: 80 %

Procedure:
The THF solution of cyclohexyl magnesium chloride as prepared above was added dropwise to the methylmethoxydichlorosilane solution obtained in Example 7, in the same manner as in Example 3(c), to effect the Grignard reaction. The post-treatment of the resulting Grignard reaction solution was carried out in the same manner as in Example 3(c), except that the saturated aqueous ammonium chloride solution used in Example 3(c), was used in a reduced amount of 80 ml instead of 120 ml. The organic layer was separated and was fractionally distilled under a reduced pressure, thereby to afford 39 g of dicyclohexylmethylmethoxysilane as a fraction boiling at 128° C.-129° C./7 mm Hg (yield; 80%).
Reaction SMILES: C(N(CC)CC)C.C(O[CH:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C(O)(=O)C(O)=O.[CH2:26]([NH:28][NH2:29])[CH3:27]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[N:29][N:28]([CH2:26][CH3:27])[C:18]=1[NH2:19])=[O:14])[CH3:17]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1N
Yield: 80.1 %

Procedure:
Triethylamine (19.6 ml, 144 mmol) was added cautiously to a solution of ethyl (ethoxymethylene)cyanoacetate (10.1 g, 60 mmol) and ethyl hydrazine oxalate (9.9 g, 66 mmol) in ethanol (200 ml). The mixture was heated at reflux for 24 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 5% KHCO3 solution then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% pet. ether:75% EtOAc) to yield the title compound (8.8 g, 80%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][S:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:36])[C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][S:47][CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Reactant: C1CSCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCSCC3)sc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (141 mg, 271 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (113 μL, 813 μmol) and thiomorpholine (77 μL, 813 μmol), and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (15 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. To the obtained residue were added diisopropyl ether and ethyl acetate, and the obtained precipitate was collected by filtration to give the title compound (117 mg, 73%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:17])=[O:16])=[C:13]=[O:14].CCCCCCC>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13](=[O:14])[NH:12][S:15]([O:18][C:19]2[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=2[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:16])=[O:17])[N:7]=1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1C(=O)OCCCl
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
2.02 g (0.013 mole) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 80 ml of dichloromethane, and 4.28 g (0.014 mole) of 2-chloroethyl 2-isocyanatosulfonyloxybenzoate, dissolved in 20 ml of dichloromethane, are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours and is then stirred into 600 ml of n-heptane. In this manner, 4.72 g (79% of theory) of 2-chloroethyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyloxy]-benzoate of melting point 148°-150° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[Br:21]Br.C(OCC)(=O)C>ClC(Cl)(Cl)Cl>[Br:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH:8]([C:12]([F:14])([F:15])[F:13])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Br)c(F)cc2OC1C(F)(F)F
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To the solution of ethyl 7-fluoro-2-(trifluoromethyl)-2H chromene-3-carboxylate (5 g, 34 mmol) in 100 mL of tetrachloromethane was added dropwise at room temperature a solution of bromine(10.5 mL, 204 mmol) in 20 mL of tetrachloromethane. The resulting solution was stirred for 24 hrs. To the reaction was added 500 mL of ethyl acetate. The resulting organic phase was then washed with aqueous sodium thiosulfite to remove excess bromine, and brine, then dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane. It gave 5.6 g product. A small fraction of the product was further purified on reverse phase HPLC for analytica characterization. It gave a white solid. m.p.=98.5-100.0° C. 1H NMR(CDCl3/300 MHz) 7.67(s, 1H), 7.46(d, J=7.5 Hz, 1H), 6.83(d, J=9 Hz, 1H), 5.74(q, J=6.6 Hz, 1H), 4.36(m, 2H), 1.39(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/300 MHz): −78.82(d, J=6.5 Hz), −98.7(t, J=7.9 Hz). 13C NMR(CDCl3/300 MHz): 163.6, 163.1, 159.7,154.0(d, J=11.5 Hz), 135.1, 133.4, 123.4(q, J=287.3 Hz), 117.3, 105.6(d, J=26.7 Hz), 102.2(d, J=22.3 Hz), 71.1(q, J=33.3 Hz), 61.9, 14.4. LC-MS(ES+): 369.2(M+1, 100). HRMS (EI+): m/z calc. For C13H9BrF4O3: 367.9671(M+), found: 367.9675.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[K+]>CN(C)C=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C#N)CC1
Temperature: 90 °C

Procedure:
2-Chloro-nicotinonitrile (2.04 g, 14.7 mmol) was added to a mixture of piperazine-1-carboxylic acid tert-butyl ester (2.74 g, 14.7 mmol) and potassium hydrogencarbonate (1.77 g, 17.6 mmol) in N,N-dimethylformamide (45 mL). The mixture was heated at 90° C. overnight. The solvent was removed and residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine then dried over magnesium sulfate and filtered. The solvent was removed to give the titled compound as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 8.428 (dd, 1H); 8.08 (dd 1H); 6.95 (dd, 1H); 3.58 (m, 4H); 3.47 (m, 4H); 1.42 (s, 9H).