Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.[C:15](O)(=[O:17])[CH3:16].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=[O:13])[C:10](=[C:15]([OH:17])[CH3:16])[C:9](=[O:14])[CH2:8]1
Reactant: O=C1CC(=O)CC(c2sccc2Cl)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2sccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.9 %

Procedure:
To a solution of 5-(3-chlorothiophen-2-yl)cyclohexane-1,3-dione (2.0 g), acetic acid (0.90 g) and dimethylaminopyridine (1.6 g) in dimethylformamide (100 ml) was added dicyclohexylcarbodiimide (2.3 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The mixture was washed with potassium hydrogensulfate solution and water, and to the mixture was added 1N sodium hydroxide solution. The aqueous layer was washed with diethylether and neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give oil of 5-(3-chlorothiophen-2-yl)-2-(1-hydroxyethylidene)-cyclohexane-1,3-dione (2.2 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11].C(N)CN.ClCCC[Si](OC)(OC)OC>>[NH2:3][CH2:2][CH2:1][NH:4][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: NCCN
Product: CO[Si](CCCNCCN)(OC)OC
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A 200-ml, four necked glass flask equipped with a stirrer, reflux condenser, and thermometer was charged with 72.0 g (1.2 mol) of ethylene diamine and heated at 112° to 117° C. From a dropping funnel, 59.6 g (0.3 mol) of 3-chloropropyltrimethoxysilane was added dropwise to the flask over 2 hours (the molar ratio of ethylene diamine/3-chloropropyltrimethoxysilane=4.0). After one hour ripening, the reaction solution was transferred to a separatory funnel and cooled for allowing the solution to separate into two layers. The lower layer of ethylene diamine hydrochloride was separated off. The upper layer containing 3-[N-(2-aminoethyl)]aminopropyltrimethoxysilane was taken out and purified by simple distillation, obtaining 46.8 g of 3-[N-(2-aminoethyl)]aminopropyltrimethoxysilane. The yield was 70.1%. A substantial amount of bis-silyl products was detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].I[CH2:25][CH3:26].[H-].[Na+].O>CN(C=O)C>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6])[CH3:26]
Reactant: CCI
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(I)ccnc21
Reaction time: 0.33 h
Yield: 78 %

Procedure:
Compound (158a) (1.50 g) and iodoethane (2.8 mL) were dissolved in DMF (35 mL), and sodium hydride (0.335 g, a 55% dispersion in paraffin liquid) was added to the resulting solution under ice cooling, followed by stirring for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 3-(ethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-(ethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (15 mL), and a hydrogen peroxide solution (30 wt %) (0.563 mL) and a 4 mol % aqueous sodium hydroxide solution (2.48 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (162a) (1.29 g, the second stage yield: 78%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[C:6]([Br:25])=[CH:7][C:8]([F:24])=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:10]=1)C=C.O.Cl.C(N(CC)[C:31]1[CH:36]=CC=C[CH:32]=1)C>>[CH2:36]([C:10]1[C:5]([OH:4])=[C:6]([Br:25])[CH:7]=[C:8]([F:24])[C:9]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]([CH3:22])[C:12]1=[O:23])[CH:31]=[CH2:32]
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Solvent: O
Product: C=CCc1c(O)c(Br)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O

Procedure:
3-(5-Allyloxy-4-bromo-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (3.17 g) was dissolved in N,N-diethylaniline (11 ml) and allowed to react at 210° C. for 2.5 hours. After the completion of the reaction, the reaction solution was poured into water, and diluted hydrochloric acid was added thereto for acidification. It was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:2 v/v) to obtain the objective 3-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluor-omethyl-2,4(1H,3H)-pyrimidinedione (2.57 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH3:27].Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC[Mg]Br
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of 9.15 g (29.7 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-2-ethoxycarbonyl-2-propenoate (prepared as described in Preparation 1) in 9 ml of diethyl ether was added to 72 ml (36 mmol) of a 0.5 M ice-cooled solution of pentylmagnesium bromide in diethyl ether, and the resulting mixture was stirred at the same temperature for 1.5 hours. At the end of this time, the reaction mixture was poured into a 10% aqueous solution of hydrochloric acid in ice, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 200 g of silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.65 g (yield 77%) of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]2[N:10]=[N:9][N:8](CC3C=CC(OC)=CC=3)[C:6]=2[N:7]=1.[CH:33]([O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[C:41]([CH3:50])=[CH:40][C:38]=1[NH2:39])([CH3:35])[CH3:34]>Cl.O1CCOCC1>[CH:33]([O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)[C:41]([CH3:50])=[CH:40][C:38]=1[NH:39][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1)([CH3:35])[CH3:34]
Reactant: COc1ccc(Cn2nnc3c(Nc4ccccc4S(=O)(=O)C(C)C)nc(Cl)nc32)cc1
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3nn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 110 °C

Procedure:
A solution of 5-chloro-N-(2-(isopropylsulfonyl)phenyl)-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (10 mg) and 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (7 mg) in 2 M HCl/dioxane (2 mL) was sealed in a pressure tube and heated at 110° C. for 2 days. It was cooled to room temperature and solvent was removed under reduced pressure. The remaining residue was dissolved in trifluoroacetic acid (2 mL) and heated to 80° C. for 2 h. Trifluoroacetic acid was removed and the remaining product was purified by preparative LC-MS to afford desired product. 1H NMR (400 MHz, MeOD-d4) δ 8.67 (d, 1H), 7.98 (m, 2H), 7.74 (t, 1H), 7.43 (t, 1H), 6.82 (s, 1H), 4.61 (m, 1H), 3.57 (m, 2H), 3.38 (m, 1H), 3.18-3.24 (m, 2), 2.26 (s, 3H), 2.03 (m, 2H), 1.82-1.93 (m, 2H), 1.41 (d, 6H), 1.31 (d, 6H) ppm; ESMS calculated for C28H36N8O3S (m/z): 564.2 (M+H+), found: 565.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH:20]4[CH2:22]C4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl.N1CCC1>>[N:18]1([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20][CH2:22]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Agent: C1CNC1
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCC4)CC3)cc2n1

Procedure:
Prepared according to the method used in the preparation of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-cyclopropylmethyl-amine using azetidine hydrochloride in place of cyclopropanemethylamine. The title compound was obtained as an orange solid (102 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[Cl:29][C:25]1[CH:24]=[C:23]([N:22]([CH3:21])[C:18]([C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:10][C:11]=3[CH:17]=2)=[O:20])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: CNc1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)c1cccc(Cl)c1

Procedure:
A solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid (107.5 mg, 0.35 mmol). N-methyl-3-chloroaniline (50 mg, 0.35 mmol), BOP (186 mg, 0.42 mmol) and DIEA (0.091 mL, 0.53 mmol) in DMF (1 mL) was stirred at room temperature for 60 h. Then 1N NaOH aqueous solution was added. The aqueous layer was extracted with EtOAc, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=20:80 to 80:10) and prep-HPLC later to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid (3-chloro-phenyl)-methyl-amide: MS (m/z) 432 (M+1); 1H NMR (CDCl3, 400 MHz) δ 9.86 (s, 1H), 7.87 (s, 1H), 7.59 (d, 1H), 7.28-7.42 (m, 4H), 7.18 (s, 1H), 7.13 (t, 2H), 6.93 (t, 1H), 3.51 (s, 3H) (major tautomer).
Reaction SMILES: [N:1]1([C:6]2[CH:22]=[CH:21][C:9]([CH2:10][CH:11]3[C:16](=[O:17])[O:15]C(C)(C)[O:13][C:12]3=[O:20])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([C:12]([OH:20])=[O:13])[C:16]([OH:17])=[O:15])=[CH:21][CH:22]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC1(C)OC(=O)C(Cc2ccc(-n3cccn3)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(Cc1ccc(-n2cccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (41.4 g, 137 mmol, Intermediate 6: step a) and 3 M aqueous NaOH solution (300 mL, 900 mmol) was heated for 48 hours at 110° C. The mixture was cooled to room temperature, diluted with water (200 mL) and extracted with EtOAc (1×100 mL) and then acidified to pH 1 with concentrated aqueous HCl at 0° C. The resulting mixture was stirred at 0° C. for 1.5 hours, filtered and the filter cake was washed with water. The solids were collected and dried under vacuum at 40° C. to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:3]=1[NH2:4].C(OCC)(=O)C.CN(C)C=O.C(Cl)Cl>C(O)C.[Pt]>[NH2:9][C:7]1[CH:8]=[C:2]([Br:1])[C:3]([NH2:4])=[C:5]([Br:12])[CH:6]=1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(Br)c(N)c(Br)c1
Reaction time: 1 h

Procedure:
20 g of 2,6-Dibromo-4-nitroaniline are taken up in 250 ml of ethanol, 250 ml of ethyl acetate, 100 ml of dimethylformamide and 90 ml of methylene chloride and, after addition of 3.3 g of 5% moist platinum/active carbon catalyst, hydrogenated at room temperature under 50 psi for one hour. The solvent is then distilled off in a rotary evaporator, and the residue is triturated with diethyl ether, filtered off with suction and washed several times with petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:8]=1)[NH2:7].[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[C:6]([NH:7][S:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:27])=[O:28])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCc1ncccn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ncccn1)c1cc2ccccc2o1
Yield: 50.7 %

Procedure:
Following General Procedure B, the title compound (243 mg, 51%) was prepared from 5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline (280 mg, 1.11 mmol) and benzofuran-2-sulfonyl chloride (240 mg, 1.11 mmol) in pyridine (3 ml).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16](O)=[O:17])[C:8]2=[O:23])#[N:2].[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH2:29]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([NH:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1)=[O:17])[C:8]2=[O:23])#[N:2]
Reactant: Nc1ccon1
Reactant: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1
Product: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)Nc5ccon5)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 1.03 (t, 3H), 2.19 (s, 3H), 2.38 (q, 2H), 2.53 (m, 4H), 3.35 (m, 4H), 7.04 (s, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 8.10 (m, 3H), 8.29 (s, 1H), 8.84 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 484.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)[CH3:4]>CO>[CH2:3]([C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH3:4]
Reactant: CCc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Reaction time: 2 h
Yield: 28.2 %

Procedure:
NaOH (22 mg, 0.55 mmol, 4.00 equiv) was added to a solution of methyl 3-ethyl-2-phenylquinoxaline-6-carboxylate (40 mg, 0.14 mmol, 1.00 equiv) in CH3OH (20 mL), and the solution was allowed to react, with stifling, for 2 hrs at 50° C. The resulting mixture was concentrated under vacuum and combined with crude product from a previous batch prior to purification. The resulting mixture was purified by prep-HPLC, affording 11 mg (29%) of 3-ethyl-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].[ClH:34].C(O)C>CO.CN(C)C=O>[ClH:34].[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH:7]([OH:8])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(O)CCN2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 Grams of 6-{4-[2-(4-methoxybenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril was suspended in 150 ml of methanol-dimethylformamide [1:1(v/v)] then 0.26 g of sodium borohydride was added thereto at room temperature and stirred for 1 hour. The excess sodium borohydride was decomposed by adding 2M-hydrochloric acid to the reaction mixture, and the solvent was removed by evaporation. The residue was treated with a mixture of water-ethyl acetate, and the organic layer was washed with water, dried then the solvent was removed by evaporation. The residue thus obtained was converted into hydrochloride by adding ethanol-concentrated hydrochloric acid, and the thus obtained hydrochloride was recrystallized from ethanol-water to obtain 0.9 g of 6-{4-[3-(4-methoxyphenyl)-3-hydroxypropyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril monohydrochloride. Melting point: 219°-224° C. (dec.). Colorless powdery substance.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][CH:6]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:5]1=[O:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:33]1[C:1]([CH2:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7][CH:6]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:5]2=[O:32])=[N:2][N:35]=[N:34]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)OCc1ccccc1
Yield: 59.9 %

Procedure:
A mixture of 150 mg of 1,3-dihydro-1-cyanomethyl-3-[(benzyloxycarbonyl)amino]-5-phenyl-2H-1,4-benzodiazepin-2-one, 124 mg of sodium azide, and 102 mg of ammonium chloride was heated in 3 ml of dry N,N-dimethylformamide at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in water, acidified with 1N HCl solution, and extracted twice with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated to give 180 mg of crude product. Purification via preparative thick layer chromatography on 4 1.0 mm×20 cm×20 cm silica gel plates (90:10:1, chloroform-methanol-acetic acid elution) afforded 99 mg of the title compound.
Reaction SMILES: I[C:2]1[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]=1
Reactant: Cc1nc(N)nc(NC2CCOCC2)c1I
Reactant: C=CC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NC1CCOCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of 5-iodo-6-methyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine (10.0 g, 30.0 mmol) in DMF (200 mL) was added triethylamine (12.50 mL, 90.0 mmol) and ethyl acrylate (9.80 mL, 90.0 mmol) successively at room temperature. The reaction was purged with nitrogen for 5 min. and Pd(PPh3)4 (10 mol %, 3.50 g) was added. The reaction was heated to 95° C., stirred for overnight under nitrogen, and then cooled to room temperature. Nearly all DMF was evaporated under reduced pressure. The reaction was poured into ethyl acetate (500 mL) and H2O (300 mL). The organic layer collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (70% ethyl acetate/hexanes to 10% EtOH/ethyl acetate) to afford (E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-5-yl)acrylate, as a light yellow semicrystal (yield: 6.85 g, 75.0%). LC/MS: calculated for C15H22N4O3 (306.17). found: 307.2 (MH+). HPLC analytical purity: >97.0%.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]1([F:34])[C:25]2[C:20](=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[CH:23][C:24]=2O)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:24]2[CH:23]=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:20]3[C:25]=2[C:17]([F:34])([F:16])[CH2:18][CH2:19]3)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCC2(F)F
Reactant: Cc1ccc(-c2snc(Cl)c2CO)cc1
Product: Cc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c3c2C(F)(F)CC3)cc1

Procedure:
The title compound 277 was prepared according to the procedure described in Example 127, following Steps 6-7, coupling (3-chloro-5-(p-tolyl)isothiazol-4-yl)methanol with ethyl 3-(1,1-difluoro-7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate. Upon hydrolysis, compound 277 was afforded as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.43 (d, J=8.1 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.07 (s, 2H), 3.06 (t, J=7.8 Hz, 2H), 2.78-2.84 (m, 2H), 2.40-2.67 (m, 4H), 2.37 (s, 3H). 19F NMR (300 MHz, CD3OD) δ: −84.86. Mass spectrum (ESI, m/z): Calcd. for C23H20ClF2NO3S, 462.1 (M−H). found 462.0.