Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(C(C)C)CC)(C)C.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 83.8 %

Procedure:
Part A: 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). After one hour the mixture is concentrated in vacuo to give an oil. This oil is crystallised from ethanol to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield). 1H-NMR (200 MHz, DMSO-d6): δ 10.90 (br s, 1H), 7.91 (br d, J=8 Hz, 2H), 7.63-7.77 (m, 4H), 7.57 (dt, J=8 Hz, J=2 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24]C=2C(O)=O)=[CH:16][CH:15]=1.CN(C=O)C>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24][C:1]=2[C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2M solution of oxaloyl chloride (3.86 mL, 7.71 mmol) was added slowly to a suspension of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (1580 mg, 5.14 mmol) in CH2Cl2 (20 mL). DMF (0.040 mL, 0.514 mmol) was added drop wise and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to deliver a yellow solid. The solid was suspended in CH2Cl2 (5 ml) and filtered to deliver 2-(4-(pyridin-2-ylamino)phenoxy)nicotinoyl chloride as a yellow solid that was taken on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:22][CH2:21]1
Reactant: CC(Cl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: OCCN1CCNCC1
Solvent: O
Product: CC(c1ccc(-c2ccc(F)cc2)cc1)N1CCN(CCO)CC1

Procedure:
With stirring, heat (on a steam bath) a mixture of 13g of 4'-fluoro-4-(1-chloroethyl)[1,1']biphenyl and 20g of 1-(2-hydroxyethyl piperazine for twenty hours. Treat the reaction mixture with 200 ml of water, filter and wash the solid with water to yield 1-(2-hydroxyethyl)-4-[1-(4'-fluoro[1,1']biphenyl-4-yl)ethyl]piperazine: m.p. 120°-123°. Recrystallize the product from acetonitrile, m.p. of 122°-123°.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1N1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O-])=O.[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38]>CN(C=O)C>[OH:38][CH2:37][CH:36]([N:35]1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)[CH2:39][OH:40]
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C(CO)CO)cnc21
Temperature: 80 °C

Procedure:
To a mixture of 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 24A (18 mg, 0.03 mmol, 1 eq) in DMF (0.3 mL) was added 2-aminopropane-1,3-diol (29 mg, 0.3 mmol, 10 eq). The reaction mixture was heated at 80° C. for 5 hours. The solvent was removed under vacuum and the residue was purified by preparatory LC/MS (30-55% CH3CN in H2O) to yield 3-(1,3-dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione Example 24 as an off-white solid (10 mg, 66% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.65 (s, 3H) 3.87-3.95 (m, 2H) 4.04 (dd, J=11.87, 7.07 Hz, 2H) 4.88-4.90 (m, 1H) 5.74 (s, 1H) 7.29 (t, J=8.34 Hz, 1H) 7.57-7.69 (m, 2H) 8.50 (s, 1H). [M+H] calc'd for C17H16FIN4O4, 487; found, 487.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32](O)([CH3:34])[CH3:33])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32]([F:43])([CH3:33])[CH3:34])/[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)F)n1C[C@H]1CCCO1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
The product from Example 43A (215 mg, 0.42 mmol) in CH2Cl2 (10 mL) was treated dropwise with DAST (66 μL, 0.504 mmol) at −78° C. The reaction mixture was allowed to warm up to room temperature for 4 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 48 mg (22%) of the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.45 (d, J=21.48 Hz, 6H) 1.50 (s, 9H) 1.82-1.99 (m, 3H) 2.19-2.37 (m, 3H) 3.67-3.83 (m, 2H) 4.14-4.23 (m, 1H) 4.24 (s, 3H) 4.48 (t, J=7.36 Hz, 2H) 4.80-4.97 (m, 1H) 5.48 (d, J=17.18 Hz, 1H) 6.97 (s, 1H) 7.13 (d, J=8.59 Hz, 1H) 7.74 (dd, J=7.98, 1.84 Hz, 1H) 8.08 (d, J=2.15 Hz, 1H); MS (DCI/NH3) m/z 514 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.N[C:13](N)=[S:14].[OH-].[Na+].CI>C(O)C>[Cl:8][C:7]1[C:2]([S:14][CH3:13])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: CSc1ncc([N+](=O)[O-])cc1Cl
Temperature: 10 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
2,3-Dichloro-5-nitropyridine (7.90 g, 0.041 mol) (Synthesis, 1990, 499) was dissolved in ethanol (150 ml) and was treated with thiourea (3.43 g, 0.045 mol). The resultant mixture was then heated to reflux with stirring under argon. After 3 h, the reaction mixture was allowed to cool, and was left stirring at room temp. for 16 h. 10% Sodium hydroxide solution (160 ml) was then added and the reaction mixture was heated to reflux with stirring. After 1 h, the reaction mixture was cooled to 10° C., and methyl iodide (2.80 ml, 0.045 mol) was added. After 1 h, the resultant precipitate was filtered off to give the title compound as an orange solid (5.90 g, 70%).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[C:47]([F:56])=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:57][CH3:58]>CC(N(C)C)=O>[F:56][C:47]1[C:46]([O:45][C:39]2[C:38]3[C:43](=[CH:44][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:21]4[CH2:22][CH2:23][N:18]([CH2:15][C:16]#[CH:17])[CH2:19][CH2:20]4)=[C:36]([O:57][CH3:58])[CH:37]=3)[N:42]=[CH:41][N:40]=2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[C:50]([CH3:55])[NH:51]2
Reactant: C#CCN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and potassium carbonate (258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at 85° C. overnight before being filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography eluting with increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:31])[CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:20][CH3:21])[N:3]=[C:2]([NH:30][CH:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:31])[CH3:22])[CH2:25][CH2:26]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: CN(C)C1CCC(N)CC1
Reactant: COc1cc2nc(Cl)c(-c3ccccn3)nc2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nc(NC3CCC(N(C)C)CC3)c(-c3ccccn3)nc2cc1OC
Yield: 74.9 %

Procedure:
A solution of 2-chloro-6,7-dimethoxy-3-pyridin-2-yl-quinoxaline (0.91 g) and N,N-dimethyl-cyclohexane-1,4-diamine (0.86 g) in toluene (30 mL) was refluxed under nitrogen atmosphere for 16 hours. The reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. This solid was recrystallized in ethyl acetate/hexane to give the product as yellow crystals (0.92 g); mp 168-171° C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc(F)cc1
Product: OC(CCCl)COc1ccc(F)cc1
Yield: 30 %

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-fluorophenol to give white title compound, m.p. 53°-55° C. in 30% yield.
Reaction SMILES: Cl[CH:2]([C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=1)[N:3]1[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1.[NH2:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>>[NH2:33][C:34]1[N:39]=[CH:38][C:37]([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:25]3[S:26][C:18]([CH2:2][N:3]4[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]4)=[CH:19][C:20]=3[N:21]=2)=[CH:36][N:35]=1
Reactant: CN(C)C(=O)CS(=O)(=O)C1CCN(C(Cl)c2cc3ncnc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: CN(C)C(=O)CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[1-(Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidine-4-sulfonyl]-N,N-dimethyl-acetamide was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 309. NMR (CDCl3): 1.98-2.08 (2H, m), 2.18-2.28 (4H, m), 3.04 (3H, s), 3.13-3.17 (2H, m), 3.22 (3H, s), 3.45-3.53 (1H, m), 3.85 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 4.08 (2H, s), 5.20 (2H, br), 7.27 (1H, s), 9.30 (2H, s). MS (ESI+): MH+ 561.20 (100%)
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[C:26]([O:25][C:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:5][CH2:6]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(=O)O)ccc1-n1cccc12

Procedure:
A solution of 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate (3.5 g, 8.8 mmol) in LiOH (18 mL of 2.0 M, 35.1 mmol) and dioxane (18 mL) was stirred at 55° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield 1′-(tert-butoxycarbonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid which was used without further purification. ESI-MS m/z calc. 384.4, found 385.3 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [OH-].[Na+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.CI.Cl.[O:18]=[C:19]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[O:18]=[C:19]([C:23]([CH3:3])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CI
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57 %

Procedure:
A 3N aqueous solution of sodium hydroxide (3.0 ml, 9.0 mmoles) and 6 ml of t-butyl alcohol were added to 0.492 g (3.0 mmoles) of phenylpyruvic acid to form a solution. Then, 0.6 ml of methyl iodide was added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was acidified with 20 ml of 1N hydrochloric acid, and extracted with ether. The organic layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated under reduced pressure to give a pale while oil. The NMR spectral analysis of the product led to the determination that 2-oxo-3-phenylbutanoic acid was formed in a yield of 57 %, and 2-oxo-3-methyl-3phenylbutanoic acid, in a yield of 30 %.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)#[N:11]>>[CH3:9][C:4]1[CH:5]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]#[N:11])[CH:17]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1cc(Cl)nc(N)n1
Product: Cc1cc(-c2cccc(C#N)c2)nc(N)n1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.7 g (18 mmol) 3-cyano-phenyl boronic acid. Yield after extraction and crystallization from diethylether: 3.2 g (100%).
Reaction SMILES: [Na].F[C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: N#CC1(c2cccc(F)n2)CCC1
Reactant: CO
Agent: [Na]
Product: COc1cccc(C2(C#N)CCC2)n1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To anhydrous methanol (6 mL) at 0° C. under nitrogen was added sodium metal (ca 1 g) and the mixture stirred for 30 min. 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol) was then added, and the resulting mixture heated to 75° C. for 45 min. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the desired product (1.7 g) as an oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].Cl>ClCCCl.O>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc2cc(C(C)=O)ccc2c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 43 g of anhydrous AlCl3 and 24.6 g (0.313 mole) of acetyl chloride in 200 ml of 1,2-dichloroethane at 10° C. was cooled to 0° C. and added dropwise under stirring with a solution of 59.25 g (0.250 mole) of 1-bromo-2-methoxy-naphthalene in 150 ml of 1,2-dichloroethane. The resulting solution was stirred for 15 minutes then poured into a cold solution of 300 ml of water and 100 ml of 2 N hydrochloric acid. The organic phase was separated, washed first with 100 ml of 1 N hydrochloric acid and then with 100 ml of water, dried under vacuum and the obtained residue was crystallized from 2-butanol. Yield 68.11 g (98%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Cc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Br)c(F)c(C(=O)O)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.7 mmol) in THF (20 mL) at −10° C., n-BuLi (0.68 g, 10.6 mmol) was added and the reaction was stirred for 1 hour at −10° C. and was then cooled to −78° C. A solution of 2-bromo-1-fluoro-4-methylbenzene (2.0 g, 10.6 mmol) in THF (10 mL) was added in dropwise and the reaction was stirred for 1 hour after which excess solid carbon dioxide (4.76 g, 106 mmol) was added. After 30 minutes the reaction mixture was allowed to warm to room temperature, allowing for pressure release, and was quenched with water. The resulting layers were separated and the aqueous portion was extracted with Et2O. The aqueous layer was then acidified with aqueous 6.0 M HCl solution and the resulting white precipitate was extracted into Et2O. The combined organic portions were dried (MgSO4), and concentrated in vacuo to afford 3-bromo-2-fluoro-5-methylbenzoic acid (2.1 g, 9.0 mmol, 85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H) 7.60 (dd, J=5.9, 1.8 Hz, 1H) 7.75 (dd, J=6.2, 1.8 Hz, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1cscc1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1scc(Br)c1Br
Reaction time: 0.17 h

Procedure:
41.4 ml of fuming nitric acid was slowly added to 500 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 78 ml of acetic acid anhydride containing 50 g of 3,4-dibromothiophene was slowly added, followed by stirring at room temperature for 18 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 40.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)[OH:28])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(O)C3CC3)n12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(=O)C3CC3)n12
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a mixed solution of 100 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(hydroxy)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 5 mL of dichloromethane was added 113 mg of Dess-Martin periodinane under ice-cooling. The mixed reaction liquid was returned to room temperature, followed by stirring for 4 hours. To the mixed reaction liquid were added a saturated aqueous sodium thiosulfate solution and chloroform, followed by stirring for a while, and then extracting with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 4 mL of methanol to give a mixed solvent, followed by warming and washing. The precipitate was collected by filtration and dried under reduced pressure to obtain 36 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-(cyclopropylcarbonyl)-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a skin-colored solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[SH:13])[CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl)(=[O:25])=[O:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[NH:26][S:23]([C:16]2[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][C:17]=2[CH3:22])(=[O:24])=[O:25])[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CCl)c(C)c1
Reactant: Cc1ccnc(-n2ccnc2S)c1
Product: Cc1ccnc(-n2ccnc2SCc2ccccc2NS(=O)(=O)c2c(C)cc(C)cc2C)c1

Procedure:
1.25 g of 1-(4-methyl-2-pyridyl)-2-mercaptoimidazole and o-(2,4,6-trimethylphenyl)sulfonylaminobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 2.19 g of 1-(4-methyl-2-pyridyl)-2-(2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio)imidazole. (2) The product obtained above is treated in the same manner as described in Example 73 to give 1-(4-methyl-2-pyridyl)-2-(2-methylaminobenzylsulfinyl)imidazole.