Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:9])[C:6]([CH3:8])=[CH2:7].C(N(CC)CC)C>O1CCCC1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: OCCBr
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCBr
Yield: 89.6 %

Procedure:
A reactor was charged with 12.50 g (100 mmol) of 2-bromoethanol and 100 ml of tetrahydrofuran (THF) at 0° C. in a nitrogen atmosphere. After the dropwise addition of 10.45 g (100 mmol) of methacrylic chloride and 11.13 g (110 mmol) of triethylamine, the mixture was reacted at 25° C. for 30 minutes with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by distillation to obtain 17.30 g of 2-bromoethyl methacrylate shown by the following formula (M-20′) (yield: 90%).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[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)([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[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)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate (158.0 mg, 0.39 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (47.0 mg, 1.18 mmol) and water (2 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylic acid as a light yellow solid (89 mg, 58%). LC/MS (ES, m/z): [M+H]+ 390.0
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([CH2:16][CH2:17][C:18]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>COCCOC>[C:10]1([CH2:16][CH2:17][CH2:18][NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccccc1NC(=O)CCc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)c1ccccc1NCCCc1ccccc1
Temperature: 0 °C

Procedure:
3.4 ml of boron trifluoride etherate are added to a solution of 5.6 g of methyl 2-(3-phenylpropanoylamino)benzoate in 35 ml of anhydrous 1,2-dimethoxyethane. After cooling to 0° C., 3.4 g of sodium borohydride are added in portions, while stirring and cooling, and then the mixture is stirred at 60° C. for 45 hours and, after cooling, is poured onto ice-water. Extraction with ethyl acetate, evaporation off of the solvent and column chromatography of the residue as described under (a) provides methyl 2-(3-phenylpropylamino)benzoate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-:13].[Na+].[Na+].O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[C:2]([OH:13])=[O:1]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1nc2ccccc2[nH]1

Procedure:
The 2-hydroxymethylbenzimidazole from Part A (4 gms.) was refluxed in a small amount of saturated sodium carbonate solution with addition of sufficient boiling water to dissolve it. A hot, dilute solution of 6.67 gms. of potassium permanganate then was added slowly with stirring. Upon completion of the addition, the resulting suspension was refluxed for 30 minutes. The resulting hot liquid was separated by filtration from manganese dioxide which had formed. The filtrate then was cooled and rendered acidic (pH 5.0) by addition of acetic acid. The resulting yellow precipitate was filtered, dried, and recrystallized from hot water to obtain 1.98 gms. of the title compound as fine yellow needles.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CCc1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3.0 g (16.6 mmol) of methyl 5-ethyl-2-hydroxybenzoate in 100 mL of CH2Cl2 at 0° C. was added 5.8 mL (41.5 mmol, 2.5 eq.) of Et3N. To this stirred solution was added dropwise 3.6 mL (21.6 mmol, 1.3 eq.) of Tf2O. Following complete addition 0.2 g (cat.) of 4-dimethylamino pyridine was added and the reaction mixture was allowed to warm to room temperature. After 4 h stirring at this temperature the reaction was judged complete, and quenched by the addition of a saturated aqueous solution of NaHCO3 (100 mL). The resulting layers were separated and the aqueous layer extracted twice with CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the desired methyl 5-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate. 1H NMR (400 MHz, CDCl3): δ=7.94 (d, J=2.3 Hz, 1H), 7.47 (dd, J=2.3, 8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.00 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[Br:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].Cl.N1C=CC=CC=1.C(OCCO)C>>[Br:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
The method of Example 312 was used as well as 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.12 ml of 3-bromo aniline, 0.1 g of pyridine hydrochloride and 4.0 ml of 2-ethoxy ethanol. This afforded an oil which was purified by silica gel flash chromatography utilizing a gradient of methylene chloride/methanol (96:4 to 92:8) to give 0.22 g of the title compound as an off white solid,mp 115-118 C; mass spectrum (ES,m/e): M+H499.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21](O)[CH3:22])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]([CH3:22])[O:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a solution of (RS)-1-benzyl-4-[2-(1-hydroxy-ethyl)-phenyl]-piperidin-4-ol (3 g, 9.6 mmol) in tetrahydrofuran (30 ml) was added triethylamine (2.95 ml, 21.2 mmol), dimethylaminopyridine (120 mg, 0.96 mmol) and methanesulfonylchloride (0.84 ml, 10.6 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, quenched with water (15 ml) and ethylacetate (15 ml). The organic phase was dried over Na2SO4 and concentrated in vacuo to yield 2.95 g (quant.) of (RS)-1′-benzyl-3-methyl-3H-spiro[2-benzofuran-1,4′-piperidine] as an orange oil. MS m/e: 294 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Cl[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=1)[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CC(C)COc1ccc(B(O)O)cc1C#N
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(OCC(C)C)c(C#N)c2)c1
Yield: 95.7 %

Procedure:
In a mixed solution of 50 ml of toluene and 30 ml of a 2M aqueous sodium carbonate solution were dissolved 1.46 g of (3-cyano-4-isobutoxyphenyl)boronic acid and 1.86 g of methyl 2-chloroisonicotinate, and the resulting solution was heated at 100° C. for 1 hour in the presence of 0.49 g of tetrakis(triphenylphosphine)palladium. The reaction solution was extracted with ethyl acetate and the organic layer was washed with brine and then dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:chloroform=70:15:15) to obtain 1.98 g of methyl 2-(3-cyano-4-isobutoxyphenyl)isonicotinate. (2) Then, 1.98 g of the compound was dissolved in a mixed solution of 30 ml of methanol and 70 ml of THF, and 9 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 50° C. for 1 hour.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=O.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:33]([O:40][NH:41][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Alternatively, to a solution of (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (2.5 g, 5.82 mmol), HOBtH2O(0.89 g, 1 eq.) and O-benzyl hydroxylamine (2.2 mL, 3 eq.) in DMF (200 mL) at 0° C. was added EDCI (2.77 g, 2.5 eq.). The resulting mixture was then stirred overnight. DHF was removed by pump distillation at 65° C. To the residue was then added methanol (14 mL) followed by ether (140 mL). With stirring at 0° C., 0.5 N HCl (140 mL) was added, followed by petroleum ether (140 mL). The mixture was stirred at 0° C. for 15 minutes, then the white solid was suction filtered and subsequently washed with water (100 mL) followed by 1:1 ether/petroleum ether (100 mL). Drying under vacuum (P2O5) for 3 hours gave (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0 13,18 ]-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide as a white solid (2.7 g, 84.9%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Agent: Cl
Product: O=C(Cc1ccccn1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(pyridin-2-yl)acetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.71-8.73 (m, 1H), 8.41-8.43 (m, 1H), 8.22 (td, J=7.8, 1.7 Hz, 1H), 7.94-8.06 (m, 2H), 7.82 (d, J=7.9 Hz, 1H), 7.73-7.75 (m, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.59-7.67 (m, 4H); MS (APCI+) M/Z 391 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([CH2:25][CH3:26])[C:19]([C:27]([O:29][CH3:30])=[O:28])=[CH:18][C:17]=3[C:16]2=[O:31])[CH2:11][CH2:10]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[CH2:25]([C:20]1[C:19]([C:27]([O:29][CH3:30])=[O:28])=[CH:18][C:17]2[C:16](=[O:31])[N:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:24][CH2:23][C:22]=2[N:21]=1)[CH3:26]
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Product: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2M hydrogen chloride (methanol solution, 236 mL) and methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (19.7 g) was stirred at room temperature under nitrogen atmosphere for 4 hours and concentrated in vacuo. The residue was crystallized from methanol and ethyl acetate. After filtration, the crystals were washed with ethyl acetate to give the title compound (18.5 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([N:11]5[CH2:15][CH2:14][CH2:13][C:12]5=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: O=C1CCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C1CCCN1c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one (35 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A. The product was purified by reverse phase HPLC to yield 19.5 mg of 438. MS (Q1) 421 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:19]2[N:23]=[CH:22][NH:21][N:20]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Sc1nc[nH]n1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2nc[nH]n2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3.5 g. 2-amino-4-chloro-1-nitrobenzene, 5.5 g. of potassium carbonate, 4.0 g. of 3-mercapto-1,2,4-triazole in 30 ml. dimethylformamide is heated under nitrogen for 4 hours at 130°-140°C. The mixture is cooled, diluted with water and the pH adjusted to about 6. The crude product is filtered off and recrystallized from methanol, yielding 2-amino-1-nitro-4-(1,2,4-triazol-3-ylthio)benzene.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([S:11]([C:13]([F:16])([F:15])[F:14])=[O:12])=[C:9]([CH3:17])[N:8]([C:18]2[C:23]([F:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)=[O:5])C.[OH-].[Li+].Cl>C(O)(C)C.O>[Cl:29][C:19]1[CH:20]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:23]([F:24])[C:18]=1[N:8]1[C:9]([CH3:17])=[C:10]([S:11]([C:13]([F:14])([F:15])[F:16])=[O:12])[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1S(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(S(=O)C(F)(F)F)c(C(=O)O)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g, 2.6 mmol) in isopropanol (10 mL) and water (2.5 mL) was added lithium hydroxide (0.2 g, 8.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. To the reaction mixture was added aqueous hydrochloric acid (37 wt %, 0.9 mL) and water (7 mL). The resulting mixture was extracted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to give 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid as an off-white solid (1.1 g). This material was used without purification for the next step. 1H NMR (400 MHz, CDCl3) δ ppm 2.52 (s, 3H), 7.56 (dd, J=8.3, 1.5 Hz, 1H), 7.73 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.4 (d, J=8.6 Hz, 0.5F), −112.9 (d, J=7.9 Hz, 0.5F), −73.9 (s, 1.5F), −73.7 (s, 1.5F), −63.8 (s, 3F).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.O.C(Cl)(Cl)Cl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Yield: 76 %

Procedure:
To 4 mL of chloroform was added 4-[4-benzhydryloxy]piperidino]-1-butanol obtained from step 2 (0.11 g), 4-nitrobenzoic acid (0.1 g), 4-dimethylaminopyridine (DMAP, 0.12 g), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.1 g). The resulting mixture was allowed to react at room temperature for 3 hrs. before adding water to end the reaction. The resulting solution was acidified with 1N hydrochloric acid, and extracted by using chloroform. An organic solution layer was washed with 1N sodium hydroxide, dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (0. 12 g, 76% yield) of the title.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21]O)[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CCN(S(F)(F)[F:31])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21][F:31])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C(=O)c1cccc(C#CCF)c1)c1ccc(OC(F)F)cc1
Temperature: -78 °C
Yield: 77 %

Procedure:
1-(4-(Difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione (0.298 g, 0.90 mmol) is dissolved in CH2Cl2 (3.0 mL) and cooled to −78° C. DAST (0.160 g, 0.99 mmol) is added and the solution is slowly warmed to RT. After 1 h at RT a saturated solution of NaHCO3 is added and the mixture extracted with CH2Cl2. The CH2Cl2 is washed with H2O and brine. The solution is dried (MgSO4) and the material purified by flash chromatography to yield 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-fluoroprop-1-ynyl)phenyl)ethane-1,2-dione (0.232, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: COc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of 2-chloro-5-methoxybenzenesulfonyl chloride (2.5 g, 10.4 mmol) (i.e. the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (3.0 mL, 25.7 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to leave an aqueous suspension of a tan solid. The solid was isolated by filtration and washed with water to afford 2.2 g of the title compound. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.43 (d, 1H), 7.03 (d, 1H), 5.13 (br s, 2H), 3.85 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3C)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (10 ml) was added 2-methylpiperidine (500 mg, 5.04 mmol) and DIEA (650 mg, 5.03 mmol). The resulting solution was stirred at 80° C. for 2 hours and then quenched by water (50 ml). The solids were collected by filtration to afford methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (520 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[O:23])=[CH:20][CH:19]=1)#[N:17].Cl>C(O)(C)C.C(OCC)C>[ClH:1].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:23])=[CH:32][CH:33]=1)#[N:17]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: N#Cc1ccc(C(=O)Nc2cccc(N)c2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccc(C#N)cc4)c3)c2cc1OC
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (225 mg) was added to 3-(4-cyanobenzamido)aniline (261 mg) in isopropanol (8 ml). A 1M solution of hydrogen chloride in diethyl ether (1.0 ml) was added and the reaction mixture stirred and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane and diethyl ether. The title compound was obtained as a solid (399 mg); NMR: 3.99 (s, 3H), 4.01 (s, 3H), 7.37 (s, 1H), 7.45 (m, 2H), 7.65 (m, 1H), 8.02 (m, 2H), 8.12 (m, 2H), 8.20 (m, 1H), 8.31 (s, 2H), 8.80 (s, 1H), 10.71 (s, 1H), 11.44 (s, 1H); m/s: M+H+ 426.