Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][N:15]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:14][CH2:13]2)[C:4]1=[O:18]
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccc(C(F)(F)F)cc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 67.2 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), 2-chloro-6-(trifluoromethyl)benzo[d]thiazole (0.089 g, 0.373 mmol), and potassium carbonate (0.172 g, 1.245 mmol) in DMSO (3 mL) was heated at 110° C. overnight. The reaction mixture was cooled, H2O was added, and the solid was collected, dried and purified by ISCO (35% EtOAc/Hexanes) to give the title compound (93.5 mg, 67%). MS (M+1): 448. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 8.03-8.18 (2 H, m), 7.52-7.68 (2 H, m), 4.51-4.68 (1 H, m), 4.23 (2 H, d, J=12.5 Hz), 3.36-3.49 (2 H, m), 2.52-2.61 (2 H, m), 1.86 (2 H, d, J=10.4 Hz), 1.33 (6 H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[N+:17]([O-])=O)[CH2:8][CH2:7]1)=O)C>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:6]3([CH2:8][CH2:7]3)[C:4](=[O:3])[NH:17][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Br)ccc2OC12CC2
Temperature: 60 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.5 g, 10.6 mmol) in glacial acetic acid (40 mL) was added iron powder (5.9 g, 106.1 mmol) at room temperature and the reaction mixture was heated at 60° C. for 3 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite bed. The filtrate was concentrated, and the resulting residue was taken in ethyl acetate and washed with water and saturated sodium bicarbonate solution, then the organic layer was dried over sodium sulfate, concentrated and the resulting residue was purified by silica gel column chromatography to furnish 6-bromospiro[4H-1,4-benzoxazine-2,1′-cyclopropane]-3-one (2.51 g).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([O:18]C)=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(O)C>ClCCl>[CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC1NCCc2c1ccc(OC)c2C
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCCCOC(=O)CC1NCCc2c1ccc(O)c2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of butyl[5-methyl-6-(methyloxy)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetate (Preparation 14; 707 mg, 2.43 mmol) in dichloromethane (20 ml) at 0° C. under nitrogen was added boron tribromide (1.15 ml; 12.1 mmol) dropwise under nitrogen. The mixture was stirred at 0° C. for 30 min, and ethanol (3 ml) was added slowly to the mixture. After 10 min, the solvent was removed in vacuo and the
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Ru+3].[OH-].[OH-].O1CCOCC1>[C:1]([CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: [Ru+3]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1CCC(O)C(C(C)(C)C)C1
Yield: 96 %

Procedure:
A mixture of 400 g (2.44 moles) of 2-tert-butyl-4-methylphenol, 400 ml of dioxane and 1 g of ruthenium hydroxide was initially taken in an autoclave and hydrogenated at 120° C. and under a hydrogen pressure of 50 bar until the pressure remained constant (total hydrogenation time about 3 1/2 hours). The catalyst was separated off, after which the dioxane was distilled off and the residue was fractionated under 0.01 mbar. After a small initial fraction (15 g with a boiling point up to 60° C./0.01 mbar), 401 g (2.36 moles, corresponding to a yield of 96%) of 2-tert-butyl-4-methylcyclohexanol distilled over at 80°-85° C./0.01 mbar and, after cooling, solidified to a semisolid mass. On the basis of 13C NMR spectroscopic data, the product was identified as a diastereomer mixture of the following composition: A:B:C:D=68:29:2:1 ##STR7##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]#[N:9].[ClH:10].[NH2:11][OH:12]>CO>[ClH:10].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8](=[N:11][OH:12])[NH2:9]
Reactant: N#CCNc1cccs1
Reactant: NO
Agent: Cl
Solvent: CO
Product: NC(CNc1cccs1)=NO
Yield: 90.8 %

Procedure:
5.6 g of the α-(2-thienyl)aminoacetonitrile thus obtained was dissolved in 30 ml of methanol and 2.8 g of hydroxylamine hydrochloride was added thereto in a water bath. After stirring for a while, the mixture began to crystallize while showing slight heat generation. The mixture was stirred at room temperature for several hours thereafter. After the completion of the reaction, the reaction mixture was concentrated and the solvent was distilled off. After recrystallizing from ethanol, 7.6 g of the aimed α-(2-thienyl)aminoacetamidoxime hydrochloride was obtained.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH2:16](OCC)C>>[CH3:16][C:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:12][C:13]=2[CH:14]=[CH:15][CH:2]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOCC
Product: Cc1cccc2c1Nc1ccccc1S2
Temperature: 0 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
To a solution of 2-chlorophenothiazine (4.67 g, 0.020 mole) in anhydrous ethyl ether (60 mL) methyl lithium (R═CH3 in product) (1.6 M solution, 62.5 mL, 0.1 mol) was added at room temperature (1 h). After the mixture had been stirred for 6 h, ice water was added slowly (30 min) and after that the stirring was continued for 30 min. The organic layer was separated and combined with ether extracts of the aqueous phase. The combined organic phase was washed with water, dried (Na2SO4) and concentrated to give the crude product (1.58 g, 37% yield). The desired final product was purified by flash chromatography.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]1[CH2:13][C@H:5]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.[Cu]I>[OH:4][C@@H:5]([CH2:13][CH3:1])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: CCCCOC(=O)[C@@H]1CO1
Reactant: C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@@H](O)CC
Yield: 99 %

Procedure:
Under argon, copper(I) iodide (594 mg) was suspended in anhydrous diethyl ether (20.0 mL). A solution of methylmagnesium bromide in anhydrous tetrahydrofuran (60.2 mL, M) was added dropwise to the suspension at −15° C. or lower, and the mixture was allowed to react at the same temperature for 20 minutes. After completion of reaction, a solution (8.0 mL) of n-butyl(S)-(−)-2,3-epoxypropionate (3.0 g, 97.3% ee) (product of Osaka Organic Chemical Industry Co., Ltd.) in anhydrous diethyl ether was added dropwise to the reaction mixture at −78° C., and the resultant mixture was allowed to react for 15 minutes at the same temperature. After completion of reaction, an aqueous saturated ammonium chloride solution (50.0 mL) was added to the reaction mixture, followed by filtration by means of a Celite. The filtrate was extracted twice with diethyl ether (50 mL×2), and the organic layer was washed with saturated brine (40 mL). The washed organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography including elution with methylene chloride/diethyl ether=5/1, to thereby yield 3.37 g of colorless oil (yield 99.0%). Since the compound was also able to be purified through distillation under reduced pressure, another aliquot of the residue obtained through the same procedure was distillated under reduced pressure, to thereby yield 2.73 g of colorless oil (yield 81.8%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:22][NH:23][C:24]1[C:29]([NH:30][CH:31]=O)=[C:28]([Cl:33])[N:27]=[C:26]([NH:34][CH:35]=[O:36])[N:25]=1)[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC(OC(=O)C)OCC)C>[Si:1]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH:34][CH:35]=[O:36])=[N:27][C:28]=2[Cl:33])[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)ONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 4-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxyamino)-6-chloro -2,5-diformamidopyrimidine (0.68 g, 1.19 mmol) in diethoxymethylacetate (10 ml) was stirred at 120° C. for 4 hours. The solvent was evaporated under high vacuum, the residue dissolved in methanol (10 ml) and 0.88 ammonia (0.3 ml) and stirred for 1 hour at 20° C. After evaporation to dryness, the residue was chromatographed on silica eluting with chloroform-methanol 40:1 affording 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)-6-chloro-2-formamidopurine (0.32 g, 49%) as a pale yellow oil. νmax (film) 3420, 1710, 1620, 1580, 1510, 1440, 1390, 1250 and 1030 cm-1 ; δH (CDCl3) 0.80(6H, s, (CH3)2Si), 0.87(9H, s, (CH3)3C), 1.30(6H, t, J7.2 Hz, 2×CH2CH3), 3.86(6H, m, CH2OSi+CH2OCH2P), 4.15(4H, m, 2×CH2CH3), 4.50(1H, m, CHON); 8.26(1H, s, H-8); 9.00(1H, br.d, J10.5 Hz, D2O exchangeable, NHCHO), 9.53(1H, d, J10.5 Hz, NHCHO). Found: C,43.02; H,6.49; N,12.18%; MH+ 552.1812. C20H35N5O7ClPSi.0.5H2O requires C,42.82; H,6.47; N,12.47%; MH+ 552.1810.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I:14]I.C(Cl)(Cl)Cl>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: II
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)2 (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I2 in 100 ml of AcOH dropwise and reaction mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAC and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to produce dark residue which was subjected to column chromatography (CHCl3, neat) to provide 4.1 g (13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:5][CH:4]([C:6]([CH:8]2[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]2=[O:17])=O)[CH2:3]1.C(O)(=O)C.[BH4-].[Na+]>C1COCC1>[F:18][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][CH:8]2[C:9](=[O:17])[O:10][C:11]([CH3:16])([CH3:15])[O:12][C:13]2=[O:14])[CH2:3]1
Reactant: CC1(C)OC(=O)C(C(=O)C2CC(F)(F)C2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(CC2CC(F)(F)C2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
A solution of 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (15.0 g, 57.3 mmol) in THF (200 mL) was cooled to −5° C. and acetic acid (38 g, 0.63 mol) was added. The mixture was stirred for 5 min and sodium borohydride (6.5 g, 0.17 mol) was added in portions. The reaction mixture was stirred for 2 h at −5° C. and then poured into ice water (200 mL). The resulting mixture was extracted with EtOAc (300 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 30:1) to afford 5-((3,3-difluorocyclobutyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.2 g, 58% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:24]([F:27])([F:26])[F:25])=[N:19][C:20]([C:21](=[O:23])[NH2:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:7][C@H:8]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:24]([F:27])([F:25])[F:26])=[N:19][C:20]([C:21]([NH2:22])=[O:23])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(N)=O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 95 %

Procedure:
(R)-[3-(1-Carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.16 g, 0.29 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid amide hydrochloride 24 (150 mg, yield 95%) as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([CH3:25])([OH:24])[CH:8]([NH:13]S(C1C(C)=CC=CC=1)(=O)=O)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Na]>N>[NH2:13][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([CH3:25])([OH:24])[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1S(=O)(=O)NC(CC(C)C)C(C)(O)COC(C)(C)C
Agent: N
Agent: [Na]
Product: CC(C)CC(N)C(C)(O)COC(C)(C)C
Yield: 79.5 %

Procedure:
To a solution of the resultant compound of Example 58 (0.40 g, 1.1 mmol) in liquid NH3 (80 ml) was added sodium (0.25 g, 11 mmol) with stirring. After 5 hours the solvent was evaporated and the residue was partitioned between benzene (40 ml), ethanol (10 ml), and water (30 ml). The layers were separated and the aqueous phase was extracted with ether. The combined organic layers were dried and evaporated to give 0.19 g (79%) of the desired compound. Mass spectrum: M+ =217.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(#N)C>>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccncc1)N1CCCC2(CCN(C3CCCCC3)C2=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (15 mg, 0.000055 mol), isonicotinoyl chloride hydrochloride (12 mg, 0.000066 mol), and triethylamine (27 μL, 0.00019 mol) in acetonitrile (0.5 mL, 0.01 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 18 mg of the desired product. LC-MS: 342.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([NH2:22])(=[O:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:19](=[O:21])[CH3:20])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: CC(N)=O
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
A solution of Example A3 (1.7 g, 6.40 mmol) in dioxane (30 mL) was sparged with Ar, treated with acetamide (1.512 g, 25.6 mmol), Cs2CO3 (2.085 g, 6.40 mmol), X-Phos (0.153 g, 0.320 mmol) and Pd2(dba)3 (0.293 g, 0.320 mmol) and heated at 80° C. for 20 h. The mixture was cooled to RT, treated with EtOAc, the solids removed via filtration through diatomaceous earth and rinsed well with EtOAc. The filtrate was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (450 mg, 24%) as a light yellow solid. MS (ESI) m/z: 289.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([O:12]CC)=[O:11])=[CH:6][N:5]=1>C(O)C>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(=O)O)cn1
Yield: 78.8 %

Procedure:
In 30 ml of ethanol and 20 ml of a 1M sodium hydroxide aqueous solution, 2.9 g of ethyl 2-methylpyrimidine-5-carboxylate was stirred for 2 hours. The solvent was removed by evaporation and an appropriate amount of water and diethyl ether were added thereto, followed by liquid-separating operation. The resulting aqueous layer was made weakly acidic with a 1M hydrochloric acid aqueous solution and then the resulting crystals were collected by filtration, washed with water, and then dried to obtain 1.9 g of the title compound.
Reaction SMILES: Br.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[C:25](=[CH2:26])[S:24][CH:23]([C:27]([O:29][CH3:30])=[S:28])[CH:22]=3)[N:20]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:31]CC(C1C=C(C(OC)=S)SC=1C)=O.O(C1C=CC(NC(N)=S)=CC=1)C1C=CC=CC=1>>[BrH:31].[O:2]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[C:23]([C:27]([O:29][CH3:30])=[S:28])[S:24][C:25]=3[CH3:26])[N:20]=2)=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C1SC(C(=S)OC)C=C1c1csc(Nc2ccc(Oc3ccccc3)cc2)n1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Agent: Br
Agent: NC(=S)Nc1ccc(Oc2ccccc2)cc1
Product: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccccc4)cc3)n2)c(C)s1
Yield: 88 %

Procedure:
Methyl 4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methlylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (200 mg, 0.64 mmol) was allowed to react with 4-phenoxyphenylthiourea (158 mg) as described in Example 154, step (a) to give 300 mg (88% yield) of methyl 4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C22H18N2O3S3, 454.6 (M+H), found 455.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13](O)=[O:14])[C:7]([CH3:17])=[CH:6]2)#[N:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[NH:32])[NH:30]O)=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CC#N>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:32]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:17])[CH3:16])[O:14][N:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)C(=O)O
Reactant: N=C(NO)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)c1nc(-c2ccc(F)cc2)no1

Procedure:
Synthesized as described in Example 37 from 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid and 4-fluoro-N-hydroxybenzenecarboximidamide using MeCN as the solvent, and HATU (1.05 eq), DIEA (1.05 eq), instead of EDCl, for the first coupling step: MS (ES) m/z 415 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14]CC)=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[OH-].[K+].O.Cl>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:20])([F:19])[F:21]
Reactant: CCOC(=O)c1nc2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Yield: 82.1 %

Procedure:
To a solution of ethyl 7-bromo-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate (120 mg, 329 μmol) in ethanol (4 ml) were added 1N aqueous solution of potassium hydroxide (1.32 ml, 1.32 mmol) and water (2 ml), and the mixture was refluxed for 30 minutes. After cooling with ice, the pH value was brought to 4 with 1.2N hydrochloric acid. The precipitate was collected by filtration, washed with water and then air-dried to obtain 91.0 mg of the title compound as yellowish brown powder. Yield 82%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]([F:33])([F:34])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)CCC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized from ethanol to yield 3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionic acid as a white crystalline solid.