Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+]>C1COCC1.O>[C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 4.8 mmol) was taken up in THF (8 mL) along with 5M aqueous NaOH (5 mL) and stirred vigorously at room temperature for 3 h. The reaction mixture was diluted with water and concentrated under reduced pressure. Enough 6N HCl was then added to adjust the pH to 2. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoic acid. This was taken up in CH3CN (15 mL) along with N-Boc-L-threonine methyl ester (1.11 g, 4.78 mmol), HATU (2.0 g, 5.3 mmol) and DIEA (1.2 mL). The resulting reaction mixture was stirred at room temperature for 6 h and diluted with EtOAc. The organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (2S,3R)-methyl 2-(tert-butoxycarbonyl)-3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate (1.0 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2].[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][N:11]([CH3:31])[C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CI
Reactant: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2c(=O)n(C)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (40 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 193 mg) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added iodomethane (0.009 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The obtained solid was suspended in toluene, and the suspension was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of hexane/ethyl acetate/methanol to give the title compound (33 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCOc1ccc(I)cc1
Yield: 81.6 %

Procedure:
Methyl 11-bromoundecanoate (10 g, 35.8 mmmol), in acetone (150 ml) was treated with 4-iodophenol (7.88 g, 35.8 mmol) and potassium carbonate (9.88 g 71.6 mmol). The stirred reaction was heated at reflux for 48 h. The reaction was then allowed to cool and the reaction concentrated in vacuo to a gum. The reaction was then partitioned between ethyl acetate (150 ml) and water (150 ml). The ethyl acetate layer was separated dried, over sodium sulfate and concentrated in vacuo to solid. The solid was dissolved in diethyl ether (100 ml) and petroleum ether 60-80 C (100 ml) added. The solution was concentrated in vacuum to a volume of 100 ml. The solution was set aside and allowed to crystallise. The product was collected by filtration and dried in vacuum to give 12.22 g of solid. The mother liquors were concentrated to ˜20 ml and allowed to crystallise. A further 0.81 g of solid was collected by filtration. The two solids were combined to give the desired product (13.03 g, 86%) δH (CDCl3) 1.29-1.78 (16H, m, 3,4,5,6,7,8,9,10-CH2), 2.30 (2H, t, 2-CH2), 3.86 (3H, s, CO2CH3), 3.90 (2H, t, 11-CH2), 6.66 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5-ArH), δC(CDCl3) 24.90, 25.93, 29.09, 29.18, 29.30, 29.42, 34.07, 51.42, 68.06, 82.35, 116.90, 138.11, 158.98, and 174.33.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18][CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:34]O>C(O)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18]([CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)N(CCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Reactant: OO
Solvent: CC(=O)O
Product: CC(=O)N(CCS(=O)CC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
There was dissolved 1.0 g (0.002 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[2-(2-thienylacetamino)ethylthio]acetamide in 30 ml, of acetic acid and added 0.24 ml, (0.0022 mol) of 30% aqueous solution of hydrogen peroxide under cooling with ice, and the mixture was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform:ethanol=5:1) to give 0.72 g of the titled compound as crystals.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[C:40]1[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1>CO>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([C:40]6[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(c6nccc(C(F)(F)F)n6)CC5)C4)cc3)oc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol) in methanol (2 ml) were added potassium carbonate (13 mg, 0.094 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (10 μl, 0.083 mmol). The mixture was heated to 50° C. and stirred at this temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (17.4 mg, 0.030 mmol, 65.7% yield). Mass spectrum (ESI) 575.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
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: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.1 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(I)cc(C(=O)O)c1N
Temperature: 60 °C
Yield: 43.5 %

Procedure:
2-Amino-3-methylbenzoic acid (10 g, 66 mmol) was dissolved in 70 mL of N,N-dimethyl-formamide (DMF) and treated with N-iodosuccinimide (16.4 g, 73 mmol). The mixture was heated at 60° C. for 17 hours and allowed to cool to 25° C. The mixture was diluted with water (150 mL and filtered. The air-dried solid was dissolved in ethyl acetate (200 mL) and dried over magnesium sulfate. Evaporation of the solvent provided the title compound of Step A (7.95 g). 1H NMR (CDCl3): δ 7.87 (1H), 7.44 (1H), 2.09 (3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13]([O:15]CC)=O)[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[NH3:18]>CO>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13]([NH2:18])=[O:15])[CH2:10][CH2:11][CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Reactant: N
Solvent: CO
Product: NC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of ethyl 1-(4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate (300 mg) obtained in Step A of Example 127 and 8 M ammonia in methanol (15 mL) was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (260 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][C:12]1[C:16](C(B(O)O)=O)=[C:15]([CH3:22])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:16]3[C:12]([CH3:11])=[N:13][O:14][C:15]=3[CH3:22])[CH:3]=[CH:4][C:5]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: Cc1noc(C)c1C(=O)B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of 5-bromo-1-benzothiophene (ABCR, CAS: 133150-64-8, 1.0 6 g, 5.0 mmol) in dimethoxyethane (60 mL) and ethanol (6.0 mL) was added 3,5-dimethyl-4-isoxazoylboronic acid (1.0 g, 7.5 mmol), and 2 m sodium carbonate (2.0 mL). The reaction mixture was degassed 2-3 times, tetrakis-(triphenylphosphine)palladium (0.813 g, 0.7 mmol) was added, and the mixture was stirred for 6 h at 80° C. and concentrated. The residue was taken up in water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude product was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 4-benzo[b]thiophen-5-yl-3,5-dimethyl-isoxazole (0.69 g) as a light yellow solid. MS (ISP): m/e 230.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[S:15]>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:14]([NH:13][CH2:12][C:11]([F:17])([F:16])[F:10])=[S:15])[CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cccc(CO)c1
Solvent: CC(C)=O
Product: OCc1cccc(NC(=S)NCC(F)(F)F)c1

Procedure:
m-Aminobenzyl alcohol (0.123 g.) and 2,2,2-trifluoroethylisothiocyanate (0.141 g.) were heated under reflux in acetone (5 ml.) for 2 hours. Volatile material was evaporated in vacuo and the crude residue was fractionated on a silica gel column (20 cm.×1 cm. diameter) eluted with ethyl acetate to give 1-(3-hydroxymethylphenyl)-3-(2,2,2-trifluoroethyl)thiourea. The n.m.r. spectrum in CDCl3 using tetramethylsilane as internal standard (δ=0) had the following resonances (δ):-7.2 (4H, multiplet); 4.6 (2H, singlet); 4.3 (2H, multiplet).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:12]=[N:11][N:10]([CH3:13])[C:9]=1[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[OH:20].CS(O[CH2:39][C:40]([CH3:45])([N+:42]([O-:44])=[O:43])[CH3:41])(=O)=O.O>CC(N(C)C)=O>[N+:42]([C:40]([CH3:45])([CH3:41])[CH2:39][O:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:9]1[N:10]([CH3:13])[N:11]=[CH:12][C:8]=1[Cl:7])([O-:44])=[O:43]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Cesium carbonate (815 mg, 2.50 mmol) was added to a solution of N-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg, 1.40 mmol) in DMA (2.0 mL), and the mixture was stirred at 160° C. After 1 hour, the mixture was allowed to cool to room temperature and poured into water, and the resulting suspension was extracted with dichloromethane. The extract was dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate-hexanes 1:2) to afford the title compound (338 mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H, 37Cl 31.5), 497.4 (M+H, 35Cl 100.0). 1H NMR (400 MHz, CDCl3) δ 1.51 (s, 3H) 1.57 (s, 3H) 3.64 (s, 3H) 4.01 (d, J=9.85 Hz, 1H) 4.49 (d, J=9.85 Hz, 1H) 7.08 (d, J=8.84 Hz, 1H) 7.49 (d, J=2.53 Hz, 1H) 7.51 (s, 1H) 7.65 (t, J=7.71 Hz, 1H) 7.79-7.89 (m, 3H) 8.07 (d, J=7.83 Hz, 1H) 8.13 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 1.5 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (490 g, 1 equiv.), prepared generally in accordance with Step A, above, was dissolved in THF (2.45 L, 5 vols) and stirred and cooled to 0-3° C. 1M lithium bis(trimethylsilyl)amide in THF (5.25 L, 3.7 equiv.) solution was charged to the reaction mixture followed addition of 2-chloro-4-methylpyrimidine (238 g, 1.3 equiv.) in THF (2.45 L, 5 vols). The reaction was then stirred for 1 hr. The reaction was quenched with 4.5M HCl (3.92 L, 8 vols). The aqueous layer (bottom layer) was removed and discarded. The organic layer was concentrated under reduced pressure to ˜2 L. IPAC (isopropyl acetate) (2.45 L) was added to the reaction mixture which was then concentrated to ˜2 L. IPAC (0.5 L) and MTBE (2.45 L) was added and stirred overnight under N2. The solids were filtered. The solids and mother filtrate added back together and stirred for several hours. The solids were filtered and washed with MTBE (˜5 vol). The solids were placed in vacuum oven at 50° C. overnight. The solids were dried in vacuum oven at 30° C. over weekend to obtain N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (479 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.9 g), 2-(4-chlorobenzyl)-3-oxopentanoic acid ethyl ester (0.95 g) and polyphosphoric acid (10 mL) was heated at 120° C. for 5 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 10:1 by volume) to afford title compound as a brown solid, 0.10 g.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+].Cl>C(O)C.O>[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)c1cn2c(ccc3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(ccc3ccccc32)n1

Procedure:
0.5 g of ethyl imidazo-[1,2-a]-quinoline-2-carboxylate was dissolved in 50 ml of ethanol and then a solution of 0.12 g of sodium hydroxide in 10 ml of water was added thereto. The mixture was heated on a steam bath for 2 hours and was subsequently acidified to a pH of 2 with concentrated hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and 50 ml of methanol were added to the residue. The solution was filtered to remove inorganic material and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized by trituration in chloroform to give imidazo-[1,2-a]-quinoline-2-carboxylic acid in the form of the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].Cl.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Product: CCN(CC)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to diethylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-diethylterephthalamide. MS (Q1) 443 (M)+.
Reaction SMILES: ClC([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[C:11]([NH2:14])(=[S:13])[CH3:12]>CC(C)=O>[CH3:12][C:11]1[S:13][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][N:14]=1
Reactant: CCOC(=O)C(C)C(=O)Cl
Reactant: CC(N)=S
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(C)s1
Temperature: 56 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
Under nitrogen atmosphere, a solution of KOtBu (11.5 g) in THF (203 mL) was cooled to 0° C., and thereto were added dropwise ethyl chloroacetate (12.5 g) and ethyl formate (7.60 g) in THF (40 mL). After the addition, the mixture was stirred at 0° C. for 3 hours, and further stirred at room temperature for 16 hours. Water and a 6N aqueous hydrochloric acid solution were added to the mixture, and the mixture was extracted with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure to give ethyl 2-chloroformyl-propionate. Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56° C. for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1→10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cu][C:14]#[N:15].CN(C=O)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C#N)cnc1N
Temperature: 25 °C
Yield: 32.4 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (2.0 g, 8.7 mmol) and copper (I) cyanide (3.9 g, 43.5 mmol) were taken into DMF (20 mL) and the mixture was heated to reflux for two hours. The mixture was allowed to cool to room temperature then diluted with ethyl acetate (250 mL). The insoluble residue was removed by filtration and the filtrate partitioned with water. The organic layer was separated and washed with water (2×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded 3-amino-6-cyano-N-methylpyrazine-2-carboxamide (500 mg, 33% yield) as a white solid: 1H NMR (400 MHz, d6-DMSO): 8.84 (br m, 1H), 8.67 (br s, 1H), 8.65 (s, 1H), 2.77 (d, 3H).