Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1cc(Br)oc1C
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: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(F)cc2C)oc1C
Yield: 92.2 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 4-fluoro-2-methylphenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 91%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:24]([NH:23][C:15]2[CH:14]=[C:13]([Cl:12])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(N)cc1
Yield: 131.1 %

Procedure:
2.7 g (15.7 mmol) of 4-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 7.9 g (yield 94%) of methyl 2-{[(4-aminobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless ambrphous, PMR (δ ppm, DMSO-d6): 3.59 (3H, s), 5.37 (2H, s), 6.45 (2H, d), 6.83 (1H, dd), 7.41 (2H, d), 7.81 (1H, d), 8.66 (1H, d), 9.64 (1H, s).
Reaction SMILES: CS[C:3]1[N:18]2[C:19]3[C:10]([S:11][C:12]4[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:17]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[C:5](=[O:24])[N:4]=1.Cl.C([OH:28])C>>[F:21][C:20]([F:23])([F:22])[C:15]1[CH:14]=[CH:13][C:12]2[S:11][C:10]3[C:19]4=[C:6]([C:5](=[O:24])[NH:4][C:3](=[O:28])[N:18]4[C:17]=2[CH:16]=1)[CH:7]=[CH:8][CH:9]=3
Reactant: CCO
Reactant: CSc1nc(=O)c2cccc3c2n1-c1cc(C(F)(F)F)ccc1S3
Agent: Cl
Product: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2

Procedure:
A stirred suspension of 53.6 g. (0.146 mol.) of 1-methylmercapto-10-trifluoromethyl-3H-pyrimido[5,4,3-kl]phenothiazine-3-one in 240 ml. of concentrated hydrochloric acid and 800 ml. of ethanol was heated under reflux for four hours. The reaction mixture was concentrated to approximately one-half its original volume by boiling off the excess solvents and chilled. The product was collected by filtration and washed thoroughly with water to give the title compound, m.p. 278°-280° (ethanol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([OH:32])=O)=[N:28][CH:29]=1.[F:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38]2.O>CN(C=O)C>[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([N:40]2[C:41]3[C:37](=[CH:36][C:35]([F:34])=[CH:43][CH:42]=3)[CH2:38][CH2:39]2)=[O:32])=[N:28][CH:29]=1
Reactant: O=C(O)c1cc(Cl)c(Br)cn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.75 mg (2.3 mmol) TBTU were added to 0.50 g (2.1 mmol) 5-bromo-4-chloro-pyridine-2-carboxylic acid, 0.29 g (2.1 mmol) 5-fluoro-2,3-dihydro-1H-indole and 0.62 mL (4.4 mmol) TEA in 11 mL DMF and the mixture was stirred overnight at RT. Then the reaction mixture was combined with water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH3:12])[C:3]=1[C:4]#[N:5].CN(C)C(=O)C.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[C:4]([NH2:5])=[CH:12][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]1)=[N:10]2
Reactant: CC(=Nc1cccc(Cl)c1C#N)N1CCCc2ccccc2C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCCc3ccccc3C2)nc2cccc(Cl)c12
Temperature: 160 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
The mixture of 2-chloro-6-{[1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethylidene]amino}benzonitrile (6 g, 18.5 mmol), zinc chloride (2.52 g, 18.5 mmol) and N,N-dimethyl-acetamide (18 mL) was heated with stirring at 160° C. for 3 hours under argon. After the reaction was allowed to cool to about 40° C., sodium hydroxide (2 N, 20 mL) was added and then stirred for 10 minutes at room temperature. The reaction mixture was poured into water and the solid was collected by filtration, washed with water and dried in vacuo to give 5 g of product as an off-white powder (yield was 83.3%). MS obsd. (ESI+) [(M+H)+] 324.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]([CH2:26][N:27]3[CH2:32][CH2:31][S:30](=[O:41])[CH2:29][CH2:28]3)[CH2:24][N:25]=1)=[CH:17]2)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of N-methyl-N-{2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (180 mg) in dichloromethane (8 mL) was added m-chloroperbenzoic acid (75 mL) under ice-cooling, and the mixture was stirred for 3 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=6:4-9:1), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (39 mg, yield: 21%) as colorless needle crystals. MS: 504 (MH+). melting point 193-194° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=1)#[N:2].CO.[OH-].[Na+].[H][H]>[Cr].[Ni].C1(C)C=CC=C(C)C=1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: [H][H]
Reactant: N#Cc1cc(C#N)cc(C#N)c1
Agent: [Cr]
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: Cc1cccc(C)c1
Product: NCc1cc(CN)cc(CN)c1
Yield: 81 %

Procedure:
1000 g of 1,3,5-tricyanobenzene (MTN) was charged in an autoclave having a 20 l capacity together with 400 g of Raney nickel-chromium catalyst (atomic ratio Ni:Cr=49:1), 1800 ml of methanol, 4.2 l of m-xylene and 32.6 g of sodium hydroxide. Hydrogen was injected thereinto under an initial pressure of 140 kg/cm2G and reaction was effected at 60°-102° C. to cause absorption of nearly theoretical amount of hydrogen for 31 minutes. The catalyst was filtered off and the solvent was distilled out. Then, distillation under reduced pressure was effected to obtain 874 g of colorless crystal of 1,3,5-tris(aminomethyl)benzene (MTA). The product had a melting point of 49°-51° C. and a boiling point of 136°-139° C./0.4 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:1][C:39]3[CH:40]=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: 135 °C
Yield: 64.3 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 500 mg, 1.49 mmol), CuI (85.2 mg, 0.45 mmol), Cs2CO3 (971.6 mg, 2.98 mmol) and 2-(dimethylamino)acetic acid (76.87 mg, 0.75 mmol) in dioxane (20 mL) was added 3-bromo-5-(trifluoromethyl)pyridine (842.9 mg, 3.73 mmol). The reaction was heated at 135° C. for 5 hours, followed by heating at 100° C. for 18 h, cooled to RT and diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (460 mg, 64.2% yield) as a yellow oil. LCMS MH+ 397 and TR=1.540 min.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:2](=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([CH3:4])[CH3:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Temperature: 90 °C
Yield: 32.3 %

Procedure:
Diethyl isopropylidenemalonate was prepared according to the procedure of E. L. Eliel, R. O. Hutchins, and Sr. M. Knoeber, Organic Synthesis Coll. Vol. VI, 442, 1988, with following modifications. A mixture of acetone (54 g, 0.93 mol, Mallinckrodt), diethyl malonate (100 g, 0.62 mol, Aldrich), acetic anhydride (80 g, 0.78 mol, Mallinckrodt), and zinc chloride (12.5 g, 0.78 mol, Aldrich) was refluxed (90° C. oil bath) for 18 h while protected from moisture. The reaction solution was diluted with dichloromethane (500 ml) and washed with cold water (3×50 ml). The aqueous washes were combined and extracted with dichloromethane. All dichloromethane layers were combined and concentrated by spin evaporation in vacuo. The residual oil was distilled under vacuum and the fractions boiling at 102°-138° C. at 12 Torr were combined with the pot residue and heated for 6 h with a 200° C. oil bath. The dark oil was redistilled to give 40.1 g (32%) of diethyl isopropylidenemalonate as a clear oil: b.p., 110°-115° C./12 mmHg;
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][CH2:8][C@H:9]([NH:20][C:21](=[O:35])[C@@H:22]([NH:26][CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33])[CH2:23][O:24][CH3:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:36][C:37]1[S:38][C:39]([C:42](O)=[O:43])=[CH:40][N:41]=1.N1C=CC=CC=1>C(Cl)Cl.Cl>[CH3:6][O:7][CH2:8][C@H:9]([NH:20][C:21](=[O:35])[C@@H:22]([N:26]([CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33])[C:42]([C:39]1[S:38][C:37]([CH3:36])=[N:41][CH:40]=1)=[O:43])[CH2:23][O:24][CH3:25])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: Cc1ncc(C(=O)O)s1
Reactant: COC[C@H](NCc1oc(=O)oc1C)C(=O)N[C@@H](COC)C(=O)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC[C@H](NC(=O)[C@H](COC)N(Cc1oc(=O)oc1C)C(=O)c1cnc(C)s1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
Referring to FIG. 38, phosphorous oxychloride (323 μL, 3.46 mmol) was added dropwise to (S)-benzyl 3-methoxy-2-((S)-3-methoxy-2-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)propanoate (1.46 g, 3.46 mmol), 2-methylthiazole-5-carboxylic acid (248 mg, 3.46 mmol) and pyridine (1.07 mL, 10 mmol) in DCM (20 ml) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, diluted with 1N HCl, and extracted with DCM. The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to give the product as a white solid (346 mg, 22%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:14][CH2:13][C:12]1[CH:18]=[CH:19][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a stirred solution of ethyl 6-(bis(tert-butoxycarbonyl)amino)nicotinate 115 (300 g, 819 mmol) in THF (1.2 L) was added LiAlH4 (57.6 g, 1.51 mol) in THF (3 L) over a period of 30 min at 0° C. The reaction mixture was stirred for 6 h, and H2O (30.0 ml) and 10% NaOH solution (60.0 mL) were added. The solids were removed by filtration and the filtrate was dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (CH2Cl2; MeOH=40:1) to give 116 (85.0 g, 46% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][CH2:11][CH:12]([OH:14])[CH3:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][CH2:11][CH:12]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(CNc1c(Cl)cccc1Cl)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
5.0 g (19.5 mmoles) of 1-(2,6-dichlorophenyl-amino)-2-propanol hydrochloride are added in small portions to 50 ml of dry pyridine, and then 3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, within 0.5 hours, to the mixture at 15° C. The mixture is stirred at room temperature for one hour, then further 0.8 ml (1.2 g, 10 mmoles) of methanesulfonyl chloride are added, and stirring is continued for one hour. The mixture is poured then onto 100 ml of ice water, and the aqueous mixture is extracted thrice with 70 ml of 1,2-dichloroethane, each. The dichloroethane solutions are combined, washed thrice with 50 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 5.52 g (79.5%) of 1-(2,6-dichlorophenyl-amino)-2-methanesulfonyloxy-propane are obtained as a dark yellow oil; this substance can be utilized in the subsequent reaction without purification.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:28]O2)[N:21]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([O:14][C:12]([C@@H:11]1[CH2:28][C@H:26]1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Fc1cccc(C2CO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
To a suspension of NaH (60% oil dispersion, 320 mg, 8 mmol) in toluene (10 mL) was added dropwise t-butyl diethylphosphonoacetate (1.92 g, 7.6 mmol). The resulting mixture was stirred at rt for 10 min., then a solution of 2-fluoro-6-oxiranyl-pyridine (530 mg, 3.8 mmol) in toluene (5 mL) was added dropwise to the reaction mixture. The resulting mixture was then heated at reflux for 12 h. The mixture was cooled to rt and diluted with EtOAc and washed with NH4Cl (saturated) and water. The EtOAc layer was dried (Na2SO4). The solvent was removed and the residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (165 mg). MS (MH+ 238).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 67.9 %

Procedure:
The methyl 2-benzyl-3-(t-butyldimethylsilyloxy)propionate (3.3 g) was dissolved in 100 ml of methanol, cooled to 0° C. and treated with 50 ml of 30% potassium hydroxide with vigorous stirring. The reaction was then allowed to warm to room temperature over five hours. The reaction was diluted with 200 ml of water, rinsed with diethyl ether, and the aqueous solution was cooled to 0° C. Dichloromethane (100 ml) was added, followed by the slow addition of 260 ml of 1M hydrochloric acid, with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by radial chromatography (2% to 4% methyl alcohol in chloroform, 4 mm plate) to yield 2.14 g of the 2-benzyl-3-(t-butyldimethylsilyloxy)propionic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:17])=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:17])=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: Cc1c(NC(=O)C2CC2)nc2ccc(O)cn12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of N-(6-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (65 mg, 0.281 mmol) and 1,2-difluoro-4-nitrobenzene (37 μL, 0.337 mmol) in dimethyl sulfoxide (1 mL) was added cesium carbonate (137 mg, 0.422 mmol), and the mixture was stirred overnight at room temperature. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1→ethyl acetate alone) to give the title compound (80 mg, 77%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C)C=O.Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:22][CH:18]([F:23])[O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OC(F)F
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 94.9 %

Procedure:
To a mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (2.00 g), N,N-dimethylformamide (54.0 mL) and water (6.00 mL), sodium chlorodifluoroacetate (6.09 g) and potassium carbonate (3.68 g) were added and the mixture was stirred at 120° C. for 4.5 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water four times and thereafter washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed by filtration and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3-88:12) to give the titled compound as a colorless solid (2.53 g).
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:18](=O)[CH3:19])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[C:18]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][O:16][CH3:17])=[C:8]([O:7][CH3:6])[CH:9]=1)([CH3:19])=[CH2:2]
Reactant: [Li]CCCC
Reactant: COCOc1ccc(C(C)=O)cc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCOC)c(OC)c1
Temperature: -80 °C
Reaction time: 12 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.1 g, 3.09 mmol, 1.3 eq.) in 5 mL dry THF cooled to −80° C. was slowly treated with BuLi (1.94 mL of a 1.6 m solution in hexane, 1.3 eq.). To this yellow suspension a solution of 1-(3-methoxy-4-methoxymethoxy-phenyl)-ethanone (500 mg, 2.38 mmol, 1 eq.) in 5 mL dry THF was added and the reaction mixture was allowed to warm to r.t. where stirring was continued for 12 h. The suspension was filtered and the solvent was evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 6:1) to yield the desired product as a color-less oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 105 °C

Procedure:
A mixture of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]benzothiazol-2-ylamine, (Example 65), (97 mg, 0.25 mmol) and acetic anhydride (0.24 mL, 2.5 mmol) was heated in a 105° C. oil bath for 8 h. The solvent was evaporated and the solid that formed was recrystallized from EtOAc/hexanes, and dried under vacuum to give the title compound. MS (ESI, pos. ion) m/z: 431 (M+1). Mp: 219.0–220.5° C. Anal. Calcd for C20H13F3N4O2S.0.75 H2O: C, 54.11; H, 3.29; N, 12.62; S, 7.22. Found: C, 54.12; H, 3.07; N, 12.61; S, 7.30.