Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1.C(O)C.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:26]([C:29]1[CH:34]=[C:33]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])[CH3:27]
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: CC(=O)c1cccc(B(O)O)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
Solvent: CCO
Product: CC(=O)c1cccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 130 mg of 3-acetylbenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate=2:1) to afford 100 mg of 4-(3-acetylphenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 189-190° C. NMR: δ1.60 (s, 6H), 2.59 (s, 3H), 3.07 (s, 3H), 7.48 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.90 (m, 2H), 7.94 (d, J=8.4 Hz, 2H). IR (cm−1): 1690, 1620, 1589, 1149, 958, 770.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:14]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:13][N:12]=[N:11]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)[CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: O
Solvent: CO
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilution with water and acidification, the solid formed was filtered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at 60° C. for 2-3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz), 7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H, J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:30](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:6])=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To a solution of trimethylsilylethyl acetoacetate (10.6 g, 50.0 mmol) and triethylamine (7.10 mL, 51.5 mmol) in acetonitrile (85 mL) was added in an ice-bath p-toluenesulfonyl azide (10.0 g, 50.7 mmol) and the reaction mixture stirred at room temperature for 20 h. After evaporation of the solvent in vacuo, the residue was extracted with Et2O (90 mL) and this extract was washed with a solution of KOH (3.0 g) in H2O (83 mL) and again a solution of KOH (0.9 g) in H2O (30 mL), then brine, and dried (Na2SO4). Evaporation of the solvent in vacuo gave 11.6 g of a crude oil which was purified by column chromatography (SiO2, 150 g) eluting with 20% EtOAc/Hexanes, to obtain 9.65 g (42.3 mmol, yield 84.5%) of the title compound as yellowish oil: Rf 0.44 (20% EtOAc/Hex); ir (neat)νmax : 2130 (C=N2), 1715 (ester), and 1660 (ketone) cm-1 ; uv (CH2Cl2)λmax : 257 nm (ε7200); 1Hmr (CDCl3)δ: 0.07 (9H, s, SiMe3), 1.03 (2H, `t` J=8 Hz, CH2Si), 2.47 (3H, s, COCH3), and 4.30 (2H, `t` J=8 Hz, CO2CH2 ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17](=[S:20])[NH:18][NH2:19]>C(O)C.ClCCl>[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17]1[S:20][C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:19][N:18]=1
Reactant: COCOCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Solvent: ClCCl
Product: COCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 2-(methoxymethoxy)-1-phenylethanone (600 mg, 3.33 mmol) in ethanol/dichloromethane (12 mL, 3:1) was added 2,5-difluorobenzothiohydrazide (627 mg, 3.33 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to afford the product (734 mg, 63%) as a yellow oil.
Reaction SMILES: Cl.[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]#CBr>C(Cl)(Cl)Cl>[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]#[N:32])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Yield: 28.2 %

Procedure:
A sample of 8.4 g of 1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride was converted to its free base and the base was dissolved in 135 ml of chloroform. The solution was stirred and 4.0 g of potassium carbonate was added followed by 2.7 g of cyanogen bromide. The reaction mixture was stirred under reflux for 16 hrs. The mixture was filtered, and the solvent was removed in vacuo. The mixture was chromatographed on a high-pressure column chromatography apparatus (silica gel), eluting with 0.3% methanol/dichloromethane. Evaporation of the appropriate fraction followed by recrystallization from toluene hexane yielded 2.2 g (28%) of the product, mp 144°-146° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>O1CCCC1.CO>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)sc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To 2-{4-[2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (470 mg, 0.94 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added 2 mL of a 5N NaOH solution. After 24 h, the solution was concentrated in vacuo. The residue was partioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to afford 385 mg (87% yield) of 2-{4-[2-(2-biphenyl-3-yl-5-methyl-thiazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.78 (d, 1H), 7.61-7.55 (m, 3H), 7.45-7.40 (m, 3H), 7.35-7.31 (m, 1H), 6.86-6.82 (m, 2H), 6.79-6.76 (m, 2H), 4.24 (t, 2H), 3.16 (t, 2H), 2.43 (s, 3H), 1.46 (s, 6H). MS EI+ (m/e) 474.1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[CH3:31])/[S:3]1.[C:35]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[C:14]([CH3:31])=[C:13]([O:12][C:11]3[CH:32]=[CH:33][CH:34]=[C:9](/[CH:8]=[C:4]4/[C:5](=[O:7])[N:6]([CH3:35])[C:2](=[O:1])[S:3]/4)[CH:10]=3)[N:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)N(C)C4=O)c3)c2C)CC1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution (Z)-ethyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (300 mg, 0.0006198 mole) in dimethyl acetamide (10 ml), K2CO3 (171 mg, 0.001239 mole) was added followed by addition of methyl iodide (0.060 ml, 0.0009297 mole) at 0° C. and reaction mixture was stirred at 27° C. for 30 minutes. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. Organic layer was washed with water and brine, dried over sodium sulfate and evaporated on a rotavpour to yield the product as yellow solid (300 mg).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[OH:10][CH2:11][CH2:12][O:13][C:14](=[O:28])[NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[O:23][CH2:24][CH2:25][OH:26]>CC(C)=O.O>[OH:10][CH2:11][CH2:12][O:13][C:14]([NH:15][CH2:16][CH2:17][N:18]([C:8]1[N:1]=[C:2]([N:18]([CH2:17][CH2:16][NH:15][C:14]([O:13][CH2:12][CH2:11][OH:10])=[O:28])[CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH2:25][OH:26])=[O:27])[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH2:25][OH:26])=[O:27])=[O:28]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCCNCCNC(=O)OCCO)OCCO
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 50 g water in a 3-neck flask equipped with stirrer and a thermometer, were added 9.2 g (0.05 m) of cyanuric chloride, dissolved in 50 g acetone below 10° C. To the white slurry of cyanuric chloride, 27.9 g of bis(2-hydroxyethyl)(iminodiethylene)biscarbamate (HEC), NH(CH2CH2NHCO2CH2CH2OH)2 dissolved in 50 g of water was added over a period of 15 minutes. During the addition, the reaction temperature was maintained below 12° C. After complete addition of HEC, the slurry turned into a clear solution. To this was added 10% caustic to maintain the reaction pH at about 7 and the reaction mixture was allowed to warm up to 25° C. At 25° C., as the reaction progressed, a white crystalline solid slowly separated out. After 4 hrs. at 25°-35° C., the solids were separated by filtration, washed with water and recrystallized from ethanol. The product yield was 24 g and m.p. 174° C. The structure of the product was confirmed by nuclear magnetic resonance (nmr) and fast atomic bombardment (fab), mass spectrometry to be that of FORMULA I: ##STR20##
Reaction SMILES: [C:1]([C:5]1([NH2:13])[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][CH:6]1[CH3:12])([CH3:4])([CH3:3])[CH3:2].C1(C)C(N)=CC=CC=1N.CC(=C)C>>[CH3:3][C:1](=[CH2:2])[CH3:4].[C:6]1([CH3:12])[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=1[NH2:13]
Reactant: CC1C=CC=C(N)C1(N)C(C)(C)C
Agent: C=C(C)C
Agent: Cc1c(N)cccc1N
Product: Cc1cccc(N)c1N
Temperature: 200 °C

Procedure:
Synthesis of the above recited ortho-tert-butyltoluenediamine was carried out in a 1 gallon stainless steel pressure vessel equipped with a mechanical stirrer. The vessel was charged with a 150 gram portion of a powdered commercially available silica-alumina catalyst containing 13% alumina and 1500 grams (12.24 moles) of 2,6-toluenediamine. The autoclave was sealed and purged with nitrogen. A residual blanket of nitrogen was left in the autoclave, leaving the pressure at 16 psig. The contents of the reactor were heated to a temperature of 200° C. with constant agitation. Isobutylene was then introduced into the reactor and 870 grams or 15.5 moles were added over a 30 minute period resulting in an initial reaction pressure of 970 psig. This provided a mole ratio of 1.26:1 isobutylene to toluenediamine. The reaction mixture was maintained at 200° C. for about 45 hours with constant agitation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
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: C1COCCO1
Product: Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A solution of 4-bromo-2-nitro-phenylamine (2.17 g, 10.0 mmol) in dioxane (40 mL) was treated with 2-fluorophenylboronic acid (1.40 g, 10.0 mmol) and NaHCO3 (40.0 mL, 80.0 mmol, 2M aqueous). The mixture was degassed via sonication and flushed with Ar. Pd(PPh3)4 (116 mg, 0.100 mmol) was added, and the mixture was heated to 80° C. for 12 h. The mixture was diluted with water (40 mL) and extracted twice with EtOAc (40 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (EtOAc/hexanes, 0:1 to 1:1, v/v) to obtain 1.80 g (78%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.36 (d, J=1.8 Hz, 1H), 7.64 (dt, J=8.6, 2.0 Hz, 1H), 7.45 (td, J=7.8, 1.8 Hz, 1H), 7.30-7.38 (m, 1H), 7.13-7.27 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.18 (br. s., 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.7) (0.19 g, 0.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.15 g, 0.6 mmol) according to the general procedure III. Obtained as off-white solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[C:28]#[CH:29]>O>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[C:28]#[CH:29]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2-propyne-1-ol was stirred while heating at 100° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.20 g of 2-(3-(2-propyne-1-yloxy)pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 73”).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:36]>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([C:25]([OH:36])([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1cc(C(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(O)(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A solution of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (139.1 mg; 0.3317 mmol) in dichloromethane (5 mL; 78.00 mmol) was treated with Dess-Martin periodinane (172.7 mg; 0.3950 mmol) and stirred at room temperature. After 3 hours, additional Dess-Martin periodinane was added (142 mg). After an additional 5 hours, 30 mL of 10% aqueous sodium thiosulfate was added and the reaction mixture stirred for 10 minutes. The reaction mixture was washed with 2 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated to yield 113.8 mg (79%) of the title compound. LCMS (ESI): M+H=436.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([C@@H:19]1[O:23][C:22](=[O:24])[C@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[C:15]([C@@H:19]1[O:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:24])[C@@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@@]1(C)O[C@H](C(C)(C)C)OC1=O
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@]1(C)O[C@H](C(C)(C)C)OC1(O)c1ccc(SC)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromothioanisole (48.5 g) in THF (600 mL) was cooled to -70° C. and a 2.5M solution of n-butyllithium in hexane (96 mL) was slowly added over 20 min. The resulting suspension was stirred for 1 h allowing the temperature of the cooling bath to raise to -50° C. It was then cooled back to -70° C. and a solution of dioxolanone from Step 2 (29.8 g) in TBF (100 mL) was added dropwise over 30 min. The reaction was allowed to proceed for another 30 min. and then quenched with AcOH (23 mL) always at -70° C. The reaction mixture was allowed to warm to r.t., diluted with a 25% aqueous solution of NH4OAc and extracted with EtOAc (2 L). The organic layer was dried over MgSO4 and concentrated. The resulting crude product was purified by flash chromatography (2→3→5→7% EtOAc in hexane) to give a light yellow solid. 1H NMR(CD3COCD3): mixture of diastereomers δ0.50 (0.5H, m), 0.68 (1.5H, s), 0.72 (1.5H, t), 0.97 (1.5H, t), 0.98 (9H, s), 1.38 (1.5H, s), 1.52 m), 1.68 (0.5H, m), 2.10 (0.5H, m), 2.48 (3H, 2s), 4.85 (1H, s, OH), 5.01 (0.5H, s), 5.32 (0.5H, s), 7.22-7.30 (2H, m), 7.50 (2H, dd).
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].NN>C(O)C>[C:1]1([S:7]([NH:10][N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NNS(=O)(=O)c1ccccc1
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(C=NNS(=O)(=O)c2ccccc2)cc1

Procedure:
Benzenesulfonyl hydrazine (20.5 g, 0.12 mole) was dissolved by warming in 110 ml absolute ethanol. p-Cyanobenzaldehyde (15.6 g, 0.12 mole) was separately dissolved in 50 ml of hot ethanol and added to the hydrazine solution The resulting slurry was refluxed 0.5 hour, cooled and filtered to yield 28.1 g; m.p. 209°-213°. Recrystallization from CH3CN gave purified title product: 23.7 g; m.p. 210°-213°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:13][C:2]([F:12])([F:1])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccc(SC(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of 4-(trifluromethylthio)benzylamine (250 mg, 1.21 mmol), benzoyl chloride (178 mg, 1.27 mmol) and sodium bicarbonate (508 mg, 6.05 mmol) in DCM (15 mL) was stirred at rt until the reaction completed. The reaction was diluted with ethyl acetate, washed with brine and dried to give 372 mg (99%) of N-(4-trifluoromethylthiobenzyl)benzamide as a white solid. 1HNMR (360 MHz, DMSO-d6) δ 9.07 (m, 1H, NH), 7.88-7.90 (m, 2H), 7.66-7.68 (d, J=8.7 Hz, 2H), 7.45-7.56 (m, 5H), 4.53 (d, J=6.1 Hz, NCH2, 2H). MS-EI m/z 311 [M+].