Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[CH:10]1([C:7]2[CH:8]=[CH:9][C:2]([NH:1][C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[N+:21]([O-:23])=[O:22])=[C:3]([CH:6]=2)[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1cc(C2CC2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C2CC2)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Heat a solution of 2-amino-5-cyclopropyl-benzonitrile (0.980 g, 6.16 mmol) with 2,4-difluoro-1-nitro-benzene (0.676 g, 6.16 mmol) and lithium hydroxide monohydrate (0.517 g, 12.33 mmol) in DMSO (12 ml) to 55° C. for 18 hours. Cool the reaction to ambient temperature and then add approximately 150 ml of ice water and stir the mixture for one hour. Precipitate the title compound and collect by filtration. Purify the solid via flash chromatography eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.452 g (1.52 mmol, 25% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 298 (M+1).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[C:13]([F:14])=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:12]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:13]([F:14])[C:8]=2[F:7])=[CH:19][CH:20]=1)[CH3:25]
Reactant: Brc1ccc[se]1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1

Procedure:
A mixture of 56.0 g (0.27 mol) of 2-bromoselenophene, 70.0 g (0.27 mol) of 2,3-difluoro-4′-ethylbiphenyl-4-ylboronic acid, 22.0 g (19.0 mmol) of tetrakis(triphenylphosphine)palladium(0) and 800 ml of 2 N sodium carbonate soln. in 2.5 l of toluene/ethanol (1:1) is heated at 90° C. for 17 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-selenophene is obtained as a yellowish solid.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][OH:15])[NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:9]2
Reactant: OCc1cc2c(OCC3CO3)cccc2[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc2c(OCC3CO3)cccc2[nH]1

Procedure:
11.5 g. 4-(2,3-epoxypropoxy)-2-hydroxymethyl-indole (see U.S. Pat. No. 3,705,907) were dissolved in 100 ml. pyridine. To this solution were added dropwise, while cooling to 0°-5° C., 6.5 g. (6.7 ml.) pivaloyl chloride. After an hour, the reaction mixture was poured on to ice and extracted with diethyl ether. The ethereal solution was successively washed with dilute sulfuric acid, aqueous sodium bicarbonate solution and water. After drying and treating with active charcoal, the solution was filtered and evaporated. The residue (13 g.; 82% of theory) crystallized upon triturating with diethyl ether/ligroin to give 4-(2,3-epoxypropoxy)-2-pivaloyloxymethyl-indole; m.p. 129°-131° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(N)cc1
Yield: 69 %

Procedure:
A mixture of (E)-ethyl 3-(4-nitrophenyl)acrylate (commercially available from Aldrich, 5.00 g, 26.0 mmol) and 2.8 g of 10% Pd/C (wet, 50% water) in MeOH (26 mL) was shaken under 20 psi of hydrogen at room temperature for 20 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated, and the residue was purified through a short column of silica gel using 20% EtOAc/hexane as the eluent to give 3.48 g (69%) of the desired product ethyl 3-(4-aminophenyl)propanoate 47.2. MS ESI (pos.) m/e: 194 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C=CC(C2C=CC(C3OC(C4C=CC=CC=4)=CN=3)=CC=2)=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:36][CH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Agent: c1ccc(-c2ccc(-c3ncc(-c4ccccc4)o3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1[nH]c(CBr)cc2ccccc12
Temperature: 25 °C

Procedure:
To a refluxing solution of 3-methylisoquinolin-1(2H)-one (1.7 g, 10.69 mmol) and 2-(4-biphenyl)-5-phenyloxazole (120 mg) in CCl4 (30 mL) was added N-bromosuccinimide (1.9 g, 10.7 mmol) in portions. The reaction mixture was stirred at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and concentrated to give the crude product, which was used for the next step without further purification. LC-MS: m/z 238 (M+H+).
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][NH:12][C:11]2=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[Cl:21])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Temperature: 110 °C
Yield: 77.8 %

Procedure:
To a mixture of 5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (300 mg, 1.20 mmol), phosphorus oxychloride (2.0 mL, 21.4 mmol) and DIEA (0.5 mL, 2.80 mmol) was added toluene (10 mL). The reaction was heated at 110° C. for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated and dried with sodium sulfate, concentrated in vacuo and purified by silica gel flash chromatography (eluted with 1–25% EtOAc/CH2Cl2) to give the title compound (250 mg, 78%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](O)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]([F:33])([F:32])[F:31].CCN(CC)CC.CCCP(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O.O>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([CH2:8][C:4]4[CH:3]=[C:2]([OH:1])[N:7]=[CH:6][N:5]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:20])=[CH:25][C:24]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Reaction time: 0.33 h

Procedure:
345 mg (1.23 mMol) 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (Step 3.8), 193 μl (1.5 mMol) 4-fluoro-3-trifluoromethyl-aniline, 1.7 ml (12.3 mMol) Et3N and 63 mg (0.52 mMol) DMAP are dissolved in 10 ml of dry DMF. Then a solution of 1.45 ml (50% in DMF; 2.48 mMol) propylphosphonic anhydride is added. After 20 min, the reaction mixture is poured into water, brine and EtOAc. The separated aq. phase is extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH 1:19) gives the title compound: MS: [M+1]+=442; TLC (CH2Cl2/MeOH 1:9): Rf=0.37; 1H-NMR (DMSO-d6): δ ppm 12.43 (s, 1H), 10.92 (s, HN), 8.36 (m, 1H), 8.17 (d, 1H), 8.11 (m, 3H), 7.92 (s, 1H), 7.78 (d, 1H), 7.7-7.5 (m, 3H), 6.25 (s, 1H), 3.99 (s, H2C).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22](O)=[O:23])=[C:20]([CH3:29])[CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[C:21]([C:22]([NH:1][CH:2]([C:3]2([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:23])=[C:20]([CH3:29])[CH:19]=1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: CSc1cc(Cl)cc(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CSc1cc(Cl)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (203 mg; 0.93 mmol), 4-chloro-2-methyl-6-(methylthio)benzoic acid (obtainable as described in F. P. Doyle, J. H. C. Nayler, H. R. J. Waddington, J. C. Hanson and G. R. Thomas. J. Chem. Soc. 1963, 497) (202 mg; 0.93 mmol), EDC (178 mg; 0.93 mmol) and HOBt (143 mg; 0.93 mmol) in DCM (20 ml) was stirred at room temperature for 4 h and then stood at room temperature for 90 h. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate (50 ml) and the organic layer separated by passage through a phase separation cartridge. The organic layer was evaporated, the residue dissolved in a minimum of DCM and chromatographed on silica gel, eluting with 0-100% ethyl acetate-pentane. The fractions were combined and evaporated under reduced pressure to afford the title compound (200 mg; 52%). 1H NMR (CDCl3) δ: 0.90-1.10 (1H, m), 1.38-1.55 (3H, m), 1.60-1.76 (2H, m), 1.80-1.90 (2H, m), 2.21 (6H, s), 2.26 (3H, s), 2.47 (3H, s), 5.11 (1H, d, J=6 Hz), 6.94 (1H, d, J=5.2 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.20-7.35 (3H, m), 7.40-7.50 (2H, m). Mass spectrum (Electrospray LC/MS), ES+: Found 417 (MH+). C23H2935ClN2OS requires 416. Ret. time 2.03 min. The title product was converted to its corresponding hydrochloride salt (210 mg).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:51]([NH:53][CH3:54])[CH3:52]>C(Cl)(Cl)Cl>[CH2:51]([N:53]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29])[CH3:54])[CH3:52]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Reactant: CCNC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CC
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In 3 ml of chloroform was dissolved 131 mg (0.170 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl) carbamoylglycerol followed by addition of 470 mg (7.951 mmol) of N-ethylmethylamine and the reaction was conducted in a sealed tube at 80° C. overnight. This reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 104 mg (81.5%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:22]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CCc1ccc(O)cc1
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 4-ethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.0 g) as yellow oil in 82% yield: 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.63 (s, 2H), 2.64 (q, J=7.5 Hz, 2H), 2.47 (s, 3H), 2.21 (s, 6H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11]CC)=O)[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl.O1CCCC1>[CH3:46][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:11][CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:14])[F:15])=[N:4]2)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: CCOC(=O)Cn1ccc(C(F)(F)F)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2ccc(C(F)(F)F)n2)cc1

Procedure:
To a tetrahydrofuran solution (4 mL) of the crude product of ethyl 2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetate synthesized in Reference Synthesis Example 53, lithium aluminum hydride (40 mg, 1.05 mmol) was added at 0° C. and the resultant solution was stirred for 3 hours. After completion of the reaction, saturated sodium sulfate aqueous solution was added to the reaction solution and the resultant mixture was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure. Subsequently, to a dichloromethane solution (2 mL) of the obtained residue, triethylamine (80 μL, 0.57 mmol) and p-toluenesulfonyl chloride (300 mg, 1.57 mmol) were added and the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and used in the next reaction.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([NH2:13])=[N:12][C:7]2=[CH:6][CH:5]=1.[N:15]1([C:20](N2C=CN=C2)=[S:21])[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C>[F:14][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([NH:13][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:21])=[N:12][C:7]2=[CH:6][CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)F)nc2s1
Solvent: CC#N
Product: FC(F)Oc1ccc2nc(NC(=S)n3ccnc3)sc2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (310 mg, 1.43 mmol) and di(1H-imidazol-1-yl)methanethione (311 mg, 1.75 mmol) were dissolved in acetonitrile (5 mL) and heated to 70° C. in a sealed vial for 10 hours. The vial was then stored in the freezer for 16 hours. The solids were collected by filtration and washed with acetonitrile to afford N-(5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-1H-imidazole-1-carbothioamide (296 mg, 0.72 mmol, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (d, J=4.77 Hz, 1 H), 8.06 (d, J=8.53 Hz, 1 H), 8.01 (s, 1H), 7.72 (s, 1 H), 7.54 (s, 1 H), 6.94-7.13 (m, 1 H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH:13]([OH:17])[C:14](O)=[O:15])[CH:8]=[CH:9][CH:10]=1>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH:13]([OH:17])[C:14](=[O:15])[NH:2][N:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: O=C(CC(O)C(=O)O)c1cccc(Br)c1
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2cccc(Br)c2)CC1O
Temperature: 65 °C
Yield: 58.2 %

Procedure:
0.25 g of hydrazine hydrate was added, at room temperature, to a mixture of 10 ml of ethanol and 1.36 g of 4-(3-bromophenyl)-2-hydroxy-4-oxobutyric acid (prepared following the procedure described in Preparation 3), and then the mixture was heated at 65° C. for 1.5 hours. The crystals which precipitated were collected by filtration at the same temperature and then washed with ethanol, giving 0.78 g (yield 58%) of the pure title compound melting at 158°-161° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH:11]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.C(N(C(C)C)CC)(C)C.C1([O:43][C:44](=O)[NH:45][C:46]2[S:47][C:48]3[N:49]=[CH:50][N:51]=[C:52]([O:55][CH3:56])[C:53]=3[N:54]=2)C=CC=CC=1>C(#N)C>[CH3:56][O:55][C:52]1[C:53]2[N:54]=[C:46]([NH:45][C:44]([N:25]3[CH2:26][CH2:27][N:22]([CH:11]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=4)[CH2:10][O:9][CH3:8])[CH2:23][CH2:24]3)=[O:43])[S:47][C:48]=2[N:49]=[CH:50][N:51]=1
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Reactant: COCC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)Nc2nc3c(OC)ncnc3s2)CC1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A mixture of 1-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine trifluoroacetate (160 mg, 0.40 mmol) and diisopropylethylamine (0.35 mL, 2.0 mmole) in acetonitrile (10 mL) was heated at 70° C. for ten minutes. After cooling to room temperature, (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (120 mg, 0.40 mmol) was added to the above solution. The mixture was stirred at reflux for three hours. LCMS analysis indicated complete consumption of starting material. The reaction was concentrated and the crude was purified using reversed phase HPLC to give 4-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (81 mg, 41% yield) as a white powder. LRMS for C21H23F3N6O3S (M+H)+ at m/z=497. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(=O)OCC>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCOC(C)=O
Product: c1cnc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)pyrimidine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.65 (m, 4H) 3.80 (m, 4H) 4.04 (s, 2H) 6.63 (t, J=4.92 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.34 (m, 2H) 8.43 (d, J=4.75 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 313 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]2[O:12][CH:11]([CH3:13])[S:10][C:9]=2[C:14]=1[CH3:15])(=O)C.C[O-].[Na+].O.C(O)(=O)C>CO>[OH:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]2[O:12][CH:11]([CH3:13])[S:10][C:9]=2[C:14]=1[CH3:15]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)SC(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(C)O2
Yield: 82.8 %

Procedure:
2.9 g of 5-acetoxy-2,4,6,7-tetramethyl-1,3-benzoxathiole, prepared as described in Example 22, were dissolved in 30 ml of methanol, 1.3 g of sodium methoxide was added to the solution, and the mixture was allowed to react at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water and the solution was neutralized by adding acetic acid. The separated product was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off. The crude product thus obtained was purified by silica gel column chromatography. From the fraction eluted with a 1:1 by volume mixture of hexane and benzene were obtained 2.0 g of the title compound, melting at 125°-127° C.
Reaction SMILES: CNCCNC.[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][NH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>[Cu]Cl.C(#N)C>[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][N:10]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:9]=1
Reactant: CC(=O)Nc1c[nH]nc1Cl
Reactant: Brc1cccnc1
Agent: Cl[Cu]
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C
Yield: 64.3 %

Procedure:
A 100-mL, 3-neck round bottom flask was charged with copper(I) chloride (59.6 mg, 0.602 mmol) and acetonitrile (10 mL), N,N′-dimethyethane-1,2-diamine (106 mg, 1.203 mmol) was added and the mixture was stirred under nitrogen to afford a solution. N-(3-Chloro-1H-pyrazol-4-yl)acetamide (480 mg, 3.01 mmol) and potassium carbonate (831 mg, 6.02 mmol) were added, followed by 3-bromopyridine (570 mg, 3.61 mmol). The mixture was purged with nitrogen three times and heated at 80° C. for 18 hours. Thin layer chromatography analysis [Eluent: ethyl acetate, SM Rf=0.5, Product Rf=0.3] indicated that a trace of starting material remained and a major product formed. It was filtered through a pad of Celite® and the Celite® pad rinsed with acetonitrile (10 mL). The combined filtrates were concentrated to about 5 mL and water (10 mL) was added to the resulting suspension. The suspension was stirred for 1 hour and filtered. The solid was rinsed with water (2×5 mL) and dried under vacuum at room temperature to afford a white solid (458 mg, 64%). Characterization matched sample prepared by previous method.