Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH2:15][CH2:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of methanesulfonyl chloride (0.158 mL, 2.04 mmol) in DCM (1 mL) was added dropwise to a stirred solution of 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (695 mg, 1.70 mmol) and triethylamine (0.473 mL, 3.40 mmol) in DCM (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with DCM (50 mL), and washed with water (50 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (796 mg, 96%).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[C:6]([CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:16](C(O[Na])=O)([F:18])[F:17])([F:15])([F:14])[F:13]>[Cu]I>[F:17][C:16]([F:18])([C:2]1[C:7]([OH:8])=[C:6]([CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1)[C:12]([F:15])([F:14])[F:13]
Reactant: CC(C)c1cccc(Br)c1O
Reactant: O=C(O[Na])C(F)(F)C(F)(F)F
Agent: [Cu]I
Product: CC(C)c1cccc(C(F)(F)C(F)(F)F)c1O

Procedure:
6-Bromo-2-isopropylphenol, made as described in Example 2, was reacted with CF3CF2COONa in the presence of CuI (Freskos J N, Synth Comm 18:965-972, 1988). This reaction resulted in the synthesis of 6-pentafluoroethyl-2-isopropylphenol.
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][OH:12])=[O:10])#[N:2].C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>O1CCCC1>[C:32]([O:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:35])[CH2:33][CH3:34]
Reactant: N#CC(CCCCCC(=O)NO)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)ONC(=O)CCCCCC(C#N)(c1ccccc1)c1ccccc1
Yield: 89.5 %

Procedure:
To a solution of 7-cyano-7,7-diphenylheptanohydroxamic acid (4.0 g, 12.4 mmol) and triethylamine (2.5 g, 25 mmol) in tetrahydrofuran (80 ml) was added, while stirring under ice-cooling, propionyl chloride (1.15 g, 12.4 mmol). The mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, which was washed with 0.5N HCl and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate--hexane to give 4.2 g of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](OC2C=CC([N+]([O-])=O)=CC=2)=[O:18])[CH2:13][N:12]1[C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:18])[CH2:13][N:12]1[C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Product: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-(4-nitro-phenoxycarbonyloxy)-pyrazolidine-1-carboxylic acid benzyl ester, 39, (462 mg, 0.882 mmol) is dissolved in dichloromethane (9 mL). Morpholine (770 μL, 8.82 mmol) is added and the reaction immediately develops a light yellow color. After stirring about 1.5 hours at room temperature, the reaction is diluted with dichloromethane (20 mL) and washed with a 5% solution of Na2CO3 (2×20 mL). The combined aqueous layers are extracted with dichloromethane (20 mL), the organic layers combined, washed with water, brine, and dried. The solvent is removed in vacuo to afford 414 mg of the desired product as a clear oil.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.C(OCC)(=[O:23])C>O1CCCC1.O>[OH:23][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C(O)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
2-Chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (0.1 g, compound No. 2) is dissolved in a mixture of tetrahydrofuran (2 ml) and water (1 ml), and the solution is standed overnight at room temperature. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is dried over anhydrous sodium sulfate, and concentrated in vacuo to give 0.1 g (quant. yield) of the titled compound as amorphous powder.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[CH3:30][S:31]([C:34]1(F)[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: CS(=O)(=O)C1(F)C=CC=CC1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (10 g, 23.7 mmol) obtained in Step 2 and 1-flourophenyl methyl sulfone (4.9 g, 28.4 mmol) in 50 ml of dimethylformamide, was added potassium carbonate (8.2 g, 59.3 mmol). The reaction mixture was stirred overnight at about 100° C., cooled to room temperature, diluted with 200 ml of ethyl acetate, and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 4.9 g of the titled compound as white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[N:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cnc2ccccc2n1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnc5ccccc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoxaline-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][Cl:17])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:19](N)=[NH:20]>C(O)C>[Cl:17][CH2:16][CH2:15][O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:19][N:20]=[C:4]2[OH:5]
Reactant: N=CN
Reactant: COC(=O)c1cc(OCCCl)c(OC)cc1N
Agent: Cl
Solvent: CCO
Product: COc1cc2ncnc(O)c2cc1OCCCl
Temperature: 130 °C
Yield: 86 %

Procedure:
To a solution of methyl 2-amino-5-(2-chloroethoxy)-4-methoxybenzoate (3.61 g, 13.9 mmol) in ethanol was added formamidine hydrochloride and the mixture heated in a sealed tube at 130° C. overnight. The reaction was cooled to room temperatureand filtered to give 6-(2-chloroethoxy)-4-hydroxy-7-methoxyquinazoline (3.05 g, 12.0 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 12.09 (br s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7.16 (s, 1H), 4.36 (t, 2H), 4.00 (t, 2H), 3.92 (s, 3H); LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH3:15][CH:16](O)[CH:17]=[CH2:18]>COC(OC)(C)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(OC)c(OC)cc2C1=O
Yield: 26.5 %

Procedure:
A solution of 20 g of 5,6-dimethoxy-1-indanone, 21.5 ml (0.25 mol) of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 21.5 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 3:2). 6.8 g (27%) of (RS)-2-(2-buten-1-yl)-5,6-dimethoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: Br.CO[C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.[OH-:15].[K+].Cl>O.C(O)(=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH2:4][CH2:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: COc1cc(=O)c2ccccc2o1
Reactant: [OH-]
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCOc2ccc(O)cc21
Yield: 81.2 %

Procedure:
Glacial acetic acid and HBr (>40%) each 20 ml are successively added to methoxy benzopyran-4-one 2.9 g (0.0163 mol), stirred and refluxed for 1 h, and then the reactant liquor is modulated pH for 10-11 by KOH, the water layer is modulated pH for 2-3 by concentrated hydrochloric acid, and then extracted by ethyl acetate; the organic layers are combined and dried over anhydrous Na2SO4, cooled to precipitate black solid, and recrystallized by ethyl acetate, to obtain bright yellow crystal 2.17 g, m.p.: 142-144° C., yield: 81.2%.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl[C:21]1[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:36])[N:22]=1>CN(C=O)C>[Cl:36][C:23]1[N:22]=[C:21]([S:4][CH2:1][CH2:2][CH3:3])[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Reactant: CCCS
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of propane thiol (2.975 mL, 32.89 mmol)l in DMF (25 mL) was added slowly a solution of 1N NaHMDS in THF (33 ml, 33.00 mmol). The mixture was stirred for ten minutes at room temperature and then added slowly to a solution of 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (Intermediate 1, 8.95 g, 32.89 mmol) in DMF (50 mL). The reaction was stirred at room temperature for two hours. The reaction was stopped and most of the THF and DMF was evaporated. The product was extracted with DCM (150 mL), washed with water (2×25 ml) and brine (25 mL). The solution was dried over MgSO4 and evaporated under reduced pressure to give a slightly pink solid. The solid was triturated in hexane and filtered; all of the coloured impurity went into solution to leave a white solid (7.84 g, 76%).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[F:50])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:51][CH3:52])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCOCC1>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[F:50])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:51][CH3:52])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(O)O
Yield: 108.3 %

Procedure:
Di(tert-butyl) ((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (310 mg, 0.41 mmol) in 1,4-dioxane (25 ml) was treated with 4.0 N hydrochloric acid in 1,4-dioxane (0.7 ml, 2.86 mmol) at 20° C. for 18 hours. The solid product was collected by suction filtration and washed successively with 1,4-dioxane (50 ml), acetonitrile (50 ml) then diethyl ether (50 ml), dried in vacuo to give the title compound (287 mg, 97% yield) as a yellow dihydrochloride salt:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C.O>CN(C=O)C.ClCCl>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:16]([CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:5]2=[O:7])([O-:15])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(cccc3[N+](=O)[O-])C2=O)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2.7 g (9.81 mmol) of methyl 2-(bromomethyl)-3-nitrobenzoate (J. Org. Chem., 1999, 9731–9734) and 2.25 g (9.81 mmol) of tert-butyl 4-(2-aminoethyl)-1-piperidinecarboxylate (J. Med. Chem., 1997, 1779–1788) are dissolved in 45 ml of absolute DMF, 2.05 ml of triethylamine are added and the mixture is stirred at 70° C. for 2 h. After cooling, water is added to the reaction mixture. The organic phase is taken up in dichloromethane, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2cccnc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (from MolBridge, 1.0 g, 6.2 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 g, 8.0 mmol) and triethylamine (4.3 mL, 31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (0.78 g, 8.0 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-65% EtOAc/hexane) to give the desired product (1.0 g, 79%). LCMS calculated for C10H12N3O2(M+H)+: m/z=206.1. Found: 206.1.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=2)=[CH:15][CH:16]=1
Reactant: COCCl
Reactant: OCc1ccc(Cc2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCc1ccc(Cc2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
[4-(4-Bromobenzyl)phenyl]methanol (2.7 g, 9.6 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (55%, 0.50 g, 12 mmol) was added at 0° C., followed by stirring at the same temperature for 30 minutes under a nitrogen atmosphere. To the reaction solution at 0° C. was added dropwise a solution of chloromethyl methyl ether (1.0 g, 13 mmol) in tetrahydrofuran (10 mL), followed by stirring at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.55 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.5 g, 7.8 mmol) as a colorless oil (yield 81%).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1)(=O)=O.[OH-:36].[K+]>C1COCC1.O>[OH:36][C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1
Reactant: [OH-]
Reactant: COc1nc(S(C)(=O)=O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 75 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
A magnetically stirred mixture of 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (250 mg, 0.47 mmol) in THF (10 mL) and water (5 mL) was treated with a 2N aqueous KOH solution (0.5 mL, 0.94 mmol). The reaction mixture was stirred at 75° C. for 4 h. The reaction was then cooled to room temperature and poured into water and extracted with methylene chloride. The organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-hydroxy-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (32 mg, 15%) as a white solid. LRMS for C19H18F3N5O4S2 (M+H)+ at m/z=469. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:23]([CH:22]([CH2:25][CH3:26])[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:13]=1[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[N:7]1)[CH3:24]
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Reactant: OB(O)c1ccccc1
Product: CCC(CC)COc1ccc(-c2ccccc2)cc1Cn1nc(CCC(=O)O)cc1C

Procedure:
The title compound was prepared from 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester and benzeneboronic acid using Suzuki chemistry and following the method in Example 1, Step 8.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1[O:8][C:9]2[CH:14]=[CH:13][S:12][C:10]=2[N:11]=1.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:13]1[S:12][C:10]2[N:11]=[C:7]([CH3:6])[O:8][C:9]=2[CH:14]=1
Reactant: Cc1nc2sccc2o1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2sc(Br)cc2o1
Temperature: 25 °C

Procedure:
Sodium acetate (1.4 g) and 2 g of 2-methylthieno[2,3-d]oxazole were dissolved in 24 ml of an acetic acid solvent, and a solution comprised of 15.8 ml of bromine and 7.2 ml of acetic acid was dropwise added thereto with stirring at room temperature. After stirring at room temperature for 2.5 hours, the reaction solution was added to 150 ml of water, followedby further stirring at room temperature for 2 hours. The crystals precipitated were recovered by suction filtration, and dried under reduced pressure, thereby 1.7 g of 5-bromo-2-methylthieno[2,3-d]oxazole was obtained as pale yellow powder (yield: 54%).
Reaction SMILES: NC1NC2C(C(C3C=CC=CC=3)C=1C#N)=CC=CC=2.[NH:20]=[C:21]1[C:30]([C:31]#[N:32])=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[C:28]2[C:23](=[CH:24][C:25]([O:41][CH3:42])=[CH:26][CH:27]=2)[S:22]1.[BH4-].[Na+].Cl>CO.CCOCC>[NH2:20][C:21]1[S:22][C:23]2[C:28]([CH:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)[C:30]=1[C:31]#[N:32])=[CH:27][CH:26]=[C:25]([O:41][CH3:42])[CH:24]=2
Reactant: COc1cccc(-c2c(C#N)c(=N)sc3cc(OC)ccc23)c1
Agent: Cl
Agent: N#CC1=C(N)Nc2ccccc2C1c1ccccc1
Agent: [BH4-]
Solvent: CCOCC
Solvent: CO
Product: COc1cccc(C2C(C#N)=C(N)Sc3cc(OC)ccc32)c1
Yield: 63.7 %

Procedure:
2-Amino-3-cyano-4-phenyl-1,4-dihydroquinoline: A solution of 2-imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene (25 mg, 0.077 mmol) in 2.3 mL of dry methanol was treated with sodium borohydride (5.0 mg, 0.13 mmol) at 0° C. The resultant mixture was stirred overnight at room temperature. It was then neutralized with 3 drops of a 1 N solution of hydrochloric acid, dissolved in 20 mL of ether, washed twice with 10 mL of aqueous saturated bicarbonate and dried with sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography using 25% ethyl acetate/hexanes to yield 15.9 mg (63%) of 2-amino-3-cyano-7-methoxy-4-(3-methoxyphenyl)-4H-thiochromene as a pale yellow solid. 1H NMR (CDCl3): 7.14–7.21 (m, 2H), 6.79–6.82 (m, 3H), 6.72–6.76 (m, 2H), 4.82 (s, 1H), 4.66 (brs, 2H), 3.79 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14]C)=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:16]>C(O)C>[CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12](=[O:14])[NH2:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Solvent: CCO
Product: CCCCc1cc(C(N)=O)cc(=O)[nH]1

Procedure:
3 g (14.3mmol) of the compound from Example 1 are heated for a few minutes in 10 ml of ethanol and 20 ml of conc. ammonia. A further 5 ml of conc. ammonia are then added three times each and the mixture is again briefly heated to boiling. After cooling, the precipitate is filtered off with suction and dried over P2O5 in vacuo.