Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cc2)c1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(OCC)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (234 mg) was added to a solution of 1-(4-hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.2 g) in N,N-dimethylformamide (12 ml) at room temperature, stirred at the same temperature for 30 minutes, then ethyl iodide (0.8 ml) was added therein and the mixture was stirred at 80° C. for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(4-ethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.32 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1.[Mg].CON(C)[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(OCC)C>[F:10][C:8]1([F:11])[C:7]([F:13])([F:12])[C:6]2[CH:14]=[C:2]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: FC1(F)Oc2ccc(Br)cc2C1(F)F
Reactant: CON(C)C(=O)C(F)(F)F
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)C(F)(F)C(F)(F)O2)C(F)(F)F
Yield: 92 %

Procedure:
The reaction of 5-bromo-2,2,3,3-tetrafluorobenzofuran (5.3 g, 0.02 mole) with magnesium turnings (0.48 g) in dry diethyl ether was followed by reaction with N-methoxy-N-methyltrifluoroacetamide (3.5 g, 0.022 mole), yielding 5.3 g of 1-(2,2,3,3-tetrafluorobenzofuran-5-yl)-2,2,2-trifluoroethanone.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH:22]C(=O)OC(C)(C)C)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH2:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(NC(=O)OC(C)(C)C)cnn1-c1ncc(C)c(-c2cccs2)n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1c(N)cnn1-c1ncc(C)c(-c2cccs2)n1
Temperature: 23 °C
Reaction time: 23 h
Yield: 38 %

Procedure:
To the solution of tert-butyl 5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-ylcarbamate from step 1 in CHCl3 (30 mL) cooled to 0° C. was injected trifluoroacetic acid (3 mL) and let stir for 23 h at 23° C. The reaction solvent was then evaporated and redissolved in CH2Cl2 and washed with saturated NaHCO3 solution. The organic layer dried (sodium sulfate) and concentrated, whereupon the residue was purified by silica gel flash column chromatography (gradient from 2% methanol in dichloromethane to 10% methanol in dichloromethane) afford 5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-amine (361 mg, 38% yield over 3 steps) as a yellow oil. 1H NMR (500 MHz, DMSO) δ 8.55 (s, 1H), 7.83 (dd, J=3.91, 0.98 Hz, 1H), 7.69 (dd, J=5.38, 0.98 Hz, 1H), 7.46 (s, 1H), 7.21 (dd, J=4.89, 3.91 Hz, 1H), 4.86 (bs, 2H), 3.19 (t, J=7.82 Hz, 2H), 2.53 (s, 3H), 4.53 (m, 2H), 1.36 (sex, J=7.83 Hz, 2H), 0.84 (t, J=7.34 Hz, 3H). LCMS (ES+) m/z 314 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25]C)=[O:24])=[O:19])=[CH:4][CH:3]=1.[OH-].[Li+].C1COCC1.Cl>O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([OH:25])=[O:24])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[6-fluoro-3′-(hydroxymethyl)-3-biphenylyl]methyl}amino)-carbonyl]benzoate (0.309 g, 0.786 mmol), lithium hydroxide (0.0282 g, 1.2 mmol), THF (6 mL), and water (2 mL) were combined and stirred under argon at room temperature overnight. Solvents were pumped off, the residue adjusted to pH 2 with 1N HCl, and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as a white solid. LC-MS m/z 379.8 (M+H)+, 1.69 min (ret time); mp 169-171° C.; analytical HPLC shows 93.2% purity, (ret time 7.059 min).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=4)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:10]([Cl:32])[CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1[CH:9]=[C:10]([Cl:32])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=4)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:12]([Cl:14])[CH:13]=1
Reactant: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(NC(=O)OC(C)(C)C)cc4Cl)sc23)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(N)cc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of {3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-carbamic acid tert-butyl ester (235 mg, 0.467 mmol) in 4N HCl in dioxane (10 mL) was heated at 50° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the precipitate collected. The solid thus obtained was purified by column chromatography on silica gel eluting with 0-5% 2N NH3/MeOH in EtOAc to afford the title compound as a pale yellow solid (142 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 7.63 (s, 1H), 6.77 (s, 2H), 6.22 (s, 2H), 2.39 (s, 3H). LCMS (Method C): RT=2.97 min, m/z: 403 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: C1COCCN1
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(Br)cc2)cc1Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(Br)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-β-(4'-bromophenyl)-3,5-dibromo-cinnamic acid (isomer ratio A:B=1.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15](N)=[NH:16]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][C:12]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=2[Cl:10])[N:16]=1
Reactant: N=C(N)COc1cccc(Cl)c1Cl
Reactant: N#Cc1nccnc1N
Solvent: CCO
Product: Nc1nc(COc2cccc(Cl)c2Cl)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 3.6 g (0.030 mole) of 3-amino-2-pyrazinecarbonitrile and 6.6 g (0.030 mole) of 2-(2,3-dichlorophenoxy)acetamidine in 100 ml of absolute ethanol. Refluxing time: 14 hours. Yld: 8.1 g (84%), m.p. 216°-218° C. (ethanol).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(=S)=S>[Br:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(C)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Acetyl chloride (1 to 1.2 eq) and AlCl3 (1 to 1.2 eq) are mixed with carbon disulfide, 3-bromoanisole dissolved in carbon disulfide is added thereto. The resulting mixture is stirred for 10 to 16 h at room temperature, to obtain 1-(2-bromo-4-methoxyphenyl)ethanone of formula 14.
Reaction SMILES: [C:1](=[S:6])([O:3]CC)[NH2:2].Br[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[C:9]1=O>O1CCOCC1>[C:14]([CH:10]1[C:9]2[NH:2][C:1](=[O:3])[S:6][C:8]=2[CH2:13][CH2:12][CH2:11]1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CCCC(Br)C1=O
Reactant: CCOC(N)=S
Solvent: C1COCCO1
Product: COC(=O)C1CCCc2sc(=O)[nH]c21

Procedure:
A mixture of 10.5 g of ethyl thiocarbamate, 25.9 g of methyl 3-bromo-2-oxo-cyclohexanecarboxylate and 200 ml of dioxane was refluxed for 16 hours and was then distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1-1 cyclohexane-ethyl acetate mixture to obtain 4-carbomethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one melting at 95° C.
Reaction SMILES: C([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:14](=[N:15][N:16]([CH3:21])[N:17]=2)[N:13]([CH3:22])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[CH3:22][N:13]1[C:14]2[C:18](=[N:17][N:16]([CH3:21])[N:15]=2)[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:23])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2nn(C)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66 mg, 0.204 mmol) in methanol (15 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixture was stirred at room temperature for 24 hours and then the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (37 mg, 65% yield) as a white solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14].CCOC(C)=O>CN(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.[Cu]I>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCO
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C#CCO
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Methyl 2-iodobenzoate (25 g, 95 mmol), prop-2-yn-1-ol (8.02 g, 143 mmol) and TEA (26.6 ml, 191 mmol) were added to a deareated mixture of Pd(PPh3)4 (0.220 g, 0.191 mmol), copper(I) iodide (0.073 g, 0.382 mmol) in DMF (60 ml). The resulting mixture was stirred at 90° C. for 5 hrs and then at 40° C. overnight. The reaction mixture was poured into EtOAc (600 ml) and washed with brine (600 ml). Organic phase was then concentrated and the dark oil was rinsed with Et2O (600 ml). The mixture was filtered, and then concentrated to give the title compound as deeply brown oil (13.0 g). This compound was used in the next step without any further purification and characterization.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:28])=[N:21][N:22]([CH2:25][CH2:26][OH:27])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N1C=CN=C1.O>CN(C)C=O>[Si:2]([O:27][CH2:26][CH2:25][N:22]1[C:23]([CH3:24])=[C:19]([O:18][C:16]2[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=2)[C:13]#[N:14])[C:20]([CH3:28])=[N:21]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Cc1nn(CCO)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 72 h
Yield: 82.1 %

Procedure:
Chloro-t-butyldimethylsilane (2.78 g, 18.5 mmol) was added in one portion to a stirred solution of the pyrazole of Example 114 (4.89 g, 16.8 mmol) and imidazole (1.48 g, 21.8 mmol) in N,N-dimethylformamide (30 ml) at room temperature under nitrogen. The reaction was stirred for 3 days and water (200 ml) was added. The aqueous phase was extracted with diethyl ether (3×200 ml) and the combined organic phases were washed with water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane to provide the title compound (5.60 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[N:18](COCC[Si](C)(C)C)[CH:19]=[CH:20][N:21]=1)=[O:16].Cl>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[NH:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)Cc1c(C(=O)c2nccn2COCC[Si](C)(C)C)[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 103.3 %

Procedure:
To a solution of methyl[5-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate (step 1, 300 mg, 0.67 mmol) in methanol (10 ml) was added 2N aqueous HCl (7 ml) and the mixture was refluxed for 1.5 h. After cooling to room temperature, the mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate (10 ml ) and then the mixture was concentrated. The residual yellow solids were dissolved in THF (100 ml) and dried (MgSO4). Removal of solvent afforded 220 mg (100%) of the title compound as yellow solids.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:35]3[CH2:34][CH2:33][N:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNCC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-piperazin-1-yl-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[CH:3]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:5]=[N:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Brc1cncc(CN2CCOCC2)c1
Reactant: C#CCCN1CCCCC1
Product: C(#Cc1cncc(CN2CCOCC2)c1)CCN1CCCCC1

Procedure:
This compound was made in a similar way as described in Example 18, Step D, using 4-(5-bromo-pyridin-3-ylmethyl)-morpholine and 1-but-3-ynyl-piperidine (57%). MS (ESI): exact mass calcd. for C19H27N3O, 313.45; m/z found, 314.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49 (d, J=1.9,1H), 8.40 (d, J=1.6,1H), 7.66-7.64 (m, 1H), 3.68 (t, J=4.5, 4H), 3.45 (s, 2H), 2.67-2.58 (m, 4H), 2.49-2.38 (m, 8H), 1.62-1.52 (m, 4H), 1.46-1.40 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:31])([F:14])[F:30])[CH:17]=1
Reactant: O=C(O)C(Sc1cccc(C(F)(F)F)c1)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.72 g, 8.92 mmol) and diethyl ester of [[3-(trifluoromethyl)phenyl]thio]propanedioic acid (1.5 g, 4.46 mmol). m.p. 228-229° C.; 1H NMR (400 MHz, DMSO-d6) δ6.89 (s, 1H), 7.4-7.61 (m, 7H), 7.89 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:23])=[C:5]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:6]([C:8](=[CH:14]OCC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([F:23])=[C:5]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:6]([C:8](=[CH:14][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC)c1F
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of ethyl 2-(3-methoxy-2,4,5-triflurobenzoyl)-3-ethoxyacrylate (590 mg, 1.8 mmol) in methylene chloride (15 mL) at 0° C. was added a solution of cyclopropylamine (114 mg, 1.98 mmol, 1.2 equiv) in methylene chloride (5 mL). The reaction mixture was warmed to room temperature and allowed to stir for 2 hours. The solvent was removed in vacuo and the crude concentrate was purified by flash chromatography on silica gel (methylene chloride/ethyl acetate 50:1 v/v) to provide 438 mg, 62% yield over two steps, of a viscous yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].[Br-].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](=[CH:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC=C1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O

Procedure:
A stirred solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.8 g., 0.0022 mole) and anhydrous lithium bromide (0.49 g., 0.0056 mole) in dimethylformamide (10 ml.) is heated at 95° in an inert atomosphere for one hour then poured into water (100 ml.) affording 4,5-dimethyl-6-oxo-7-propylidene-7,8-dihydro-6H-indeno-[5,4-b]furan-2-carboxylic acid which melts at 301°C after recrystallization from ethanol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1ccc(-c2nnc(CN3CCOCC3)o2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCOCC3)o2)cc1

Procedure:
Example 14 was prepared from 4-[5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-morpholine (Intermediate 10) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].[N-]=C=O>>[NH2:19][C:17]1[N:18]=[C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=4[F:20])=[O:33])=[CH:3][CH:4]=3)=[N:15][N:14]2[CH:16]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Agent: [N-]=C=O
Product: Nc1cn2nc(C#Cc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2n1

Procedure:
The compound of Example 4 was made by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18][N:19](C)C)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl.N[OH:24]>CCO>[F:1][C:2]1[C:3]([NH:17][CH:18]=[N:19][OH:24])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: NO
Reactant: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: Cl
Solvent: CCO
Product: ON=CNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.10 g, 0.34 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (0.047 g, 0.68 mmol) and the mixture was agitated on an orbital shaker for 1.5 h at 50° C. The reaction mixture was cooled and evaporated to dryness. Water was added to produce a slurry which was filtered to isolate the title compound (0.090 g, 94% yield) as a white solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.2 Hz, 1H), 8.02 (bs, 2H), 7.49-7.43 (m, 2H), 7.11-7.02 (m, 3H), 5.35 (s, 2H); HPLC-MS (ESI) m/z 281 (M+H)+, 279 (M−H)−.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CN(C=O)C.O>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][CH2:22][P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCOC1CCCCO1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=P(CCCOC1CCCCO1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dibenzyl phosphite (1.70 mL, 7.63 mmol) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.381 g, 9.53 mmol) in dry DMF (11.4 mL) at 25° C. under N2. After 15 min 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.29 mL, 7.63 mmol) was added and the mixture was stirred at 25° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to afford dibenzyl [3-(tetrahydro-2H-pyran-2-yloxy)propyl]phosphonate. Rf=0.06 (20% EtOAc/hexanes). LCMS calc.=427.17; found=427.15 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)Cl>[Br:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:19](=[O:20])[N:18]([CH3:17])[C:4]2([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN=C=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Br)cc2C1(O)c1ccccc1
Yield: 91.6 %

Procedure:
A solution of 14.70 g (0.053 mole) of 2-amino-5-bromobenzophenone and 6.0 g (0.21 mole) of methyl isocyanate in 75 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 16.18 g (90% yield) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone as a white crystalline powder: mp 293°-294° (dec.).