Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([OH:13])=O)[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:13])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 17.6 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol), commercially available 2-aminopyridine (60 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-pyridin-2-ylpropionamide (50 mg, 20.8%), as a white solid. 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 8.28-8.41 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.70-7.86 (m, 1H), 7.20-7.40 (m, 2H), 7.03-7.16 (m, 2H), 5.09 (br. s., 1H), 5.00-5.01 (m, 1H), 4.36-4.37 (m, 1H), 4.43 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 3H), 3.99-4.15 (m, 1H), 3.75 (s, 2H), 1.49-1.90 (m, 6H), 1.05-1.29 (m, 4H), 0.88-1.02 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH:16]([CH3:18])[CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)c1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
143 mg (99%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal (86 mg, 0.357 mmol), 1-(2-fluorophenyl)piperazine (65 mg, 0.362 mmol), DIPEA (0.094 mL, 0.540 mmol) and NaBH(OAc)3 (237 mg, 1.118 mmol).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1.[Cl:16][C:17]1[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]([Cl:28])=[C:21]2[C:26](=[O:27])[O:25][C:23](=[O:24])[C:22]=12>C(OC(=O)C)(=O)C>[CH3:12][C:10]1([CH3:13])[CH2:11][CH:6]([NH:5][C:26](=[O:27])[C:21]2[C:22](=[C:17]([Cl:16])[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]=2[Cl:28])[C:23]([OH:25])=[O:24])[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9]1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)CC(C)(C)N1

Procedure:
The acetic acid salt of N-(2,2,6,6-tetramethyl-4-piperidinyl)tetrachlorophthalamic acid was prepared by refluxing 7.8 grams (0.05 mole) of 4-amino-2,2,6,6-tetramethylpiperidine, 14.3 grams (0.05 mole) of tetrachlorophthalic anhydride in 100 ml of acetic anhydride for 4 hours. The acetic anhydride was stripped off on a rotary evaporator under reduced pressure. The light yellow residue was slurried in 300 ml hexane and filtered. The filter cake was reslurried in fresh hexane and refiltered. The filter cake was air dried for 3 days on a watch glass. The dried product weighed 26.5 grams.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.Cl>CCO.O>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
5-amino-4,6-dichloropyrimidine (5.0 g, 30.49 mmol) and 4-chloroaniline (5.1 g, 40.0 mmol) were added to the solution of hydrochloric acid (1.3 mL, 15.24 mmol) in EtOH/H2O (8:1 v/v) (100 ml). The resulting reaction mixture was stirred for overnight at 80° C. The resulting mixture was filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (6.8 g, 88%) as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH2:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NC1CCCOC1
Temperature: 135 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of tetrahydropyran-3-ylamine (0.43 g, 4.05 mmol) in DMF (2 mL) was added to a mixture of 1-fluoro-2-nitrobenzene (0.57 g, 4.05 mmol) and potassium carbonate (1.68 g, 12.1 mmol) in DMF (10 mL). The reaction mixture was heated for 1 h at 135° C. under microwave irradiation. Additional tetrahydropyran-3-ylamine (40 mg) was added and microwave irradiation at 135° C. was continued for further 30 min. Volatiles were then removed in vacuo and the resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% MeOH in DCM) affording (2-Nitrophenyl)(tetrahydropyran-3-yl)amine as an orange oil (0.73 g, 81%). LCMS: RT 3.31 min [M+H]+ 223.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([C:16](=[O:18])[CH3:17])[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.5 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline (Rami et al, WO 03/068749) (500 mg, 2.42 mmol), DMAP (5 mg) in pyridine (2 mL) was added acetic anhydride (0.46 mL, 4.9 mmol). The mixture was stirred at room temperature for 10 h, and then heated at 60° C. for 5 h. After cooling, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaHCO3, 1N HCl, brine, dried, and evaporated. The residue was purified by chromatography to give a light yellow solid (550 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCN2CCCC2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90 mg, 77%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.CC[N:15](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-indancarboxylic acid (1.4 g, 8.63 mmol) was dissolved in anhydrous DMF (20 mL), and the following was added sequentially: DIPEA (3.02 mL, 17.26 mmol), HATU (3.94 g, 10.36 mmol), and HMDS (2.17 mL, 10.36 mmol) after 30 min of stirring at rt. After stirring for 20 h at rt, the solution was taken up in EtOAc and washed with 0.5M HCl (3×), water (3×), and 10% aq. sodium carbonate (3×). The organic phase was collected and dried over magnesium sulfate, and concentrated in vacuo. The solid residue was recrystallized from EtOH to afford the title compound as sharp, colorless crystals. (Yield: 861 mg, 5.06 mmol, 59%) 1H NMR (400 MHz, CDCl3) 7.34-7.12, 5.52, 3.41-3.08
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH:12]=O)[C:9]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[N:8]2)=[CH:4][CH:3]=1.[OH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][OH:35])[CH2:39][CH2:40]3)[C:9]([CH2:14][N:15]3[CH2:16][CH2:17][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20]3)=[N:8]2)=[CH:33][CH:34]=1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: OCCN1CCN(Cc2cn(Cc3ccc(Cl)cc3)nc2CN2CCC(c3ccccc3)(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 15 (0.001 g) was dissolved in N,N-dimethylformamide (0.2 ml), N-(2-hydroxyethyl)piperazine (0.0008 g) and 1 drop of acetic acid were added. After 1 hour a solution of sodium triacetoxyborohydride (0.0013 g) in N,N-dimethylformamide (0.1 ml) was added and the solution shaken at room temperature for 24 hours. The solvent was removed to give the product as an oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[SH:30])[CH:24]=[CH:25][CH:26]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[S:30][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH:24]=[CH:25][CH:26]=2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1nc2cccc3ncc1n32
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2nc3cccc4ncc2n43)CC1
Temperature: 80 °C
Reaction time: 11 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (3.5 g, 12.5 mmol) in DMF (60 ml) were added 1,4,7b-triazacyclopenta[cd]inden-2-thiol (3.7 g, 21.3 mmol) and DBU (3.7 ml, 25 mmol), and the mixture was stirred at 80° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added water (200 ml) The mixture was extracted with a mixed solution of THF and ethyl acetate (3/2, 500 ml). The organic layer was washed with saturated aqueous solution of sodium chloride (200 ml), successively, and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 30 g, ethyl acetate/hexane=1/2 to 1/0), and the desired fraction was concentrated under reduced pressure. To the concentrate was added disopropyl ether and the precipitates were collected by filtration to give the titled compound (2.5 g, 7 mmol) as yellowish powdery crystals.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([N:11]1[C:16](=[O:17])[C:15]([NH:18]C(OC(C)(C)C)=O)=[CH:14][N:13]=[C:12]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:9]=[CH2:10]>CO>[CH2:8]([N:11]1[C:16](=[O:17])[C:15]([NH2:18])=[CH:14][N:13]=[C:12]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:9]=[CH2:10]
Reactant: C=CCn1c(-c2ccccc2)ncc(NC(=O)OC(C)(C)C)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=CCn1c(-c2ccccc2)ncc(N)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride/dioxane (31 ml, 122.2 mmol) was added to a solution of 1-allyl-5-t-butyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine (2 g, 6.11 mmol) in methanol (12 ml) under cooling on ice and stirred at 0° C. for 30 minutes and at room temperature overnight. The reaction solution was concentrated under reduced pressure whereby the title compound (1.49 g, 93%) was obtained as white solid.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([OH:56])=O)[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]>CN(C=O)C>[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([NH:2][CH3:1])=[O:56])[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)O)c2)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)NC)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (73.7 mg, 0.19 mmol), DIEA (78.6 mg, 0.45 mmol) and methylamine (2M soln in THF, 0.15 mL, 0.30 mmol) were added to a solution of 6′-{[(ethylamino)carbonyl]amino}-4′-(4-phenyl-1,3-thiazol-2-yl)-3,3′-bipyridine-5-carboxylic acid (Example 132, 66.4 mg, 0.15 mmol) in DMF (1.5 mL). The resulting light yellow solution was stirred at room temperature for three hours. The reaction mixture was partitioned between water and ethyl acetate and layers separated. The organic layer was washed with saturated NaHCO3, water, brine, then dried over magnesium sulfate. The solvent was removed and the resulting residue was washed with acetonitrile and filtered to yield 33 mg of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=[C:18]2[C:23](=[O:25])[CH3:24])[CH2:16][CH2:15][CH2:14]1.[CH:26](=[O:28])[CH3:27].[NH4+].[Cl-]>O1CCCC1>[OH:28][CH:26]([CH3:27])[CH2:24][C:23]([C:18]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:25]
Reactant: CC(=O)C1=CCCCC12CCCC2
Reactant: CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)CC(=O)C1=CCCCC12CCCC2
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 125.7 %

Procedure:
At −70° C., a solution of diisopropylamine (40.9 g, 0.4 mol) in tetrahydrofuran (200 ml) was treated within 10 min. with n-butyl lithium (271 ml, 1.6M in hexane, 0.437 mol). The resulting solution was stirred at −40° C. for 20 min., cooled to −78° C., and treated within 20 min. with a solution of 1-(spiro[4.5]dec-6-en-6-yl)ethanone (62 g, 0.35 mol). The resulting solution was stirred 20 min. at −70° C. and treated with a solution of acetaldehyde (76.6 g, 1.75 mol) in tetrahydrofuran (100 ml). After 90 min. stirring, the reaction mixture was poured into a cold saturated aqueous solution of NH4Cl (400 ml) and extracted twice with MTBE (400 and 200 ml). The combined organic phases were washed with a water (200 ml), and twice with a saturated solution of NaCl, dried (MgSO4), and concentrated to give the desired intermediate 3-hydroxy-1-(spiro[4.5]dec-6-en-6-yl)butan-1-one (97.8 g) which was dissolved in acetic anhydride (70 ml, 0.73 mol). The resulting solution was treated with sodium acetate (31.4 g, 0.383 mol), heated at 80° C. for 8 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 15 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 2 h. The reaction mixture was cooled to 0° C., poured into ice/water and extracted three times with MTBE (200 ml). The combined organic phases were washed with 2N aqueous NaOH (300 ml), with a saturated aqueous NaCl solution (250 ml), dried (30 g MgSO4) and concentrated. Short-path Vigreux distillation (0.08 mbar, bath temperature 140-180° C., head temperature: 80-146° C.) of the crude product (89.6 g) followed by distillation (0.08 mbar, bath temperature 150-180° C., head temperature: 98° C.) using a microdistillation column (20×1.5 cm, filled with 3×3 mm rolled wire netting) gave (E)-1-(spiro[4.5]dec-6-en-6-yl)but-2-en-1-one (55.6 g, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([CH:23](P(OC)(OC)=O)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22].CN(C)C(N(C)C)=N.Cl>ClCCl>[CH3:19][O:20][C:21](=[O:22])/[C:23](/[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[CH:14]/[C:13]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:18])=[CH:11][C:12]=1[Br:17]
Reactant: Cc1cc(Br)c(C=O)cc1OCc1ccccc1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(OCc2ccccc2)c(C)cc1Br)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
To a solution of 5-benzyloxy-2-bromo-4-methylbenzaldehyde (0.39 g) and N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester (0.38 g) in dichloromethane (2 mL) was added 1,1,3,3-tetramethylguanidine (0.18 g) at room temperature and this mixture was stirred at room temperature for 2 days. To this reaction mixture was added 1 mol/L hydrochloric acid and the precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (0.34 g).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:7]([Sn:11]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]I)[CH2:8][CH2:9][CH3:10].CN(C)C=O>O1CCCC1>[CH2:18]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:4][CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)O
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
To a mixture of isopropanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydride (66%, 58 mg, 1.6 mmol) on an ice bath, then, the solution was stirred for 20 minutes at room temperature. To the reaction solution was added a solution of tributyl-iodomethyl-stannane (230 mg, 0.53 mmol), synthesized according to the document (Synthetic Communications, Vol. 24, No. 8, pp. 1117-1120), in tetrahydrofuran (1 mL) dropwise on an ice bath, then, N,N-dimethylformamide (0.5 mL) was added thereto, followed by stirring overnight at room temperature. The reaction solution was partitioned into water (20 mL) and diethyl ether (50 mL). The organic layer was separated, washed with brine, and then, evaporated in vacuo. The residue was purified by neutral silica gel column chromatography (heptane:ethyl acetate=30:1), and the title compound (63 mg, 0.17 mmol, 32%) was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:4]4[N:5]=[CH:6][CH:7]=[N:3]4)=[CH:13][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2nccn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4nccn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.0 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-2-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 254 mg (52%) colorless powder.
Reaction SMILES: [N:1]1[C:9]2[C:8]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:3][CH:2]=1.[H-].[Na+].Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([CH3:33])[N:24]=1>CN(C=O)C.O>[CH3:33][C:25]1[N:24]=[C:23]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8]3[C:9]4[N:1]=[CH:2][S:3][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:14][CH:15]=2)[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: Oc1ccc(CCNc2ncnc3scnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(Oc2ccc(CCNc3ncnc4scnc34)cc2)n1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
4-[2-(Thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenol (0.1 g, 0.37 mmol) was dissolved with magnetic stirring in DMF (1 mL) in a microwave reactor tube, and then treated with NaH (60% dispersion in oil; 13 mg, 0.55 mmol). After bubbling had subsided, 2-chloro-6-methyl-4-trifluoromethylpyridine (86 mg, 0.44 mmol) was added and the reaction mixture was sealed and placed in a CEM Discover® microwave reactor and irradiated for 30 min, with heating to 150° C. After cooling, the reaction mixture was diluted with H2O (5 mL) and partitioned into Et2O (3×10 mL). The pooled organic fractions were diluted with an equal volume of pentane, washed with H2O, dried (Na2SO4) and filtered through a SiO2/Celite plug. The filtrate was concentrated in vacuo to provide a brown wax (126 mg). Prep RP-HPLC purification (CH3CN/H2O eluent; C18 column) afforded {2-[4-(6-methyl-4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 62; 36 mg) as an off white powder: mp 111-112° C.; 1H NMR (CDCl3) δ 8.76 (s, 1H), 8.55 (s, 1H), 7.31-7.29 (d, J=8.6 Hz, 2H), 7.11-7.07 (m, 3H), 6.83 (s, 1H), 6.22 (br s, 1H), 3.96-3.95 (br m, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.51 (s, 3H); ESIMS m/z 432.2 ([M+H]+).