Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:21]2[CH2:22][CH2:23][CH:19]([O:18][C:17]3[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:28])[F:27])[CH:16]=3)[CH2:20]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)c1cccc(OC2CCNC2)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 57.6 %

Procedure:
The title compound (D92) (270 mg) was prepared according to the experimental procedure described in Description 62 starting methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and from 3-(3-(trifluoromethyl)phenoxy)pyrrolidine (D58) (323 mg, 1.39 mmol).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Into a glass flask having an internal volume of 50 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 10.72 g (6.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 1.92 g (6.0 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 10 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under at 110° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 7.0 mL (7.0 mmol) of a 1 mol/L sodium hydroxide aqueous solution was added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 1.57 g (yield: 91%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[C:15]([NH2:26])=[CH:16][CH:17]=[C:18]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:19]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:36][C:37](OCC)=[O:38]>O1CCCC1>[ClH:36].[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:14]4[CH:19]=[C:18]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])[CH:17]=[CH:16][C:15]=4[NH:26][C:37]3=[O:38])[CH2:11][CH2:12]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=c1[nH]c2ccc(OCC(F)(F)F)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 150 °C

Procedure:
A stirred solution of N2-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-[(2,2,2-trifluoroethyl)oxy]-1,2-benzenediamine (D57, 95 mg, 0.25 mmol) in tetrahydrofuran (5 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (100 mg, 0.78 mmol) followed by ethyl chloroformate (33 mg, 0.30 mmol) and maintained for 3 days. The mixture was concentrated under vacuum and the residue treated with dimethylformamide (5 ml) and heated at 150° C. under argon for 7 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to leave a brown oil, which was purified by Mass-Directed Automated HPLC to afford the title compound as a white solid. This was converted to its HCl salt and isolated as a beige solid (30 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]>CS(C)=O.CCOC(C)=O>[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:9]3[O:10][CH2:11][CH2:12][O:13]3)[CH:4]=2)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Reactant: CCOC(=O)c1ccc(F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of compound 2 (9.27 g, 37.83 mmol) in DMSO (50 mL) was added potassium carbonate (15.68 g, 113.48 mmol). The resulting mixture was stirred at rt for 30 min. followed by addition of compound 5 (8.99 g, 45.39 mmol). The resulting mixture was heated at 120° C., O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 6 (5.6 g, 35%) as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ: 7.81 (d, J=9.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.97 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.49 (dd, J=8.6, 2.4 Hz, 1H), 6.01 (s, 1H), 4.39 (q, J=7.4 Hz, 2H), 4.20-4.01 (m, 4H), 3.81 (s, 3H), 1.40 (t, J=7.4 Hz, 3H); MS (ES) m/z: 423 (M+1)+, 425 (M+3)+.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH2:8][CH:3]([CH2:4][CH2:5][CH:6]=C)[O:2]1.CC[O:13]CC.I([O-])(=O)(=O)=O.[Na+].I([O-])(=O)(=O)=O>[Os](=O)(=O)(=O)=O.O>[CH2:1]1[CH2:10][O:9][CH2:8][CH:3]([CH2:4][CH2:5][CH:6]=[O:13])[O:2]1
Reactant: CCOCC
Reactant: C=CCCC1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=CCCC1COCCO1
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A mixture of 5-ethylenedioxy-1-hexene (6.0 g.), osmium tetroxide (0.5 g.) , ether (150 ml.) and water (150 ml.) is treated portionwise with sodium metaperiodate (19.3 g.) so that the reaction temperature does not exceed 30°. After the addition of the periodate, a voluminous white solid precipitates out. The mixture is stirred 2.5 hrs. at room temperature, then filtered, and the solid portion is washed with more aqueous ether. The aqueous portion of the filtrate is separated and extracted with three portions of methylene chloride. The combined organic phases are dried with magnesium sulfate, filtered, and evaporated in vacuo. Distillation of the residue yields 4-ethylenedioxy-pentanal (65% yield) b.p. 56°-58°/10.5 mm nmr (CDCl3)δ: 1.27 (s, CH3), 2.04-2.80 (m, --CH2 --CH2 --); 3.9 (s, --OCH2 --CH2 --O), 9.73 (t, O=C--H). IR (film) μ: 3.66; 3.79.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH2:33]1>CN(C)C=O.C(#N)C>[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:39]=2[CH2:40][CH2:41][C@@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33]3)[CH2:47][CH2:46]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at 70° C. for 18 h and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave after crystallization from acetonitrile, 65 mg (30% yield) of the title compound as white crystals: mp 127-128° C.; [α]21D +51° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (14, M+).
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH:6]1([N:12]([C:39](=[O:53])[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=2)[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][C:28]2[C:36]3[S:35][C:34](=[O:37])[NH:33][C:32]=3[C:31]([OH:38])=[CH:30][CH:29]=2)C(=O)OCC2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C.COC(C)(C)C.C(O)C>[BrH:1].[BrH:1].[CH:6]1([N:12]([CH2:13][CH2:14][NH:15][CH2:26][CH2:27][C:28]2[C:36]3[S:35][C:34](=[O:37])[NH:33][C:32]=3[C:31]([OH:38])=[CH:30][CH:29]=2)[C:39](=[O:53])[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]2[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cc(F)cc(F)c1)C1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C(CCNCCc1cc(F)cc(F)c1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1 h

Procedure:
Hydrogen bromide/acetic acid (33%, 2 mL) was added to a solution of the carbamate of step i) (0.350 g) in acetic acid (2 mL) and the reaction was stirred for 1 h. The solution was diluted with t-butyl methyl ether (20 mL) and the resulting precipitate filtered off, washed with more t-butyl methyl ether (10 mL) and dried to afford a peach coloured solid. The solid was slurried in ethanol (7.5 mL), filtered off and dried to yield the title product (0.22 g) as a white solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[N:21]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:19]=3[N:20]=2)=[N:12][CH:13]=1)(C)(C)C.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:26]1([N:21]2[C:19]3[N:20]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][N:12]=4)[N:16]=[CH:17][C:18]=3[CH:23]=[C:22]2[C:24]#[N:25])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Nc2ncc3cc(C#N)n(C4CCCC4)c3n2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cc2cnc(Nc3ccc(CO)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a stirred solution of 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile in THF (2.0 mL) is added HF.pyridine (0.080 mL) at 0° C. The reaction mixture stirred at room temperature for 16 h before it is diluted with ethyl acetate, ished with saturated NaHCO3 solution, dried (MgSO4), filtered and concentrated. Trituration with diethyl ether gave 7-cyclopentyl-2-(5-hydroxymethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, 68 mg, 53% yield (over 2 steps). MS (ESI) m/z 335.0 (M+H)+ (method A).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](OCC(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogen carbonate (1.93 g) and dimethyl sulfoxide (5 mL) was stirred at 60° C. for 30 min, 4′-({4-[cis-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (620 mg) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (224 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (210 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (479 mg, 70%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:16](O)=[O:17])=[CH:10][C:11]=2[O:13][CH2:14][CH3:15])[N:6]([CH:19]2[CH2:21][CH2:20]2)[CH:5]=1)(=[O:3])[NH2:2].Cl.[CH3:23][O:24][C:25](=[O:48])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])[CH:27]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:16]([N:40]3[CH2:39][CH2:38][C:37]4([CH2:36][C:35](=[O:47])[C:34]5[C:44](=[CH:45][CH:46]=[C:32]([C:28]6[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=6)[C:25]([O:24][CH3:23])=[O:48])[CH:33]=5)[O:43]4)[CH2:42][CH2:41]3)=[O:17])=[CH:10][C:11]=2[O:13][CH2:14][CH3:15])[N:6]([CH:19]2[CH2:21][CH2:20]2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C(N)=O)cn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cccc(C(=O)OC)c4)ccc2O3)cc2c1c(C(N)=O)cn2C1CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.22 mL) was added to a solution of 3-carbamoyl-1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (229 mg), 3-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)benzoic acid methyl ester hydrochloride (306 mg), WSC hydrochloride (166 mg) and HOBT (133 mg) in DMF (4 mL), and the mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, then washed successively with water, aqueous saturated sodium bicarbonate and saturated saline water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to obtain the intended ester derivative as a colorless amorphous substance. 1H-NMR (400 MHz, CDCl3) δ: 8.71 (1H, s), 8.25 (1H, dd, J=1.5, 1.5 Hz), 8.14 (1H, d, J=2.4 Hz), 8.04-8.00 (2H, m), 7.83-7.74 (2H, m), 7.51 (1H, dd, J=7.8, 7.8 Hz), 7.37 (1H, d, J=1.5 Hz), 7.13 (1H, d, J=7.8 Hz), 6.74 (1H, d, J=1.5 Hz), 5.54 (1H, s), 4.62-4.41 (1H, br m), 4.29 (2H, q, J=7.0 Hz), 3.95 (3H, s), 2.28-1.71 (4H, br m), 3.88-3.32 (4H, br m), 2.82 (2H, s), 1.55 (3H, t, J=7.0 Hz), 1.16-1.00 (4H, m); MS [M+H]+=622.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:5]2[C:6]3[C:11]([CH2:12][N:4]2[N:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([NH:1][C:2]1[N:13]=[C:5]2[C:6]3[C:11]([CH2:12][N:4]2[N:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:16])[CH3:15]
Reactant: Nc1nc2n(n1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1nc2n(n1)Cc1ccccc1-2

Procedure:
2-Amino-5H-s-triazolo[5,1-a]isoindole (12.08 g) and acetic anhydride (8 ml) are boiled for one hour in 150 ml of benzene. After cooling, the solid precipitate is recovered on filter and then is crystallized from ethyl acetate. Yield 14.35 g (97%). M.p. 258-9°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:30]([O:34][C:35]([N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:30]([O:34][C:35]([N:37]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([O:28][CH3:29])[C:5]3[N:6]([C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5([NH2:21])[CH2:18][CH2:19][CH2:20]5)=[CH:13][CH:12]=4)[N:10]=3)[CH:7]=2)[CH:39]=[N:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 120 °C

Procedure:
A mixture of 1-[4-(6-bromo-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (120 mg), [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid (170 mg) and potassium phosphate (170 mg) in toluene (0.9 mL), EtOH (1.86 mL) and water (0.93 mL) was placed under argon and bis(tri-tert-butyl phosphine)palladium(0) (13.7 mg) was added. The mixture was heated at 120° C. under microwave irradiation for 30 minutes. On cooling the mixture was partitioned between DCM and water and the phases separated. The organic portion was concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=4[CH3:33])[N:14]=3)=[CH:9][C:8]=2I)[CH2:3]1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].C(NC(C)C)(C)C>O1CCOCC1.[Cu](I)I.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=4[CH3:33])[N:14]=3)=[CH:9][C:8]=2[C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(N3CCC(F)(F)C3)c(I)c2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(N3CCC(F)(F)C3)c(C#C[Si](C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 61 mg (0.10 mmol) of tert-butyl 3-(4-(5-(6-(3,3-difluoropyrrolidin-1-yl)-5-iodopyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 34) in 5.0 mL of 1,4-dioxane were added 1 mg (0.005 mmol) of copper(II) iodide, 20 mg (0.21 mmol) of (trimethylsilyl)acetylene, 12 mg (0.12 mmol) of diisopropylamine, and 2.6 mg (0.005 mmol) of bis(tri-tert-butylphosphine)palladium(0). The mixture was stirred at rt for 16 h and concentrated. Chromatography on a Biotage 25S cartridges using 9:1 v/v hexanes/EtOAc as the eluant afforded 43 mg of a yellow solid as the title compound: 1HNMR (500 MHz, CDCl3) δ 0.26 (s, 9H), 1.45 (s, 9H), 2.46 (m, 2H), 2.58 (t, J=7.8, 2H), 2.66 (s, 3H), 2.96 (t, J=7.8, 2H), 4.15 (t, J=7.3, 2H), 4.32 (t, J=13, 2H), 7.18 (s, 1H), 7.19 (s, 1H), 8.01 (m, 1H), 8.34 (d, J=2.3, 1H), 8.88 (d, J=2.3, 1H).
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([N:9]1[CH2:15][CH:14]([NH:16]CC2C=CC(OC)=CC=2)[C:13]2=[N:26][C:27]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[CH:28][C:29](=[O:30])[N:12]2[CH2:11][CH2:10]1)=[O:8])[CH3:5].O.[N+]([O-])([O-])=O.[Ce].[NH4+]>>[CH2:4]([O:6][C:7]([N:9]1[CH2:15][CH:14]([NH2:16])[C:13]2=[N:26][C:27]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[CH:28][C:29](=[O:30])[N:12]2[CH2:11][CH2:10]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccc(OC)cc2)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of 10.75 g (23.86 mmol) of 9-(4-methoxy-benzylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester acetonitrile/water (160/80 mL) was added 26.16 g (47.73 mmol) of ammonium cerium nitrate. The reaction was stirred at room temperature for 2 hours. 13.08 g (23.86 mmol) of ammonium cerium nitrate was added and the reaction was stirred at room temperature for 0.5 hours. After an acido-basic work-up and extraction with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to afford 5.15 g (65%) of a powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2Oc2ccccc2)OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 162.3 g (0.5 mmole) of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 75 mg (0.80 mmole) of phenol and 120 mg (0.87 mmole) of potassium carbonate in 1.5 mL DMF. The mixture was heated to 110° C. and allowed to stir overnight. After cooling, the mixture was diluted with water and extracted three times with diethyl ether. The combined organic fractions were washed with water, dried and concd to give a crude oil. Preparative reverse phase chromatography (C 18, 4.0 cm×25 cm column, gradient 50%-100% CH3CN) afforded 50 mg (25.1%) of a clear, colorless oil: 1H NMR (CDCl3/400 MHz) 1.28 (t, 3H, J=7.1 Hz), 4.26 (m, 2H), 5.70 (q, 1H, J=6.7 Hz), 6.82 (d, 2H, J=7.9 Hz), 6.87 (d, 1H, J=8.7 Hz), 7.06 (t, 1H, J=7.4 Hz), 7.31 (t, 2H, J=8.1 Hz), 7.38 (d, 1H, J=8.9 Hz), 7.79 (s, 1H); 19F NMR (CDCl3/400 MHz) −78.7 (d, 3F, 6.8 Hz); MS (ESI+) 399 (M+1, 100); MS (EI) 398 (M+, 50), 329 (100), 283 (79), 231 (32); HRMS (EI) m/z calcd for (C19H14O4ClF3) 398.0533, found 398.0538.