Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]([C@@H:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C@@H:13]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: O=C1CC[C@@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cn2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of 9.93 g (30.9 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step F) in DMF (65 mL) was added 2.47 g (60 wt. % in mineral oil, 61.8 mmol) of sodium hydride. The resulting yellow slurry was stirred at 0° C. for 5 min, then was warmed to room temperature and stirred for an additional 12 min. The reaction was re-cooled to 0° C. and 11.4 mL (77 mmol) of ethyl 2-bromobutyrate was added slowly via syringe over 10 min. The resulting orange slurry was warmed to room temperature and stirred for 4.75 h, and then was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic layers were washed with water (2×) and sat. aq. NaCl solution (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (38 to 40% EtOAc/hexanes, gradient elution) provided the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1C1C(C(O)=O)=CON=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(F)cn1
Agent: O=C(O)c1conc1-c1ccccn1
Product: OCc1conc1-c1ccc(F)cn1
Yield: 70 %

Procedure:
As described for example 358c, 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid (562 mg, 2.7 mmol) was converted, instead of 3-pyridin-2-yl-isoxazole-4-carboxylic acid, to the title compound (367 mg, 70%) which was obtained as an off white solid. MS: m/e=195.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][N:7]2[C:10](=[O:23])[CH:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:12](=[O:13])[N:6]2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][N:3]1[CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[C:10]([O:23][C:33](=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31])[N:7]2[CH2:8][CH2:9]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON1CCn2c(OC(=O)C(C)(C)C)c(-c3c(C)cc(C)cc3C)c(=O)n2CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (162 mg, 0.51 mmol), triethylamine (0.107 ml, 78 mg, 0.77 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (4 ml) at 0° C. was added 2,2-dimethyl-propionyl chloride (pivaloyl chloride, 0.082 ml, 80 mg, 0.67 mmol) dropwise. The suspension was stirred at 0° C. for 45 minutes, the solvent evaporated and the residue diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Yield: 160 mg of 2,2-dimethyl-propionic acid 3-methoxy-9-oxo-8-(2,4,6-trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl ester (title compound P1.1) as an off-white solid, mp 147-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[NH:43][C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:43]2[C:38]([C:36](=[O:37])[C:35]3[CH:34]=[C:33]([CH3:32])[CH:51]=[C:50]([CH3:52])[CH:49]=3)=[C:39]([CH:46]([CH3:47])[CH3:48])[C:40](=[O:45])[NH:41][C:42]2=[O:44])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(Cl)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Yield: 66.4 %

Procedure:
[2-Chloro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (278 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with (20) (286 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 363 mg (66%) of a white solid. m.p. 211-212° C.; 1H-NMR (300 MHz, CDCl3) δ 1.12 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.29-2.32 (7H, m), 3.79 (3H, s), 4.24-4.29 (3H, m), 4.89-4.98 (2H, m), 5.94 (1H, s), 6.14 (1H, s), 6.84-6.87 (2H, m); 7.19-7.32 (5H, m), 9.22 (1H, s); HRMS (EI) Calcd, 546.203384, Found 546.204693.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:11]=[O:12].C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC.[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[CH:6]=[CH:5][CH:3]=[C:2]1[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:11]=[O:12]
Reactant: C1COCCO1
Reactant: O=Cc1ccc(N2CCOCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(N2CCOCC2)c(-c2ccco2)c1
Reaction time: 3 h
Yield: 84 %

Procedure:
EX-604B) To a dioxane (8 mL) solution of the aldehyde from EX-604A (0.77 g, 2.8 mmol) was added 2-(tributylstannyl)furan (1.07 mL, 3.42 mmol) and Pd(PPh3)2Cl2 (0.12 g, 0.17 mmol). The mixture was heated to reflux under argon for 18 h. The cooled mixture was poured into a mixture of saturated aq. KF and ethyl acetate and stirred 3 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to a yellow oil. Purification by silica gel flash chromatography eluting with 20% ethyl acetate in hexane gave 0.61 g (84%) of the desired 3-(2-furanyl)-4-(4morpholinyl)benzaldehyde product as a yellow oil. MS: m/z=258.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[NH:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C2NCCO2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five and eight tenths grams of 2-m-nitrophenyl oxazolidine was dissolved in 50 ml. methylene chloride containing 3.5 g. of triethylamine. Dichloroacetyl chloride 4.4 g. was added dropwise with stirring to the reaction flask and cooled in a water bath at room temperature. When addition was complete, the mixture was stirred at room temperature for about 30 minutes, washed with water, separated and dried over anhydrous magnesium sulfate. The solvent was stripped off under vacuum. There was obtained a yield of 8.6 g. of the title compound, ND30 = 1.5590.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:31][N:32]([CH3:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:9]1[C:8]2[CH:23]=[C:4]([C:1](=[O:2])[NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([N:32]([CH3:41])[CH3:31])=[CH:34][CH:35]=3)[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(C(=O)NCc3ccc(N(C)C)cc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
Four-hundred milligrams of 6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole were dissolved in 3 ml of methylene chloride containing 1 drop of N,N-dimethylformamide. Oxalyl chloride (28 mg) was added to this solution at 5° C. The thus-obtained solution was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The residue was dissolved in 3 ml of methylene chloride, and the mixture was added to a mixed solution prepared by adding 271 mg of 4-dimethylaminobenzylamine hydrochloride and 1 ml of triethylamine to 10 ml of methylene chloride at room temperature. The resulting reaction mixture was stirred at the same temperature for 1 hour, washed with water, dried and then concentrated under reduced pressure. The residue was developed and purified through thin-layer chromatography to give 215 mg of 1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole (61).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCOCC1.O>[CH3:32][C@H:30]1[O:29][C@H:28]([CH3:33])[CH2:27][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:31]1
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (109.5 mg, 0.225 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1,4-Dioxane (5 mL) and Water (1.5 mL) stirred in air at room temp was added solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120° C. for 2 hr. After this time, sodium hydroxide solution (2N, 0.5 mL) was added and the reaction mixture left to stir at room temperature for two hours. On cooling, the reaction mixture was passed through a celite cartridge (10 g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue purified by MDAP (Method C). Appropriate fractions were combined and concentrated in vacuo to afford the title compound (43 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:15]([CH3:16])=[C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=3)[C:13]([CH3:26])=[C:12]([CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=3)[C:11]=2[CH3:36])[CH:5]=[CH:4][CH:3]=1.CO[CH:39](OC)[CH2:40][C:41](=O)[CH3:42].OP(O)(O)=O>O>[CH3:39][C:40]1[N:35]=[C:31]2[C:32]([CH:33]=[CH:34][C:29]([NH:28][CH2:27][C:12]3[C:11]([CH3:36])=[C:10]([CH2:9][NH:8][C:6]4[CH:5]=[CH:4][C:3]5[C:2](=[N:1][C:4]([CH3:5])=[CH:3][CH:2]=5)[N:7]=4)[C:15]([CH3:16])=[C:14]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]5[C:21](=[N:25][C:11]([CH3:12])=[CH:10][CH:9]=5)[N:20]=4)[C:13]=3[CH3:26])=[N:30]2)=[CH:42][CH:41]=1
Reactant: Cc1c(CNc2cccc(N)n2)c(C)c(CNc2cccc(N)n2)c(C)c1CNc1cccc(N)n1
Reactant: COC(CC(C)=O)OC
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2ccc(NCc3c(C)c(CNc4ccc5ccc(C)nc5n4)c(C)c(CNc4ccc5ccc(C)nc5n4)c3C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
1,3,5-Tris[(6-amino-pyridin-2-yl)aminomethyl]-2,4,6-trimethylbenzene (2a) (2.0 g, 4.1 mmol), 4,4-dimethoxy-2-butanone (12.3 mmol), and H3PO4 (50 mL) were held at 90° for 4 h and then stirred at room temperature for 2 h. The reaction mixture was poured into water (200 mL), neutralized, and extracted several times with chloroform. The collected organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified several times by column chromatography (silica gel, CHCl3/CH3OH, 7:1 to 2:1 v/v). Yield 30%. M.p. 207-208° C. 1H-NMR (400 MHz, CDCl3): δ=2.34 (s, 9H), 2.61 (s, 9H), 4.71 (d, 6H, 3H, J=3.0 Hz), 5.12 (t, 3H, J=3.0 Hz), 6.60 (d, 3H, J=8.8 Hz), 6.98 (d, 3H, J=8.0 Hz), 7.65 (d, 3H, J=8.8 Hz), 7.74 (d, 3H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): δ=15.9, 25.0, 41.1, 112.4, 114.9, 115.9, 133.3, 136.0, 136.5, 137.2, 156.5, 158.7, 161.3. HR-MS calcd for C39H38N9: 632.3250; found: 632.3256. Rf=0.80 (CHCl3/CH3OH 2:1 v/v).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[CH:27]=[N:26][N:25]=[C:24]1[CH:28]([OH:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[O-]S([O-])(=S)=O.[Na+].[Na+].CO.C(Cl)Cl>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[O:23]1[CH:27]=[N:26][N:25]=[C:24]1[C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(O)c1nnco1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
(140) A suspension of the Dess-Martin periodinane (1.2 equiv, 0.025 mmol, 11 mg) in anhydrous CH2Cl2 (0.5 mL) was treated with a solution of 1-([1,3,4]oxadiazol-2-yl)octadec-9-en-1-ol (7 mg, 0.021 mmol) in anhydrous CH2Cl2 (0.5 mL) at rt under N2. After 6 h the suspension was diluted with Et2O (10 mL), and poured into a solution of Na2S2O3 (77 mg) in saturated aqueous NaHCO3 (6.5 mL). The mixture was stirred at rt for 1 h and the layers were separated. The ethereal layer was washed with saturated aqueous NaHCO3 (1×10 mL) and H2O (1×10 mL), dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, 1.5 cm×15 cm, 2% MeOH—CH2Cl2) afforded 1-([1,3,4]oxadiazol-2-yl)octadec-9-en-1-one (140) (5 mg, 0.016 mmol, 75% yield) as a dark yellow oil: 1H NMR (CDCl3, 250 MHz) d 9.34 (s, 1H), 5.42-5.26 (m, 2H), 3.04 (t, J=7.4 Hz, 2H), 2.12-1.87 (m, 4H), 1.82-1.75 (m, 2H), 1.43-1.19 (m, 20H), 0.88 (br t, J=6.8 Hz, 3H); IR (CDCl3)umax 2940, 2860, 1705, 1612, 1547, 1510, 1423, 1380 cm−1; MALDI-FTMS (DHB) m/z 335.2689 (C20H34N2O2+H+ requires 335.2698).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([N:11]2[CH2:14][CH:13]([F:15])[CH2:12]2)=[O:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[OH:16][C:17]1[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=2)[CH:5]=[N:4][C:3]=1[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ncc(F)cc1F)N1CC(F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CC(F)C3)c(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 110 °C
Yield: 72 %

Procedure:
A mixture of (3,5-difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone (7.49 g, 34.60 mmol), methyl 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (7.69 g, 34.60 mmol) and Cs2CO3 (16.90 g, 52.0 mmol) in DMF was heated to 110° C. for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a white foam with ˜20% impurity (10.49 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.27 Hz, 1 H) 7.21-7.30 (m, 2 H) 6.98-7.06 (m, 1 H) 5.26-5.49 (m, 1 H) 4.64-4.77 (m, 1 H) 4.46-4.60 (m, 1 H) 4.28-4.42 (m, 1 H) 4.07-4.23 (m, 1 H) 3.88 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H20F2N2O5 m/z 419.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)=[O:24])=[CH:21][N:20]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:16]=2[N:17]=[CH:18][N:19]=1>N1C=CC=CC=1>[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:26]=[C:27]([NH:31][S:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Cl:1])(=[O:11])=[O:10])[CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:21][N:20]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NS(=O)(=O)c3ccc(F)cc3Cl)c1)cn2C1CCCC1
Temperature: 120 °C
Yield: 24.9 %

Procedure:
2-Chloro-4-fluorobenzenesulphonyl chloride (85.7 mg, 0.37 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (80 mg, 0.25 mmol) in pyridine (3 mL). The resulting solution was heated to 120° C. for 3 h. The reaction was quenched with water and concentrated. The residue was dissolved in EtOAc and washed with 1N NaOH (1×) and water (1×). The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a white solid (32 mg, 25%). MS: 514.1/516.1 (MH+); HPLC Rf: 6.12 min. (HPLC method 4).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1c(Br)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc(Br)c1N
Temperature: 25 °C

Procedure:
3,5-Dibromo-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dibromo-6-nitroaniline (500 mg, 1.69 mmol) and SnCl2.2H2O (1.90 g, 8.45 mmol) dissolved in 5 mL ethyl acetate and 2 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The thick yellow white emulsion was vacuum filtered and the filtrate extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale yellow oil which crystallized on standing to yield 400 mg (89%). 1H NMR (CDCl3) δ3.62 (br s, 4H, 2(NH2)); 6.78 (d, J=1.8, 1H, H-6); 7.01 (d, J=1.8, 1H, H-4).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:22]2[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:19][CH2:20][CH2:21]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)NCCO2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCOc2ccccc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in dichloromethane (1.5 mL) was added 3,4-dihydro-2H-benzo[1,4]oxazine (22.9 mg, 0.17 mmol, 1.1 equiv; [CAS RN 5735-53-5]), triethylamine (30.4 mg, 42 μL, 0.3 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (42.2 mg, 0.17 mmol, 1.1 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11 mg (18%) of the title compound. MS (ISP): 401.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[Br:14]N1C(=O)CCC1=O.[OH-].[K+]>CN(C=O)C.[Cl-].[NH4+]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([Br:14])=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]ncc12
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]nc(Br)c12
Reaction time: 1 h

Procedure:
To a solution of 1H-indazole-4-carboxylic acid methyl ester (380 mg, 2.2 mmol) in DMF (5 mL) was added N-bromosuccinimide (NBS) (976 mg, 4.32 mmol) and KOH (485 mg, 8.64 mmol). After 1 hour, the reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine (20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a solid.