Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.ClCI.[C:15]12([CH2:25][CH2:26][N:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]([NH:30][CH2:31]/[CH:32]=[CH:33]\[C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:29])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.[Cl-].[NH4+]>ClCCCl.C(OCC)(=O)C>[C:15]12([CH2:25][CH2:26][N:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]([NH:30][CH2:31][C@@H:32]3[CH2:1][C@@H:33]3[C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)=[O:29])[CH2:16][CH:17]3[CH2:18][CH:19]([CH2:20][CH:21]([CH2:23]3)[CH2:22]1)[CH2:24]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NC/C=C\c1ccncc1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NC[C@@H]1C[C@@H]1c1ccncc1
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A 1.0 M solution of diethylzinc in hexane (3.1 ml, 3.1 mmol) and chloroiodomethane (0.44 ml, 6.1 mol) were added to a solution of (Z)-1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea (Compound No. 1-111) in anhydrous 1,2-dichloroethane (3 ml) under a nitrogen atmosphere and ice-cooling, and the mixture was stirred for one hour. A saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture under ice-cooling, and the whole was stirred at room temperature for 20 minutes and distributed with ethyl acetate (20 ml) and a saturated aqueous ammonium chloride solution (10 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 9.0 mg (3.5%) of the titled compound as colorless crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].O.[CH:5]1([C:8]([C@H:10]2[C@H:15]([CH3:16])[CH2:14][C@H:13]3[C@H:17]4[C:26]([C@@H:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)=[CH:31][CH:30]=5)[CH2:28][C@:11]23[CH3:12])=[C:25]2[C:20](=[CH:21][C:22](=O)[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)=[O:9])[CH2:7][CH2:6]1>O1CCOCC1>[CH:5]1([C:8]([C@H:10]2[C@H:15]([CH3:16])[CH2:14][C@H:13]3[C@H:17]4[C:26]([C@@H:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)=[CH:31][CH:30]=5)[CH2:28][C@:11]23[CH3:12])=[C:25]2[C:20](=[CH:21][C:22](=[N:2][OH:3])[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)=[O:9])[CH2:7][CH2:6]1
Reactant: NO
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=NO)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Hydroxylamine hydrochloride (20 mg, 0.30 mmol) and water (1 mL) were added to a stirred solution of 100 mg (0.20 mmol) of (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature and then extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification of the crude product by HPLC followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one 3-oxime as an E/Z mixture (2:1) (85 mg, 0.17 mmol, 84% yield). 1H NMR (400 MHz, CDCl3): δ 0.31 and 0.32 (2×s, in total 3H), 0.83-2.95 (m, 25H), 4.37-4.42 (m, 1H), 5.89 and 6.55 (2×s, in total 1H), 7.26-7.32 (m, 2H), 7.35 (dd, J=8 and 5 Hz, 1H), 7.47-7.51 (m, 2H), 7.86 (dt, J=8 and 1 Hz, 1H), 8.57 (dd, J=5 and 1 Hz, 1H), 8.84 (d, J=1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])/[CH:14]=[CH:15]/[CH3:16].C1(N(C)C2CCCCC2)CCCCC1.O>O1CCOCC1.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(OCC)(=O)C>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2](/[C:15](/[CH3:16])=[CH:14]\[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: C/C=C/C(=O)OCC
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: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(/C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A solution of 8-bromo-2-methylquinoline (2.00 g, 9.01 mmol), (E)-ethyl but-2-enoate (3.36 mL, 27.0 mmol), N-cyclohexyl-N-methylcyclohexanamine (5.79 mL, 27.0 mmol), and Pd(PtBu3)2 (0.23 g, 0.45 mmol) in dioxane (10 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 40M column, 0-100% CH3CN/water gradient; 30 column volumes) to give (Z)-ethyl 3-(2-methylquinolin-8-yl)but-2-enoate (0.81 g, 35.2%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A solution of 16 (1.77 g, 3.90 mmol) in anhydrous DMF (20 mL) under Ar was treated with NaH (206 mg, 5.1 mmol, 1.3 equiv, 60% oil dispersion) and the reaction mixture was stirred for 30 min. The mixture was cooled to 0° C. and 4-bromo-2-methyl-2-butene (1.35 mL, 11.7 mmol, 3 equiv) was added dropwise by cannula. The solution was stirred at 0° C. for 1 h before being allowed to warm to 25° C. and stirred overnight. Water (20 mL) was added and the aqueous phase was extracted with EtoAc (3×15 mL). The combined organic phases were washed with saturated aqueous NaCl (1×30 mL), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) afforded 17 (2.05 g, 2.03 g theoretical, >99%) as an amber oil: 1H NMR (CDCl3, 400 MHz) δ8.66 (d, 1H, J=0.5 Hz), 8.40 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.51-7.34 (m, 5H), 6.85 (s, 1H), 5.24 (d, 1H, J=9.5 Hz), 5.20 (d, 1H, J=11.7 Hz), 5.17 (d, 1H, J=11.7 Hz), 4.40 (dd, 1H, J=6.1, 14.5 Hz), 4.01 (dd, 1H, J=7.7, 14.9 Hz), 1.61 (s, 3H), 1.57 (s, 3H), 1.37 and 1.30 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ153.7, 140.9, 136.3, 135.8, 133.5, 128.8, 128.5, 127.3, 126.7, 124.1, 119.8, 119.5, 118.8, 111.7, 110.9, 81.0, 80.5, 70.8, 47.7, 46.3, 28.5, 28.2, 25.7; IR (film) vmax 3467 (br), 2928, 2229, 1701, 1676, 1596, 1503, 1438, 1387, 1335, 1255, 1164, 1090, 863, 738 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>CN(C)C=O>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(N)=O)cc1
Yield: 60 %

Procedure:
4-Aminobenzamide (29 mmol) and triethylamine (33 mmol) were dissolved in dimethylformamide (100 mL) and acryloyl chloride (33 mmol) was dropped thereinto under ice-cooling. After the completion of the addition, the resultant mixture was stirred at room temperature for 2 hours. After filtering off the precipitate, the solvent was distilled off. Then the solid matter thus obtained was recrystallized from a solvent mixture of water with methanol to give 4-acrylamidobenzamide at a yield of 60%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:51]1[S:52][CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[N:55]=1>>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:51]3[S:52][CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[N:55]=3)=[CH:22][CH:23]=2)[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)S(=O)(=O)c2ccccn2)n1
Reactant: FC(F)(F)c1csc(Br)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nc(C(F)(F)F)cs3)cc2)S(=O)(=O)c2ccccn2)n1
Yield: 90 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 22-(c) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (490 mg, containing 0.700 mmol of a pure content) obtained in Example 22-(b), and using 2-bromo-4-trifluoromethylthiazole (see WO 2005/077912A) (341 mg, 1.47 mmol) in place of 2-bromo-5-methylthiazole to afford the title compound (454 mg) as a white foam. (Yield: 90%)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][N:22]=[C:21]2[N:31]([CH2:40][C:41](O)=[O:42])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=12.Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Cl:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][N:22]=[C:21]2[N:31]([CH2:40][C:41]([N:14]3[CH2:15][CH2:16][CH2:17][N:11]([CH3:10])[CH2:12][CH2:13]3)=[O:42])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CN1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and 1-methyl 1,4-diazepane (34 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h. The reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 65 as a white solid (25 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13]C(C2CC2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:20])[C:8]=2[F:19])[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:20])[C:8]=2[F:19])[N:3]=1
Reactant: Cc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2ccc(F)c(F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
2,3-Dimethyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1.5 g) prepared as described in Example 4 was dissolved in 15 ml of methanol. A 10% aqueous sodium hydroxide solution (15 ml) was added to the solution, and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.1 g of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline. In 5 ml of dimethyl formamide was suspended 11.5 mg of 60% sodium hydride. Separately, 50 mg of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) prepared above was suspended in 5 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 20 mg of acetyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 54.2 mg of 2,3-dimethyl-4-acetoxy-5,6-difluoroquinoline (compound 44). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.C1(C)C=CC=CC=1.O=S(Cl)[Cl:30]>CN(C=O)C>[ClH:30].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([Cl:30])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Cl)cc2[nH]1
Product: Cl
Reaction time: 18 h

Procedure:
To a mixture of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (8.0 g) in SOCl2 (30 mL) was added 5 drops of DMF. After the suspension was stirred for 18 h, toluene (20 mL) was added and mixture was stirred for an additional 1 h. The suspension was filtered, washed with toluene and CH2Cl2. The white solid was dried under reduced pressure give 2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carbonyl chloride HCl salt; MS (ESI)m/z 267 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1>CN(C=O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:25][C:26]2[CH:30]=[C:29]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][N:27]=2)[C:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:8][N:7]=1)=[O:5]
Reactant: CCOC(=O)c1ncc(C(=O)OC(C)(C)C)[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(C(=O)OC(C)(C)C)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 260 mg of 3H-Imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester [prepared by adopting a procedure described by J.-C. Aloup, F. Audiau, M. Barreau, D. Damour, A. Genevois-Borella, P. Jimonet, S. Mignani, Y. Ribeill PCT Int. Appl. (1996) WO96/02544 A1] in DMF (10 ml) was added potassium carbonate (178 mg) and 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (301 mg). The mixture was stirred for 2 h at RT. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica (n-heptane/ethyl acetate 2:1 to ethyl acetate) to provide 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-2,5-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester (73 mg, 15%; MS (ESI+): m/e=437, chloro pattern) and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester (342 mg, 72%; MS (ESI+): m/e=437, chloro pattern) as white solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCOCc1cccnc1

Procedure:
1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-(1-naphthoyl)piperazine (0.300 g, 0.780 mmol) was reacted with sodium hydride (0.312 g, 60% dispersion in oil, 7.8 mmol) and 3-chloromethylpyridine (0.497 g, 3.9 mmol) according to the procedure described in Example 7, Step C. The crude product was chromatographed on silica gel with 3% methanol in chloroform. The title compound was obtained as an oil, (0.180 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:11]([NH:13][CH3:14])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20]CO[CH2:17][CH2:16]2)[N:3]=1.[C:21](=[O:24])([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29]Br>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:21][O:24][CH2:17][CH2:16]2)[C:5]2[N:6]=[C:7]3[N:8]([C:9]=2[N:10]=1)[CH2:29][CH2:28][N:13]([CH3:14])[CH:11]3[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CNC(C)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: BrCCBr
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1c2nc3c(N4CCOCC4)nc(Cl)nc3n2CCN1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
A mixture of: [1-(2-chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-methyl-amine (95 mg, 0.32 mmol), cesium carbonate (652 mg, 2 mmol) and 1,2-dibromoethane (0.030 mL, 0.35 mmol) in DMF (5 mL) was stirred at RT for 4 h. Another portion of 1,2-dibromoethane (0.030 mL, 0.35 mmol) was added and stirring was continued for 20 h. The reaction mixture was diluted with water and extracted seven times with ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2) gradient 0-4% methanol in DCM) to give 3-Chloro-7,8-dimethyl-1-morpholin-4-yl-5,6,7,8-tetrahydro-2,4,4b,7,9-pentaaza-fluorene (76 mg, 74%). LCMS RT=1.82 min, [M+H]+=323/325
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11](Cl)=[O:12])#[N:3]>O1CCCC1.O>[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11]([NH2:1])=[O:12])#[N:3]
Reactant: N
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a stirred, ice-cold solution of 10 mL (0.15 mole) of concentrated aqueous ammonia in 15 mL of tetrahydrofuran was added dropwise a solution of 0.35 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 15 mL of tetrahydrofuran. Upon completion of the addition, the cooling bath was removed. The reaction vessel was closed by placing a rubber balloon over the open inlet of the reaction vessel. The reaction mixture was then allowed to warm to ambient temperature where it was stirred for one hour. After this time, the reaction mixture was concentrated at 45° C. under reduced pressure to a residual solid. The solid was triturated with petroleum ether and filtered, yielding a solid that did not completely melt at 212° C. The filtrate was concentrated in an air current, yielding a tan-yellow solid. Both solids were stirred in water separately. Each of the solids was then collected by filtration. The tan-yellow solid was triturated with two drops of isopropyl alcohol and petroleum ether. The suspension was cooled in a dry ice bath, and the solid was collected by filtration. The two solids were combined and dried, yielding 0.18 gram of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]-acrylamide, m.p. 208°-210° C., dec. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (307 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (549 mg) and HOBT (439 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (420 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (3.7 g) was added. The reaction mixture was heated at reflux overnight. The organic solvent was evaporated off in vacuo and purified by column chromatography to give ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D164) (240 mg) as white solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([O:14][C:15](=[O:16])[C:10]=12)=O.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>CN(C=O)C>[O:24]=[C:23]1[CH:22]([N:21]2[C:15](=[O:16])[C:10]3[C:11](=[CH:17][CH:18]=[CH:19][C:9]=3[OH:8])[C:12]2=[O:14])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3-hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and rac-α-aminoglutarimide hydrochloride (3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90° C. overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50° C. the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.45-2.61 (m, 2H), 2.82-2.96 (m, 1H), 5.08 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.23-7.33 (m, 2H), 7.66 (dd, J=8.2 Hz, J=7.2 Hz, 1H), 11.10 (s, 1H), 11.19 (s, 1H).