Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=3)=[O:33])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ccc(F)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (300 mg) in ethanol (5 mL) were added 5-fluoropyridine-2-carbaldehyde (130 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (26 mg) and triethylamine (52 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (65 mg, yield 16%) as a brown oil. MS: 474 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1([F:42])[O:34][C:33]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:32]=2[O:31]1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:42][C:30]1([F:29])[O:31][C:32]2[CH:38]=[CH:37][C:36]([O:27][C:25]3[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:35][C:33]=2[O:34]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OC(F)(F)O3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.4 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.20 g, 0.493 mmol), (2,2-difluoro-1,3-benzodioxol-5-yl)boronic acid (303 mg, 1.5 mmol), copper (II) acetate (0.202 g, 1.11 mmol), triethylamine (0.52 mL, 3.71 mmol) and freshly activated 4 Å molecular sieves (1 g) in DCM (40 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2×10 mL), the DCM removed in vacuo. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual oil dissolved in methanol (5 mL) and the mixture stirred at room temperature for 20 minutes. The solution was neutralised with saturated sodium bicarbonate solution, the methanol removed in vacuo and the residual solution partitioned between ethyl acetate (50 mL) and water (10 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 3% methanol in DCM, to give the desired compound (3.1 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CN(CCN(C)C)C.C([Li])(CC)C.C1CCCCC1.C1C[O:42][CH2:41]C1>CN(C)C=O>[CH:41]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:18])([F:19])[F:1])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:42]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A magnetically stirred solution of tert-butyl 4-(trifluoromethoxy)phenylcarbamate (19.95 g, 72 mmol) and TMEDA (16.7 g, 144 mmol) in THF (300 mL) at −78° C. was treated with the dropwise addition of a 1.4M solution of sec-butyllithium in cyclohexane (170 mL, 237 mmol), at a rate which maintained the internal temperature below −60° C. The mixture was stirred for 1 h at −78° C., then allowed to warm to −50° C. and stirred an additional 30 min. The solution was returned to −78° C., treated with the dropwise addition of N,N-dimethylformamide, at a rate which maintained the internal temperature below −60° C. The reaction was stirred at −78° C. for 30 min, allowed to warm to −20° C., then quenched with the addition of saturated ammonium chloride solution (200 mL). The mixture was transferred to a 1 L seperatory funnel, diluted with diethyl ether (400 mL), and the layers were separated. The organic phase was washed successively with saturated ammonium chloride solution (100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo to a yellow solid. The solid was purified over silica gel, eluting with 5% ethyl acetate/hexanes, to yield 18.36 g of a colorless solid as product. 1H NMR (400 MHz, CDCl3) δ ppm 1.55 (m, 9 H) 7.26 (s, 4 H) 7.43 (dd, J=9.23, 2.64 Hz, 6 H) 7.48 (s, 1 H) 8.54 (d, J=9.23 Hz, 1 H) 9.88 (s, 1 H) 10.33 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:34])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:34])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([O:32][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][O:35]4)([CH3:31])[CH3:33])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)Cc1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Cc1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)OC1CCCCO1
Temperature: 25 °C

Procedure:
A solution of the alcohol of Step 2 (390 g, 8.29 mmol), 3,4-dihydro-2H-pyran (7.4 mL, 81 mmol) and pyridinum p-toluenesulfonate (684 mg, 2.7 mmol) in 44 mL of CH2Cl2 was heated at reflux for 23 hours. The reaction mixture was allowed to cool to r.t. and 10% aq. NaHCO3 was added. The title product was extracted with CH2Cl2, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 5:95. Yield: 4.22 g, 92%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.O.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[I:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cnc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml) was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). The reaction mixture was stirred at RT for 2 days and then added to water (800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO3 solution and the resulting suspension was filtered, washing with water (×3) and dried under vacuum to afford the titled compound as an orange solid;
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12](B4OC(C)(C)C(C)(C)O4)[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][N:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:38]4[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][N:39]=4)[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: O=Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cn3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) and 6-bromonicotinaldehyde (0.047 g, 0.25 mmol) in dioxane/water mixture (2 mL+0.5 mL), Cs2CO3 (0.219 g, 0.239 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.031 g, 0.025 mmol) was added and argon was purged again for 10 min. Reaction mixture was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(5-formylpyridin-2-yl)-1H-indazole-4-carboxamide (0.053 g, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[CH2:14][O:13][C:12]3=[O:24])=[N:7][C:6]=12.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[C:41]1[N:45]=[CH:44][N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:42]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[O:22][CH3:23])[CH2:14][O:13][C:12]4=[O:24])=[N:7][C:6]=23)[CH:29]=[CH:28][C:27]=1[C:41]1[N:45]=[CH:44][N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:42]=1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Reactant: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(F)c3)c2n1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
To a round bottom flask were added (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-methoxyphenyl)oxazolidin-2-one (0.103 g, 0.265 mmol), 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.144 g, 0.344 mmol), dioxane (2 mL) and 2.0 M Na2CO3 (0.40 mL, 0.80 mmol). The mixture was degassed by bubbling N2 through the solution. Pd2 dba3 (0.012 g, 0.013 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.013 g, 0.027 mmol) were added, and the mixture was heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with H2O, and extracted thoroughly with EtOAc and DCM. The combined organic extracts were washed with brine, dried, and concentrated. Purification of the crude material on silica, eluting with 70% EtOAc/hexanes, to provide (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-methoxyphenyl)oxazolidin-2-one as a bright yellow solid (0.0848 g, 53%). MS (APCI+) m/z 601 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>C(Cl)Cl>[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (17.5 mmol, 75% pure) in 40 mL of DCM was added Et3N (2.69 mL, 19.3 mmol) and (R)-(+)-3-(dimethylamino)pyrrolidine (2.0 g, 17.5 mmol). After stirring overnight at ambient temperature under an atmosphere of N2, the reaction solution was concentrated, added aq. NaHCO3 (100 mL), and the resulting mixture extracted with DCM (4×50 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM) to provide 3.35 g of product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][CH2:10][C:11](=[O:13])[NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)OC(C)(C)C
Yield: 20 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl) prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.30 mL, 0.40 g, 3.18 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with glycine tert-butyl ester (H-GlyOtBu) (0.53 g, 3.18 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.16 g (20% yield) of the title compound (34) as a semi-solid material. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.95-6.69 (m, 2H), 6.63 (br. m, 1H), 4.73 (s, 2H), 3.99 (d, J=4.8 Hz, 2H), 3.83 (s, 3H), 1.48 (s, 9H). MS (ESI): m/z 324.05 (M+Na+)+.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.[NH2:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[C:44]([CH3:49])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:46]4[CH:45]=[C:44]([CH3:49])[N:43]=[C:42]([NH2:41])[N:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(N)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-amino-4-chloro-6-methylpyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]([OH:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:33](=[O:34])([O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[O:16][CH:14]([CH3:15])[C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:10]1)[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 420 mg (0.91 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol, prepared according to the procedures of Example 35, and 222 mg (1.82 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 276 mg (1.37 mmol) of 4-nitrophenyl chloroformate and was stirred for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound as a white solid. Mass Spectrum: m/e=627 (M+1 35Cl, 35Cl) and 629 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]([O:11][CH2:12]C)[CH:9]=C>>[CH2:8]([O:11][CH2:12][CH:4]=[CH:3][CH2:2][CH2:1][CH:5]1[CH2:7][O:6]1)[CH3:9]
Reactant: C=CCOCC
Reactant: C=CCCC1CO1
Product: CCOCC=CCCC1CO1

Procedure:
The cross metathesis of (±)-2-(but-3-enyl)oxirane (3.80 g, 38.7 mmol) with ethyl allyl ether (10.0 g, 116 mmol) was performed as described previously in Example 9.2, Step A to give (±)-2-(5-ethoxypent-3-enyl)oxirane as an inseparable mixture of olefin isomers (trans:cis=10:1) after silica gel chromatography. 1H NMR (400 MHz, CDCl3): trans isomer: δ 5.73 (1H, m), 5.63 (1H, m), 3.91 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.48 (1H, dd, J=5.0, 2.7 Hz), 2.22 (2H, m), 1.63 (2H, m), 1.21 (3H, t, J=7.0 Hz). cis isomer: δ 5.62 (2H, m), 4.04 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m), 2.22 (2H, m), 1.63 (2H, m), 1.22 (3H, t, J=7.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[CH:14]2)=[CH:9][CH:8]=1)=[O:6])C.[Li+].[OH-].Cl>C1COCC1>[N:15]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5](=[O:6])[C:4]([OH:22])=[O:3])=[CH:12][CH:11]=2)[CH:14]=1
Reactant: CCOC(=O)C(=O)c1ccc(-n2cnc3cccnc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(-n2cnc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of (4-imidazo[4,5-b]pyridine-3-yl-phenyl)-oxo-acetic acid ethyl ester (123 mg, 0.417 mmol) and 1N LiOH (0.5 mL, 0.5 mmol) in THF (4 mL) is stirred at rt for 5 min. 1M HCl (500 μL) is then added and the resulting precipitate filtered off. (4-Imidazo[4,5-b]pyridine-3-yl-phenyl)-oxo-acetic acid is obtained as a grey solid. Title compound: ES-MS=268.05 [M+H]+; tR=0.8 min (System 2).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH:9]=3.Cl[CH2:25][C:26](=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:25][C:26](=[O:28])[CH3:27])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH:9]=3
Reactant: CC(=O)CCl
Reactant: O=c1cc2c(nn1-c1ccc(O)cc1)-c1cc(F)ccc1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1
Yield: 84.6 %

Procedure:
A mixture of 5 g of 9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, 4.5 g of chloroacetone, 8.8 g of potassium carbonate and 100 ml of acetone is heated under reflux for 9 hours. After acetone is distilled off, water and isopropyl ether are added to the residue. The resultant crystals are collected and washed with ethanol to give 5 g of crude 9-fluoro-2-[4-(2-oxopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, which is subjected to the following reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][C:19]1[N:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[K+]>C1COCC1.CO>[OH:17][CH2:18][C:19]1[N:24]=[CH:23][C:22]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: CC(=O)OCc1ccc(O)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(CO)nc1
Yield: 13 %

Procedure:
A sample of (S)-1-t-butoxycarbonyl-2-azetidinemethanol (1.64 g, 8.18 mmol) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36 (1983), were reacted with triphenylphosphine (540 mg, 2.06 mmol) and DEAD (0.33 mL, 2.06 mmol) in THF (25 mL ) according to the procedure of Example 2a. The product was stirred in methanol (4 mL) containing KOH (450 mg) at room temperature for 4 hours, then neutralized and concentrated. The residue was purified by chromatography (silica gel; 1:1 ether:hexane and ethyl acetate) to give title compound (240 mg, 41% for two steps). MS (DCI/NH3) m/e: 295 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.42 (s, 9H), 2.24-2.48 (m, 2H), 3.84-3.96 (m, 2H), 4.18 (dd, J=2.6, 11 Hz, 1H), 4.40 (m, 1H), 4.53 (m, 1H), 4.82 (s, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.51 (m 1H), 8.31 (d, J=3.0 Hz, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)([CH3:3])[CH3:2]>C(O)C.[Ni]>[CH:1]([NH:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: CC(C)NC(=O)Cc1cccc(N)c1
Yield: 91 %

Procedure:
22.2 g (0.1 mol) of 3-nitrophenyl-acetic acid isopropylamide were dissolved in 150 ml of ethanol and hydrogenated under a hydrogen pressure of 40-50 atmospheres in the presence of Raney nickel at 50°-60° C. When the reaction had finished, the catalyst was filtered off, the filtrate was concentrated by evaporation under reduced pressure and the residue which remained was recrystallized from petroleum ether. 17.5 g (91% of theory) of 3-amino-phenylacetic acid isopropyl-amide of melting point 93°-95° C were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Reactant: C=CC(=O)Cl
Agent: Cl
Product: C=CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 68 for 158, 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide HCl salt and acryloyl chloride reacted to give 8-acrylamido-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide which was treated with dimethylamine to give 161. MS: (ESI+) 484.1