Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.C(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=4)=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (44.2 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-5-(6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one as a white solid (20 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:29])/[C:21](=[CH:22]/[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)/[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:29])[CH:21]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1Cc1ccccn1
Yield: 83.9 %

Procedure:
(E)-1-(4-Fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (19.53 g, 50.8 mmol) (assumed 100% for previous reaction), in toluene (500 mL) with palladium hydroxide on carbon (20% wet) (1.784 g, 2.54 mmol) was stirred for about 22 h under an atmosphere of hydrogen provided by a balloon. The catalyst was removed by filtration through a pad of Celite® and the pad was washed with DCM (250 mL). The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using a gradient from 0-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield 1-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (115, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (16.47 g, 84%); LC/MS, method 3, Rt=1.97 min, MS m/z 387 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.47-8.46 (m, 1H), 8.34 (s, 1H), 8.33-8.26 (m, 2H), 8.09 (s, 1H), 7.72-7.68 (m, 1H), 7.46-7.34 (m, 3H), 7.23-7.17 (m, 1H), 5.00-4.97 (m, 1H), 3.88-3.82 (m, 1H), 3.72-3.65 (m, 1H), 3.36-3.29 (m, 1H), 3.25-3.19 (m, 1H), 3.07-2.99 (m, 1H), 2.54-2.48 (m, 1H), 2.33-2.25 (m, 1H), 1.80-1.69 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[N:13]=[C:14]([CH3:20])[N:15]2[CH:19]=[CH:18][S:17][C:16]=12)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Si:1]([O:8][CH2:9][C:10]([C:12]1[N:13]=[C:14]([CH3:20])[N:15]2[CH:19]=[C:18]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[S:17][C:16]=12)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(C(=O)CO[Si](C)(C)C(C)(C)C)c2sccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C(=O)CO[Si](C)(C)C(C)(C)C)c2s1
Reaction time: 1 h

Procedure:
7-t-Butyldimethylsilyloxyacetyl-5-methylimidazo-[5,1-b]thiazole (49.5 mg) was dissolved in 2 ml of THF and 0.4 ml of HMPA. Tri-n-butylstannyl chloride (0.059 ml) and 0.319 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to the solution in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for one hr. A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (0.160 ml) was added dropwise thereto. The mixture was stirred at the same temperature for additional 40 min. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and washing three times with brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 66.9 mg of the title compound.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)C)=O)(C)(C)C.[ClH:20]>O1CCOCC1>[CH3:6][NH:8][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.[ClH:20]
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 10 °C

Procedure:
A solution of 3.86 g (14.23 mmol) of trans-4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexanecarboxylic acid was dissolved in 36 mL of dioxane, cooled to 10° C. and treated with 35.5 mL (142.25 mmol, 10 eq) of 4M HCl in dioxane, then warmed to RT. The solution was evaporated after 2 h to ca. 15 mL, cooled to 0° C. and precipitated with ˜100 mL of Et2O. The solid precipitate was filtrated, washed with Et2O (×3) and dried under reduced pressure to yield 2.66 g (90%) of trans-4-methylaminomethyl-cyclohexanecarboxylic acid·HCl, MS: 172 (MH+), MP: 261° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](=[O:8])[O:6][CH:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:20](=[CH2:22])=[N-:21]>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)C>[N+:20](=[CH:22][C:11](=[O:13])[CH2:10][CH2:9][CH:5]1[O:6][C:7](=[O:8])[C:3]([O:2][CH3:1])=[C:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N-:21]
Reactant: C=[N+]=[N-]
Reactant: COC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=C(c2ccccc2)C(CCC(=O)C=[N+]=[N-])OC1=O
Reaction time: 1 h

Procedure:
A solution of 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (500 mg) in thionyl chloride (2 ml) was heated at 70° C. with stirring for 1 hour. After cooling, the solvent was removed under the reduced pressure to give a residue which was taken up in methylene chloride. To this solution was added dropwise a solution of diazomethane in diethyl ether. The solvent was removed under the reduced pressure to give 5-(4-diazo-3-oxobutyl)-3-methoxy-4-phenyl-2(5H)furanone (465 mg) which was recrystallized from diisopropyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][C@H:27]12>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:30][CH2:29][N:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]5[CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1C[C@@H]2CNCCN2C1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN5CCC[C@@H]5C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-octahydropyrrolo[1,2-a]pyrazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 4 H) 2.33 (d, J=2.53 Hz, 3 H) 2.81-4.24 (m, 9 H) 7.64 (br. s., 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.95-8.83 (m, 4 H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(Cl)c2)cn1
Yield: 29 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (49 mg, 29%) which was obtained as a white solid. MS (ESI): m/e=335.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>CCCCO>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 60 %

Procedure:
225 mg of 6-chloro-N-(4-phenoxyphenyl)pyrimidin-4-amine, 82 mg of ethanolamine and 173 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC purification (EtOAc:EtOH=10:1). 2-(6-(4-Phenoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([CH:18]([C:21]1[C:22]2[N:23]([C:28](I)=[C:29]([CH3:31])[N:30]=2)[N:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:19][CH3:20])[CH3:17]>C1COCC1.CCCCCC.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:28]1[N:23]2[N:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH:18]([CH2:16][CH3:17])[CH2:19][CH3:20])[C:22]2=[N:30][C:29]=1[CH3:31]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Brc1csc2ncccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ncccc4c3Br)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 14.3 %

Procedure:
214 mg of 3-Bromo-thieno[2,3-b]pyridine (1.0 mmol) is dissolved in 1.5 ml of dry THF and cooled to −78° C. 0.44 ml of n-butyl lithium 2.5M in hexane is added slowly and stirred at −78° C. for 10 min. 2.2 ml of 0.5 M ZnCl2 in THF (1.1 mmol) is added and stirred at room temperature for 20 min. 274 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.8 mmol) and 33 mg of PdCl2(dppf) (0.04 mmol) are added. The reaction vial is capped and heated at 80° C. for 3 days. The reaction is filtered and applied onto a silica-gel chromatography column (Hexane: AcOEt=8:1) to give 49 mg of the 3-(3-bromo-thieno[2,3-b]pyridin-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (11%) and 33 mg of reduced compound, 8-(1-ethyl-propyl)-2,6-dimethyl-3-thieno[2,3-b]pyridin-2-yl-imidazo[1,2-b]pyridazine, (9%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[C:16]([O-])(=[O:18])[CH3:17].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>CS(C)=O>[C:16]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13])(=[O:18])[CH3:17]
Reactant: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Yield: 79.9 %

Procedure:
A solution of 2,6-dichloro-3-nitrobenzenesulfonamide (2.04 g, 7.5 mmol), potassium acetate (2.21 g, 22.5 mmol) and 18-crown-6 (5.95 g, 22.5 mmol) in 50 mL of dimethyl sulfoxide was heated to 45° C., for 7 days. The mixture was acidified with 1N aq. HCl, and extracted with ethyl acetate. The organic layer was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v) gave the desired product (1.67 g, 76%). EI-MS (m/z) 293.1, 295.1 (M−).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:24][C:22]1[CH:23]=[C:18]([CH2:17][C:16]([NH:15][CH2:14][CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[O:28])[CH:19]=[C:20]([Br:27])[C:21]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(Br)cc(CC(=O)NCCc2cccc(N)c2)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2cccc(NS(C)(=O)=O)c2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.0313 g, 0.000273 mol) was added to DMAP (0.0334 g, 0.000273 mol) in methylene chloride (6 mL). To the resulting white complex N-[2-(3-amino-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.1 g, 0.000226 mol) in methylene chloride (6mL) was added dropwise. The reaction mixture was stirred for 18 h at room temperature, washed with 1 N HCl and 1 N NaOH. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, 1:1 ethyl acetate-hexane mixture). Yield 0.058 g, 49%. MS m/e 518.7 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].Cl[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: CC[Si](Cl)(CC)CC
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](CC)(CC)CC

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.4 eq chlorotriethylsilane. Purification by HPLC with 1:19 ethyl acetate/hexanes gave 6.0 g of the desired product as a clear oil, a 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:41]4[CH2:42][CH2:43][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=590.99 (M+H+); retention time=1.04 minutes.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[C:21]([CH3:26])=[N:22][N:23]([CH3:25])[CH:24]=4)[OH:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[CH3:29][C:30]([OH:34])([CH3:33])[C:31]#[CH:32]>>[CH3:25][N:23]1[CH:24]=[C:20]([CH:18]([OH:19])[C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:28])[C:2]([C:32]#[C:31][C:30]([OH:34])([CH3:33])[CH3:29])=[CH:27][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[C:21]([CH3:26])=[N:22]1
Reactant: C#CC(C)(C)O
Reactant: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: Cc1nn(C)cc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 19 %

Procedure:
3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 11.3 mg of the titled compound (19% yield). M+1=436.1. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.87 (br s, 1H), 7.40 (br s, 1H), 7.25 (s, 1H), 6.99 (d, J=10.5 Hz, 1H), 6.72 (d, J=6.3 Hz, 1H), 6.52 (d, J=6.2 Hz, 1H), 5.54 (s, 1H), 4.58-4.25 (m, 4H), 3.65 (s, 3H), 2.06 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[O-:16][C:17]#[N:18].[K+]>O.CN(C)C1C=CN=CC=1>[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)[C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrochloride (1.0 g) was dissolved in water (25 ml), to which solution potassium cyanate (0.4 g) and 4-dimethylaminopyridine (about 0.005 g) were added. The mixture was stirred at room temperature for 18 hours and the resulting suspended material collected by filtration. This was washed in hot dimethylformamide (30 ml), the insoluble material being collected and washed with water to afford the title compound, m.p.>300° C.; n.m.r. δ(DMSO-d6) 5.90 (s, 2H,--CONH2), 7.98, 8.10 (2d, 2H, pyridine H's); ν(liquid paraffin) 1710, 1665 cm-1.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][O:27][C:28]4[CH:32]=[CH:31][O:30][N:29]=4)[O:23][C:22]3=[O:33])=[CH:17][C:16]=2[F:34])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][O:27][C:28]4[CH:32]=[CH:31][O:30][N:29]=4)[O:23][C:22]3=[O:33])=[CH:17][C:16]=2[F:34])[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(-n2cnc(CO)c2)c(F)c1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (0.59 g, 1.2 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0°. A solution of tetra-n-butylarnmonium fluoride (1 M, 5 ml, 5 mmol) was added and the mixture stirred 3 hours as the temperature rose to ambient. The mixture was evaporated to drvness, redissolved in dichloromethane (50 ml), washed with water (3×25 ml), and dried over magnesium sulfate. After filtration and evaporation the residue was purified by chromatography on a 10 g silica Mega Bond Elut® column. cluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (245 mg). MS (ESP): 375 (MH+) for C17H15FN4O5.
Reaction SMILES: [N:1]#[C:2]Br.[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([NH:11][NH2:12])=[O:10])([O-:6])=[O:5]>C(#N)C>[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]1[O:10][C:2]([NH2:1])=[N:12][N:11]=1)([O-:6])=[O:5]
Reactant: N#CBr
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1nnc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
4 ml of a 5M cyanogen bromide solution in acetonitrile were added dropwise to the solution of 3.6 g of 2-nitrobenzoic hydrazide in 20 ml of acetonitrile. This resulted first in a clear solution, then a solid precipitated out which was filtered off with suction after continuing to stir for a short time, washed again with acetonitrile and dried under reduced pressure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:16][C:13]1[CH:14]=[CH:15][N:10]=[N:11][CH:12]=1)=[O:48]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Nc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.61 ml, 9.23 mmol), 4-pyridazinamine (0.53 g, 5.54 mmol) and HATU (2.63 g, 6.92 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.5 g, 4.61 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours and the solid was filtered and washed with ethyl acetate to yield the title compound as a white solid. 658 mg.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25](O)[CH3:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18]
Reactant: CC(O)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5 mmol) of (thiophen-2-yl)-ethanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:6) to obtain the product as a oil (0.28 g).