Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[N:25]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CS(C)=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>[F:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([C:26]2[N:25]=[C:24]([C:9]3[CH:21]=[CH:20][C:12]4[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=4[CH:10]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])=[CH:38][CH:37]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cccc(Cl)n1
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: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cccc(S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.3 g, 1 mmol), 2-chloro-6-(4-fluorophenylsulfonyl)pyridine (0.230 g, 0.8 mmol), 2M Na2CO3 (0.8 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.1 mmol), and dioxane (6 mL). The flask was heated in a pre-heated (95° C.) bath and allowed to stir under an inert atmosphere for 2.5 hours. The mixture was allowed to cool to ambient temperature and diluted with DMSO and filtered. The crude material was purified by reverse-phase HPLC to give N-(6-(6-(4-fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428 (MH+). Calculated exact mass for C20H14FN3O3S2: 427. 1H NMR (400 MHz, DMSO-d6): 8.06-8.27 (m, 5H), 7.97-7.99 (m, 1H), 7.82-7.84 (m, 1H), 7.52-7.54 (m, 2H), 7.37-7.40 (m, 1H), 1.96 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([OH:13])[N:7]2[N:6]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:20]O>>[OH:13][C:12]1[N:7]2[N:6]=[C:5]([CH2:4][C:1]([O:3][CH3:20])=[O:2])[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=1
Reactant: CO
Reactant: Cc1cc(O)n2nc(CC(=O)O)nc2n1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1nc2nc(C)cc(O)n2n1

Procedure:
A solution of the product obtained in Step 2 (1.5 g) in 50 ml of methanol was cooled to 0° C., 24 ml of thionyl chloride was added by dropwise to this solution at that temperature, and the mixture was refluxed for 1.5 hours. After removing the solvent by distillation under reduced pressure, the residue was recrystallized from ethyl acetate/ether, giving 1.5 g of the objective compounds.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:42])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)(=[O:29])=[O:28].[Cl:43][C:44]1[C:45]([C:54]([F:57])([F:56])[F:55])=[N:46][N:47]([CH2:50][C:51](O)=[O:52])[C:48]=1[CH3:49]>>[Cl:43][C:44]1[C:45]([C:54]([F:56])([F:55])[F:57])=[N:46][N:47]([CH2:50][C:51]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:32]=[CH:31][C:30]([S:27]([N:26]([CH3:42])[CH3:25])(=[O:28])=[O:29])=[CH:35][CH:34]=3)[CH2:37][CH2:38]2)=[O:52])[C:48]=1[CH3:49]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C)S(=O)(=O)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(S(=O)(=O)N(C)C)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein N,N-Dimethyl-4-piperazin-1-yl-benzenesulfonamide and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.54 (d, 2H), 7.08 (d, 2H), 5.38 (s, 2H), 3.62 (m, 4H), 3.48 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=494.1, found=494.0.
Reaction SMILES: [CH2:1]([C:4]1([C:14]([OH:16])=O)[S:11](=[O:13])(=[O:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)[CH:2]=[CH2:3].CN([P+](O[N:28]1N=N[C:30]2C=CC=C[C:29]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([NH:28][C:14]([C:4]1([CH2:1][CH:2]=[CH2:3])[S:11](=[O:12])(=[O:13])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)=[O:16])[CH3:30]
Reactant: C=CCC1(C(=O)O)Cc2ccsc2S1(=O)=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)NCC)Cc2ccsc2S1(=O)=O
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A solution of 2-allyl-2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (8 g, 0.031 mol) and BOP reagent (17.8 g, 0.041 mol) in degassed DMF (150 mL) was cooled to 0° C. under nitrogen. Ethylamine was bubbled into the stirred reaction mixture until the solution was quite basic. After 1.5 hours, the DMF was removed in vacuo and the residue partitioned between ethyl acetate and 6N HCl. The aqueous phase was extracted a total of four times with ethyl acetate and the combined extracts washed with saturated sodium bicarbonate, brine, then dried over magnesium sulfate. Filtration and solvent removal gave the title compound as an oil (7.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16]([N:18]1[CH2:23][C:22]([CH3:24])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[N:20]2[N:35]=[CH:36][C:37]([C:38]#[N:39])=[C:19]12)=[O:17]>>[ClH:14].[ClH:14].[CH3:24][C:22]1[CH2:23][N:18]([C:16](=[O:17])[CH2:15][N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[C:19]2[N:20]([N:35]=[CH:36][C:37]=2[C:38]#[N:39])[C:21]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1
Product: Cl

Procedure:
The above compound was prepared by the reaction of N-benzylpiperazine with the compound of Example 10 by the methods of Example 16 then 77, mp 204°-206° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19]([OH:21])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19](=[O:21])[NH2:25])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(Cl)ccc21
Reaction time: 16 h

Procedure:
To a mixture of 1-tert-butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid (400 mg, 1.29 mmol) in CH2Cl2 (6 mL) were added successively NH4Cl (138 mg, 2.58 mmol), HBTU (1.22 g, 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol). Stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 4 h, the reaction mixture was diluted with CH2Cl2 and the solution was washed with water (2×), 0.1N aqueous HCl (2×), saturated aqueous NaHCO3 (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0) to give the title compound as a white solid. TLC Rf (EtOAc/c-hexane 2:1)=0.20; MS (LC/MS): 309 [M+H]+, 617 [2M+H]+; tR (HPLC conditions b): 4.75 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH2:22]1.[H-].[Na+]>CN(C=O)C>[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure M using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (250 mg, 0.92 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (213 mg, 0.92 mmol) and sodium hydride (44 mg, 1.833 mmol) in DMF (2.0 mL) and heating the reaction at 120° C. for 3 h. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(3-pyridinyl)-quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, br. s.), 8.66-8.81 (1H, m), 8.00 (1H, dt, J=7.8, 2.0 Hz), 7.89 (1H, dd, J=9.4, 5.9 Hz), 7.81 (1H, dd, J=10.0, 2.5 Hz), 7.48 (1H, dd, J=7.8, 4.7 Hz), 7.23-7.30 (1H, m), 7.09 (1H, d, J=8.2 Hz), 6.34 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 3.68-3.81 (6H, m), 2.90-3.02 (4H, m), 2.30 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [CH3:1][S:2][CH3:3].[CH3:4][O:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7]>ClCCl>[O-:8][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:7])=[O:5].[CH3:1][S+:2]([CH3:4])[CH3:3]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CSC
Solvent: ClCCl
Product: C[S+](C)C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
16 mmol of dimethyl sulfide was dissolved in 10 ml of dichloromethane at 0° C., and about 17 mmol of methyltrifluoromethane sulfonate was slowly dripped to the mixture to obtain a white solid product. The solid product was filtered and dried for 1 hour in an oven at 50° C. to obtain the following product:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:30][OH:31])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 121.9 mg, 0.29 mmol) and hydroxylamine hydrochloride (30.4 mg, 0.43 mmol) in methanol (0.85 mL) and pyridine (0.85 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 80-100% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (68.8 mg, 55%) as a white solid: mp 205-207° C.; (ES)+-HRMS m/e calcd for C19H21ClN4O4S (M+H)+ 437.1045. found 437.1048.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1.[CH3:17][N:18]=[C:19]=[S:20]>CO>[CH3:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1
Reactant: CN=C=S
Reactant: NC1=NN(c2ccc3ccccc3c2)CC1
Solvent: CO
Product: CNC(=S)NC1=NN(c2ccc3ccccc3c2)CC1

Procedure:
3-Amino-1-(2-naphthyl)-2-pyrazoline (1 g) and methylisothiocyanate (1.4 g) were heated at 130° for 7 hours. The cooled reaction mixture was diluted with methanol and the solid product collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[CH:42][C:40]#[N:41])[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a stirred solution of 3-{3-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy}-5-methyl-benzaldehyde (533 mg, 1 mmol) and diethyl cyanomethyl-phosphonate (162 μl, 1 mmol) in THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (224 mg, 2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.19 was collected.) to afford 445 mg (80%) of a white foam. 1H NMR (300 MHz, CDCl3) δ 1.10 (6H, d, J=6.9 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.79 (3H, s), 4.31 (2H, d, J=5.5 Hz), 4.73 (2H, s), 5.02 (1H, t, J=5.5 Hz), 5.81 (1H, d, J=16.6 Hz), 5.85 (1H, s), 5.98 (1H, s), 6.64 (2H, s), 6.86-6.89 (2H, m), 6.98 (1H, s), 7.20-7.24 (3H, m), 8.98 (1H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].Cl[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:16][O:15][C:13]([C:12]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:11]=1[O:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCN1CCCC1
Agent: [Na]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3.43 g (29.8 mmol) of 2-pyrrolidin-1-ylethanol is dissolved in 60 mL of toluene and 575 mg (25.0 mmol) of sodium is added batchwise. The mixture is heated to 100° C. and then stirred for a further 12 hours at 50° C. After cooling, 5.00 g (22.5 mmol) of methyl 2-chloro-5-nitrobenzoate are added batchwise and the mixture is stirred for 1 day at ambient temperature. After this time, the solvent is eliminated, the residue is taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate and concentrated by rotary evaporation. Finally the product is purified through a silica gel column with a gradient of methylene chloride/methanol/ammonia (8:2 to 8:2:0.1) as eluant. Yield: 1.65 g (25% of theory); Rf value: 0.45 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); C14H18N2O5; EII mass spectrum: m/z=295 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Agent: CN
Product: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2N1CCOCC1

Procedure:
By substituting the product of Example 11 in the procedure of Example 5 and substituting morpholine for the methylamine, 1-benzyl-4-(morpholino)-5,6-dihydrobenzo-[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].C(Cl)(=O)C([Cl:21])=O.C(=O)=O>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:21])=[O:14]
Reactant: O=C(O)CCCCCCCCCCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCC(F)(F)F

Procedure:
Dissolve 12,12,12-trifluorododecanoic acid (244 mg, 0.96 mmol) in methylene chloride (5 mL) and add dimethylformamide (3 drops). Add oxalyl chloride (85 μL, 0.96 mmol) and stir until evolution of carbon dioxide is complete to give 12,12,12-trifluorododecanoyl chloride.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14])#[N:7].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>CCOCC.O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][CH2:13][OH:14])#[N:7]
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(C=CCO)c1
Reaction time: 6 h

Procedure:
Dimethylformamide (0.1 ml) was added to a stirred suspension of 3-cyano-cinnamic acid (30 g) in dry ether (500 ml) containing oxalyl chloride (15 ml). The mixture was stirred for 6 hours, filtered and evaporated to give the crude acid chloride as a pale solid. A solution of this acid chloride in ether (100 ml) and tetrahydrofuran (100 ml) was added to a stirred suspension of sodium borohydride-doped alumina (20 g sodium borohydride on 200 g alumina) in ether (200 ml). The mixture was stirred for 1 hour and then filtered. The filtrate was evaporated and the residue was chromatographed on silica-gel eluting with 2:1 ether:hexane to give the product as a pale oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br-].[Cl:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:20][C:19]([O:44][CH3:45])=[CH:18][CH:17]=2.[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]=O)[CH2:55][CH2:54]1)([CH3:49])([CH3:48])[CH3:47].C(OCC)(=O)C>O1CCCC1>[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:54][CH2:55][C@H:56]([CH:59]=[CH:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:44][CH3:45])[CH:20]=3)[N:15]=[CH:14][C:13]=2[Cl:12])[CH2:57][CH2:58]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1ccc2ncc(Cl)c(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(CC=C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
Sodium hexamethyldisilazide (1.0 M in tetrahydrofuran, 3.27 mL, 3.27 mmol, 2.3 eq) is added dropwise at −78° C. to a stirred solution of [2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-triphenyl-phosphonium bromide (800 g, 1.42 mmol, 1.0 eq) in tetrahydrofuran (25 mL). The reaction mixture is then stirred for 45 minutes at −10° C. before lowering down the temperature to −78° C. followed by the addition of (trans-4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (420 mg, 1.85 mmol, 1.3 eq). The reaction mixture is then stirred at 0° C. for 1 hour, extracted with ethyl acetate (3×30 mL) and a saturated ammonium chloride aqueous solution (30 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 8:1, v/v) to afford {trans-4-[3-(3-chloro-6-methoxy-quinolin-4-yl)-propenyl]-cyclohexyl}-carbamic acid tert-butyl ester as an off-white solid (374 mg, 61% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20].N1C=CC=CC=1.O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 6.4 %

Procedure:
A solution of pyridine-3-boronic acid (0.68 g, 5.5 mmol) and 2-methyl-5-nitro phenol (0.85 g, 5.5 mmol) in DCM (10 mL) was treated with pyridine (1.00 mL, 12.4 mmol), copper acetate (1.5 g, 8.3 mmol) and powdered 4A molecular sieves (330 mg). The reaction mixture was stirred for 7 days at RT open to air. The mixture was poured into water (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were washed with saturated aq NaHCO3 (25 mL), water (25 mL), satd NH4Cl (2×25 mL) and brine (25 mL), dried (Na2SO4), concentrated in vacuo and purified via chromatography on silica gel to provide 3-(2-methyl-5-nitrophenoxy)pyridine (81 mg, 6% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (dd, J=4.6, 1.0 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.39-7.30 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z: 231.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:12](=[N:14]\[OH:15])\[NH2:13])[CH:5]=[CH:4][CH:3]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:12]2[NH:13][C:27](=[O:28])[O:15][N:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=N\O)/C(=N\OCc1cccc(N)n1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of (1Z,2Z)-2-{[(6-aminopyridin-2-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (3 g, 10.51 mmol, 1 eq.) in DMF (50 ml) was added CDI (1.70 g, 10.51 mmol, 1 eq.) and stirring at room temperature was allowed for 30 min before heated to 80° C. for 6 h. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was triturated in MeCN and a white solid was isolated by filtration giving a first crop of 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (1.36 g, 36% yield). The mother liquor was concentrated and purified by chromatography on silica gel to give a second crop (2.9 g, 50% purity, 40% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Brc1cnccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromopyrazine. LC-MS Method 2 tR=1.249, m/z=374; 1H NMR (CDCl3) 1.12 (s, 3H), 1.28 (s, 3H), 1.58 (m, 3H), 2.19-2.20 (m, 4H), 2.39 (m, 1H), 2.89 (m, 1H), 5.74 (m, 1H), 7.09 (m, 2H), 7.28-7.40 (m, 5H), 7.78 (m, 2H), 8.48 (m, 1H), 8.59 (m, 1H), 8.94 (m, 1H).