Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([CH3:20])([C:16]([O:18]C)=[O:17])[CH3:15])=[CH:11][CH:12]=1)=O)(C)(C)C.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[C:26]([NH2:28])=[NH:27].CCN=C=NCCCN(C)C.Cl.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:26]([C:25]1[CH:29]=[CH:30][C:31]([O:32][C:6]([C:8]2[S:9][C:10]([CH2:13][C:14]([CH3:20])([CH3:15])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)=[O:5])=[C:23]([F:22])[CH:24]=1)(=[NH:28])[NH2:27]
Reactant: COC(=O)C(C)(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: N=C(N)c1ccc(O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To 5-(2-Methyl-2-methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester (5.0 g, 16.8 mmol) was added trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was dissolved in pyridine (30 mL), 3-fluoro-4-hydroxybenzamidine hydrochloride (3.2 g, 16.8 mmol) and WSC hydrochloride (3.8 g, 19.8 mmol) were added, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, 4N-hydrochloric acid solution (10 mL) and 4N-Hydrogen chloride in 1,4-Dioxane (10 mL) were added to the obtained residue, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (2.8 g, 5.86 mmol, 35%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO>[CH3:27][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:18]1[C:16]1[CH:17]=[C:12]([NH:11][CH2:10][C:6]2([C:4]([OH:5])=[O:3])[CH2:9][CH2:8][CH2:7]2)[CH:13]=[N:14][CH:15]=1
Reactant: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(-c2cncc(NCC3(C(=O)O)CCC3)c2)cc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester (0.107 g, 0.288 mmol) in THF (2 mL) and methanol (1 mL) is added aqueous lithium hydroxide (1M, 0.58 mL, 0.58 mmol) and the solution is stirred overnight. The product is isolated by RP HPLC on an Xbridge C18 eluting with an acetonitrile in 0.1% aqueous NH4OH gradient to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.86 (m, 1H), 1.87-1.97 (m, 3H), 2.26-2.35 (m, 2H), 3.33 (br. s., 1H), 3.39 (s, 2H), 3.75 (s, 3H), 6.60 (s, 1H), 7.05-7.09 (m, 1H), 7.15 (m, 1H), 7.17-7.21 (m, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H). MS (ESI) m/z 336 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: Cc1cc(CCC(=O)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH:15][CH3:16])=[O:14].Cl.[O:23]([NH2:25])[CH3:24].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:25]\[O:23][CH3:24])/[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1Oc1cc(C)cc(C)c1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cc(C)cc(C)c1
Reaction time: 8 h
Yield: 68.9 %

Procedure:
2-[2-(3,5-dimethylphenoxy)phenyl]-2-oxo-N-methyl-acetamide (2.58 g) and methoxylamine hydrochloride (1.52 g) were dissolved in methanol (50 ml), and the mixture was heated under reflux with stirring overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (1.96 g). mp. 90°-91° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH:28]=O)[N:24]([CH3:30])[C:23](=[O:31])[CH2:22][CH2:21]2>>[CH3:1][C:2]1([CH3:15])[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH:14][CH2:28][C:27]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23](=[O:31])[N:24]3[CH3:30])=[CH:19][C:18]=2[O:17][CH3:16])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Product: COc1cc2c(cc1CNC1CCC(C)(C)NC1c1ccccc1)N(C)C(=O)CC2

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6,6-dimethyl-2-phenyl-piperidin-3-ylamine with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde. Mass spectrum calcd for C25H34N3O2 (M+1) 408; found 408.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2([CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)[CH2:7][CH2:8][OH:9])=[CH:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:9][CH2:8][CH2:7][C:6]1([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]1)(=[O:17])[CH3:16]
Reactant: OCCC1(c2ccsc2)C=CC=CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
1-(3-Thienyl)phenethyl alcohol (10 g, 49 mmol) was dissolved in a 2:1 pyridine and acetic anhydride mixture (50 ml). This was stirred at 80° C. for 4 h. Excess of pyridine and acetic anhydride mixture was removed under reduced pressure and the residue was dissolved in water (100 ml). This was extracted with methylene chloride (3×75 ml) and the combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl acetate (10.2 g, 84% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[CH:28]=[C:2]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:16][CH:17]=[N:18]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(-c4cccnc4)ccc2OCC3)c(F)c1

Procedure:
5-(9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole was treated with 3-pyridineboronic acid pinacol ester using standard Suzuki condition to yield 408. NMR: (CDCl3): 3.15 (2H, t), 4.31 (2H, t), 6.82 (1H, s), 7.03-7.18 (3H, m), 7.32-7.38 (2H, m), 7.51-7.55 (1H, m), 7.72 (1H, s), 7.82 (1H, d), 8.05 (1H, s), 8.55 (1H, d), 8.80 (1H, s). MS. ESI+500 (MH++MeCN)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C=O.Cl.[C:23](O)(=O)C>C1C=CC=CC=1.CO>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:23][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
A suspension of 6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 50 ml of absolute benzene is admixed with a suspension of 7 mmoles (0.02 g) of paraformaldehyde in 10 ml of absolute methanol. The reaction mixture is refluxed for two hours in the presence of a catalytic amount of hydrochloric acid or acetic acid, whereupon the obtained pale-yellow solution is evaporated in vacuo. The residual oily product is triturated with a small amount of acetone to yield the aimed compound in crystalline form in a yield of 89%.
Reaction SMILES: [CH2:1]([Li])CCC.[NH2:6][C:7]1[N:8]=[C:9]([CH:30]=[CH2:31])[C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=O)=[N:11][C:12]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[NH2:6][C:7]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[CH:22]=[CH2:1])=[C:9]([CH:30]=[CH2:31])[N:8]=1
Reactant: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
Under an argon atmosphere, to a suspension of methyltriphenylphosphonium bromide (1.29 g, 3.61 mmol) in anhydrous THF (5 mL) was gradually dropwise added n-butyl lithium (1.65 M in n-hexane) (1.70 mL, 2.81 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minutes as it was. To the mixture was added 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (871 mg, 2.52 mmol) at 0° C. After elevating to room temperature, stirring was continued for 1.5 hours. After to this was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (570 mg, 1.66 mmol, 65.8%) as a white solid. TLC Rf=0.37 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 4.16 (s, 2H), 4.39 (s, 2H), 5.18 (dd, 1H, J=1.0, 10.5 Hz), 5.30 (dd, 1H, J=2.0, 10.5 Hz), 5.67 (dd, 1H, J=1.0, 17.5 Hz), 6.25 (dd, 1H, J=2.0, 17.5 Hz), 6.47 (dd, 1H, J=10.5, 17.5 Hz), 6.50 (dd, 1H, J=10.5, 17.5 Hz), 6.90 (dd, 1H, J=2.5, 8.0 Hz), 7.20-7.26 (m, 5H), 7.29-7.35 (m, 2H); 13C MR. (126 MHz, CDCl3) δ 41.2, 55.6, 110.5, 113.8, 115.4, 119.3, 127.2, 128.7 (2C), 129.2 (2C), 129.8, 132.1, 133.0, 135.1, 137.0, 138.3, 140.3, 141.9, 144.8, 151.4, 159.8.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].C(OCC)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of 300 mg of 1-(2-chloroethyl)-3-(β-D-galactopyranosyl)urea in 2 ml of 99% formic acid was slowly added 150 mg of sodium nitrite in an ice-bath under stirring. The mixture was stirred for 1 hour under ice-cooling to complete the nitrosation. The reaction mixture was admixed with 50 ml of ethyl ether to deposit an oily substance. The ethyl ether phase was separated from the oily substance by decantation. The operation of adding ethyl ether to and separating the ethyl ether phase from the oily substance by decantation was repeated three times, using 50 ml, 20 ml and 20 ml of the ether, respectively. Thereafter, the oily substance was taken up into 30 ml of methyl alcohol, and the resultant solution was admixed with 3 ml of Amberlite IR-120 (H+ form). The admixture was filtered to remove cation-exchange resin, and the filtrate was concentrated under a reduced pressure, depositing crystals of the titled compound. Yield 210 mg (63.6%). mp. 145° C (decomposition with foaming). [α]D21.0 +13.0° (c 0.5, H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19]Cl.[OH-].[K+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:15]#[N:16])[CH2:19][CH2:18]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: N#CC1(c2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 18 h

Procedure:
A suspension of 3.1 g (14.7 mmol) of (4′-fluoro-1,1′-biphenyl-4-yl)acetonitrile, prepared in step 7.1., 2.4 ml (29.4 mmol) of 1-bromo-2-chloroethane and 0.067 g (0.294 mmol) of N-triethylbenzylammonium chloride, heated to approximately 50° C., is admixed dropwise with 6.7 g (102.8 mmol) of aqueous 60% potassium hydroxide solution. Stirring is continued at 50° C. for 18 hours.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]=[O:1]
Reactant: OCCc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(CCO)c1
Reaction time: 6 h

Procedure:
Manganese (IV) dioxide (2.0 g) was added to a stirred solution of 2-(3-(hydroxymethyl)phenyl)ethanol (example 20, step a) (0.50 g) in DCM (10 mL) at room temperature. After 6 h, the reaction mixture was filtered through Celite eluting with DCM. The solution was evaporated in vacuo to give the subtitled compound as a gum. Used directly. Yield 0.46 g.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[Cl:20][C:17]([F:19])([F:18])[S:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 217.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=5.27 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=478.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=10.90, 4.30 Hz, 2H) 3.32-3.44 (m, 1H) 4.12-4.26 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.67 (d, J=8.60 Hz, 2H) 7.91 (d, J=8.99 Hz, 2H) 8.09 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.33 (m, 1H) 10.27 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][O:10][C@@H:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:20][OH:21])[CH2:9][O:10][C@@H:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13]
Reactant: C=C[C@H](OCC(=O)c1ccccc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@H](OCC(=NO)c1ccccc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
(S)-1-(2-Fluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone (41.22 g) was dissolved in anhydrous methanol (400 mL) and hydroxylamine hydrochloride (14.0 g) and sodium acetate (19.0 g) were added. The reaction mixture was heated to 50° C. for 90 min, then cooled to RT, concentrated in vacuo and the residue purified by silica gel chromatography (2% to 15% EtOAc in hexanes) to afford the title compound as a mixture of geometric isomers (40.54 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.04-4.15 (m, 0.8 H), 4.18-4.26 (m, 0.2 H), 4.44-4.57 (m, 0.4 H) 4.79-4.90 (m, 1.6 H) 5.37-5.56 (m, 2 H) 5.64-5.78 (m, 1 H) 7.03-7.26 (m, 2 H) 7.33-7.54 (m, 2 H), 7.90 (br s, 0.2H), 8.51 (br s, 0.8H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[NH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]([N:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:26]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: Nc1cccc(B(O)O)c1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(N)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-aminophenyl boronic acid were reacted to give 124. MS: (ESI+) 461.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[N:8]([CH3:10])C)\[CH3:7])[CH3:2].[CH:16]1(N)C[CH2:17]1>C(O)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[NH:8][CH:10]1[CH2:17][CH2:16]1)\[CH3:7])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)/C(NC(C)=O)=C(\C)N(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(NC(C)=O)=C(\C)NC1CC1

Procedure:
(Z)-2-Acetylamino-3-dimethylamino-but-2-enoic acid ethyl ester (4.3 g, 20 mmol) and cyclopropylamine (1.14 g, 20 mmol) were stirred at room temperature in acetic acid (40 ml) for 2 hrs. The reaction mixture was diluted slowly with 30 ml of water and evaporated under vacuum at 35° C. Water (30 ml) was added to the residue and evaporated again at 35° C. The same procedure was repeated twice with toluene (30 ml each) to obtain the desired crude product as a dark brown oil [MS: m/e=227.4 (M+H+)], which could be used without any further purification for the next step.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)(Cl)Cl>[CH3:8][C:2]1[CH:3]=[CH:4][C:5]([CH3:7])=[CH:6][N+:1]=1[O-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C)nc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2,5-Lutidine (1419 g) was dissolved in chloroform (13.5 L) and cooled to below 10° C. m-Chloroperoxybenzoic acid (70%, 3354.21 g) was added portion-wise to maintain the temperature at below 10° C., and then the reaction was warmed to room temperature and stirred overnight. Once no starting material was seen by tlc analysis, the mixture was cooled to 10° C. and quenched with aqueous 20% sodium hydroxide (2.5 L to 3 L) dropwise while maintaining a temperature below 20° C., which resulted in the formation of a very thick suspension. The mixture was stirred for 30 minutes and then allowed to separate. Water (5 L) was added, the organic layer was separated, and the aqueous layer was extracted twice with chloroform (4 L). The combined organic layers were washed with aqueous 1% sodium hydroxide, followed by aqueous 1N hydrochloric acid, and then concentrated under vacuum to give the desired product (1365 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[N:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1cccnc1Cl
Product: CCOC(=O)c1cccnc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[S:34]1(=[O:40])(=[O:39])[CH2:38][CH2:37][CH2:36][NH:35]1>>[O:39]=[S:34]1(=[O:40])[CH2:38][CH2:37][CH2:36][N:35]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:22][CH2:23]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCNC3=O)CC2)nc1C
Yield: 52.6 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (190 mg) described in Preparation Example 258 and isothiazolidine 1,1-dioxide (73 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (109 mg) was obtained.
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:8][C:9](=[O:13])[CH:10]=[N+]=[N-])[C:4]([O:6][CH3:7])=[O:5].[BrH:25]>CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:8][C:9](=[O:13])[CH2:10][Br:25])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CF)(CC(=O)C=[N+]=[N-])N1C(=O)c2ccccc2C1=O
Reactant: Br
Solvent: CCOCC
Product: COC(=O)C(CF)(CC(=O)CBr)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-4-oxo-5-diazo-pentanoate (1.53 g, 4.62 mmol) in ether (22.5 ml) is added dropwise and with vigorous stirring to cold (ice cooling) aqueous HBr (47%, 0.95 ml). Stirring is continued for 1 hour at room temperature. The organic phase is separated, washed with water, dried, and evaporated to give the title compound as a yellow oil (1.52 g).