Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[C:10]([C:15]([O:17]CC)=[O:16])=[CH:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:20])[C:10]([C:15]([OH:17])=[O:16])=[CH:11][N:12]([CH3:14])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 4 mmol) and NaOH (1.6 g, 40 mmol) in water (25 mL) was stirred at RT overnight. The mixture was extracted with EtOAc (2×25 mL) to remove impurities. The aqueous pH was adjusted to pH 1-2 with 37% HCl. The resulting precipitate was collected by filtration and dried under vacuum to afford 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (810 mg, 81.9% yield). 1H-NMR (400 MHz, CDCl3): δ 15.76 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.58 (m, 3H), 7.14 (t, J=8.8 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 15 g of phosphorus oxychloride were mixed. The mixture was stirred for 6 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.50 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 82 (0.5 g, 1.9 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4 and concentrated to give a solid. The solid was triturated with CH2Cl2 and filtered to give a solid (0.20 g, 47%); Mp=216–218° C.; 1H NMR (DMSO-d6) δ 9.95 (br s, 1 H), 7.74 (d, 2 H, J=8.8 Hz),7.66 (d, 1 H, J=1.9 Hz), 7.59 (d, 1 H, J=8.8 Hz), 7.27 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 7.17 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz); MS 243/245 [M−H]−
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.O>CN(C)C(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:15][C:11]2[C:12]([F:14])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=2[F:16])[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cc(F)c(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Potassium tert-butoxide (2.4 g, 22 mmol) was added to a solution of 4-amino-2,6-difluorophenol (2.9 g, 20 mmol) in N,N-dimethyl-acetamide (50 mL) and the mixture was stirred at RT under nitrogen for 0.5 h. A solution of 2,4-dichloro-pyridine (2.9 g, 20 mmol) in N,N-dimethyl-acetamide was added, and the reaction was heated to 100° C. under nitrogen for 10 h. After cooling to RT, the reaction was poured into water (100 mL) and the aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline (3.0 g, 59% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.01 (dd, J=5.7 Hz, 2.1 Hz, 1H), 6.38 (d, J=10.8 Hz, 2H), 5.86 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][C:7]=1[CH:8]=O.Cl.[NH2:17][OH:18].N1C=CC=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][C:7]=1[CH:8]=[N:17][OH:18]
Reactant: O=Cc1nc(-c2ccccn2)ccc1F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1nc(-c2ccccn2)ccc1F

Procedure:
5-Fluoro-[2,2′]bipyridinyl-6-carbaldehyde (0.36 mmol, 73 mg), hydroxylamine hydrochloride (1.8 mmol, 125 mg), pyridine (1.6 mmol, 0.12 mL) and EtOH were heated at reflux during 2 h. The solvent was evaporated under vacuum, and H2O was added. The filtration of the white precipitate obtained provided the final product without needing any purification (Florence Mongin; Francois Trecourt; Bruno Gervais; Oliver Mongin; Guy Quequiner, J. Org. Chem., 2002, 67, 3272-3276). Yield: 47 mg (60%), white solid. 1H-NMR (DMSO): 12.0 (N—OH); 8.76 (d, 1H, J=4.4 Hz); 8.46 (dd, 1H, J1=8.5 Hz, J1=3.4 Hz); 8.40 (d, 1H, J=7.9 Hz); 8.34 (s, 1H); 8.01 (m, 2H); 7.54 (m, 1H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=[CH:37][N:36](C(N2C=NC=C2)=O)[CH:35]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:36]([CH3:37])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 65 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 0.1.3 mmol) and dimethylamine (2N in THF, 0.7 ml, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide (0.35 g, 67% yield): mp, 163-165° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.90 (s, 3H, NCH3), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.05 (s, 4H, NCH3+CH2), 3.91 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.81-5.87 (m, 1H, CHN), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 7.11-7.17 (m, 3H, Ar), 7.45 (d, J=7.0 Hz, 1H, Ar), 7.62 (t, J=8.0 Hz, 1H, Ar), 8.73 (d, J=8.8 Hz, 1H, Ar), 9.53 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 34.8, 35.5, 37.1, 51.3, 64.7, 111.9, 113.8, 115.4, 116.1, 117.9, 120.1, 120.2, 122.7, 124.7, 131.3, 135.8, 137.5, 138.1, 150.6, 168.1, 169.2, 169.3, 170.0; Anal Calcd for C24H25F2N3O6: C, 58.89; H. 5.15; N, 8.58. Found: C, 58.53; H, 4.78; N, 8.51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]2[OH:15])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]2[O:15][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(c2ccc(Cl)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of 1.12 g (5 mmol) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-piperidine-3-ol in 5 ml of tetrahydrofuran was added dropwise to a suspension of 0.264 g (5 mmol) of sodium hydride (50% dispersion in refined oil) in 8 ml of tetrahydrofuran and the mixture was stirred at 50° C. for 60 minutes. Subsequently, it was cooled to room temperature and treated with 1.10 g (5 mmol) of 2-bromomethyl-naphthalene in 5 ml of tetrahydrofuran. After 2 hours at 50° C. the reaction solution was poured into 60 ml of ice-water and extracted three times with 25 ml of ethyl acetate each time. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 95:5 mixture of methylene chloride and ethanol as the eluent. There was obtained 0.53 9 (28% of theory) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-3-(naphthalen-2-ylmethoxy)-piperidine as a pale yellow oil; MS: 366 (M)+.
Reaction SMILES: Cl.[CH:2]1([NH:5][CH3:6])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:14]([O:16][C:17](=[O:34])[CH2:18][C:19]1[N:32]=[C:31](Cl)[C:22]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]=3[S:30][C:21]=2[N:20]=1)[CH3:15]>CO>[CH2:14]([O:16][C:17](=[O:34])[CH2:18][C:19]1[N:32]=[C:31]([N:5]([CH:2]2[CH2:4][CH2:3]2)[CH3:6])[C:22]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]=3[S:30][C:21]=2[N:20]=1)[CH3:15]
Reactant: CNC1CC1
Reactant: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCCC3
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
Cyclopropyl-methyl amine HCl (1.32 g, 0.0123 mol) and Et3N (2.4 g, 0.0246 mol) were added to a solution of (4-chloro-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (2 g, 0.00615 mol) in 20 ml of methanol and the mixture was stirred for 18 h at ambient temperature. The methanol was removed under vacuum and the crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes to give [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-acetic acid ethyl ester (1.8 g, 81%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 4.18 (q, 2H), 3.89 (s, 2H), 2.92-3.00 (m, 5H), 2.78-2.90 (m, 3H), 1.85-1.92 (m, 2H), 1.68-1.77 (m, 2H), 1.60-1.67 (m, 2H), 1.25 (t, 3H), 0.68-0.75 (m, 2H), 0.40-0.47 (m, 2H); LC-MS: [M+H]: =359.9 m/z.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl>C(O)C>[CH3:12][C:11]1[C:3]([CH2:2][S:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: Cc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc2c(cc1CSCC(=O)O)OCO2
Yield: 20.5 %

Procedure:
A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50% hydrous ethanol was heated under reflux for 1 h. The reaction mixture was concentrated. Water was added thereto and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1Nhydrochloric acid. After extraction with chloroform, the extract was dried over magnesium sulfate. The solvent was distilled off and the product was isolated according to silica gel column chromatography (chloroform). The crystals thus obtained were recrystallized from diisopropyl ether to obtain 1.6 g of the intended compound in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=475.08.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(N)cc2)cn1C
Reaction time: 6 h

Procedure:
5 (1 g, 3.027 mmol) was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid 7. The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 7 (065 g, 94.2%). IR (FTIR, vmax/cm−1): 3366, 2987, 1688, 1629, 1566, 1422, 1372, 1262, 1181, 1103, 1067, 951, 821, 784, 756; 1H-NMR (400 MHz, CDCl3): δ 7.28 (2H, d, J=8.4 Hz), 7.11 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.68 (d, 2H, J=8.0 Hz), 3.94 (s, 3H), 3.83 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 161.7, 144.7, 126.2, 125.4, 125.2, 115.5, 114.4, 51.0, 36.8; EIMS m/z (+EI) calc. for C13H14N2O2 (M)+ 230.26. found 231.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[N:37]1([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: NCCCCN1CCCC1
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCCN2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Intermediate A and 4-pyrrolidin-1-ylbutan-1-amine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-N-(4-pyrrolidin-1-ylbutyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide as a white solid (169 mg, 67%); 1H NMR (500 MHz, DMSO) δ 1.50-1.36 (4H, m), 1.63 (4H, dd), 1.73 (3H, s), 2.40-2.30 (6H, m), 3.24 (2H, q), 6.72 (1H, d), 7.65 (2H, d), 7.71 (1H, d), 7.87-7.81 (2H, m), 7.95-7.89 (4H, m), 8.06 (1H, s), 9.30 (1H, t); APCI-MSm/z: 589[MH+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:63][C:64]1[C:69]([OH:70])=[CH:68][CH:67]=[CH:66][N:65]=1>CN(C=O)C>[OH:70][C:69]1[C:64]([NH:63][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:20])=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncccc1O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 30 %

Procedure:
Intermediate 1 (see Example 1.1, 50 mg, 0.181 mmol) was dissolved in DMF (1 mL). PyBOP (104 mg, 0.199 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) were added. The reaction mixture was stirred at room temperature for about 3 min. 2-aminopyridin-3-ol (19.93 mg, 0.181 mmol) was then added to the mixture to give an amber solution which was stirred overnight at room temperature. The mixture was purified by HPLC to provide the title compound (20 mg). LCMS m/z=369.2 [M+H]+; 1H NMR: (400 MHz, CD3CN) δ ppm 0.53 (td, J=4.8 and 3.5 Hz, 1H), 1.23 (td, J=7.9 and 4.8 Hz, 1H), 2.21-2.27 (m, 1H), 2.33-2.40 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 3.05 (dd, J=16.6 and 6.3 Hz, 1H), 7.16-7.23 (m, 1H), 7.23-7.32 (m, 2H), 7.73-7.83 (m, 3H), 9.80 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 61.2 %

Procedure:
2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.142 g, 0.394 mmol) and ethyl formate (0.095 mL, 1.18 mmol) were dissolved in anhydrous ethanol (4.73 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.181 mL, 1.97 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.093 g, 0.241 mmol, 61%).
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21]>C(O)C.[Pd]>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21]
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])cc2)c2ccccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: Cn1nc(-c2ccc(N)cc2)c2ccccc2c1=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a suspension of 2-methyl-4-(4-nitrophenyl)-1-(2H)-phthalazinone (3.0 g, 10.7 mmol) in ethanol (150 mL) under N2 was added 10% Pd/C (0.75 g). The mixture was hydrogenated on a Parr hydrogenator at 50 psi for 2 hours, the catalyst was removed by filtration and the solvent was removed in vacuo to afford 2.67 g (97%) of 2-methyl-4-(4-aminophenyl)-1-(2H)-phthalazinone as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=1[NH:12][S:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of methyl 4-chloroanthranilate (0.50 g, 2.7 mmol) and pyridine (0.87 mL, 10.8 mmol) in DCM (10 mL) at rt was added 2,4-difluorobenzenesulfonyl chloride (0.64 g, 3.0 mmol). The mixture was stirred overnight at rt, poured into 1 N HCl, and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes) to provide 0.69 g (70%) of the desired sulfonamide as a solid. 1H NMR (400 MHz, CDCl3): 11.02 (s, 1H), 8.07-8.00 (m, 1H), 7.91 (d, J=8.6, 1H), 7.64 (d, J=2.0, 1H), 7.04-6.98 (m, 1H), 7.02 (dd, J=8.6, 2.0, 1H), 6.93-6.86 (m, 1H), 3.94 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:12]([C:16]#[C:15][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol) and triethylamine (5 g, 50 mmol) were suspended in tetrahydrofuran (20 ml) and the mixture heated to 50° C. Dichlorobis(triphenylphosphine)palladium (45 mg, 0.06 mmol) and copper(I)iodide (76 mg, 0.4 mmol) were added with stirring. After about 15 min a practically clear solution had formed. After 3 h at 50° C. the solution was taken to dryness and triturated with isobutylmethylketone and dilute hydrochloric acid. The organic phase was separated and the solvent evaporated. The oily residue was triturated with a small amount of acetonitrile to form crystals. These were recrystallized from acetic acid. The product was dissolved in a small amount of chloroform and the solution applied on top of a short silica gel column and eluted with 25% isobutylmethylketone in toluene. The pure product resulted after evaporation of the solvent Yield 2.0 g, 44%.