Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (36 mg, 0.1882 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 50% yield (0.051 g, 0.078 mmol).
Reaction SMILES: C[C:2]1[CH:34]=[C:5]2[N:6]=[CH:7][C:8]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:9]([C:10]3[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:12][CH:11]=3)[N:4]2[N:3]=1.CC1[N:37]=C(N)NN=1>>[CH3:34][C:2]1[N:37]=[C:5]2[N:6]=[CH:7][C:8]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[C:9]([C:10]3[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:12][CH:11]=3)[N:4]2[N:3]=1
Reactant: Cc1n[nH]c(N)n1
Reactant: Cc1cc2ncc(-c3ccncc3)c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n2n1
Product: Cc1nc2ncc(-c3ccncc3)c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n2n1

Procedure:
Following the procedure for the preparation of 2-[4-(2-Methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline but substituting 5-Methyl-2H-[1,2,4]-triazol-3-ylamine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.55 (m, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.1 Hz, 1H), 7.73 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (m, 1H), 7.42 (d, J=8.7, 2H), 7.08 (m, 4H), 5.39 (s, 2H) 2.60 (s, 3H); MS: (M+H m/z=445.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:14][CH3:15])[C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1c2cc(Cl)nc(=O)n2C[C@@H]1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 139.2 %

Procedure:
To a solution of (S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50.0 mg, 0.269 mmol) and iodoethane (63.0 mg, 0.404 mmol) in acetonitrile (1 ml) was added Cs2CO3 (176 mg, 0.539 mmol). The reaction mixture was stirred at 90° C. for 1 h, filtered and concentrated to give crude product (80 mg) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH3:20])=[N:6][CH:7]=1
Reactant: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN(C)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry round bottom flask containing 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine (1.0 g, 3.45 mmol) in dry DMF (4.5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.28 g, 7.02 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then iodomethane (0.66 mL, 10.6 mmol) was added dropwise. Upon complete addition, the mixture was allowed to warm to 23° C. After 19 h, the reaction was carefully diluted with water then extracted five times with EtOAc. The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford a light yellow oil as 5-bromo-N-(3-methoxy propyl)-N-methyl-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, d, J=2.3 Hz), 8.21 (1H, d, J=2.3 Hz), 3.79 (2H, m), 3.47 (2H, m), 3.33 (3H, s), 2.86 (3H, s), 2.01 (2H, m).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]([F:16])([F:15])[F:14].[OH-].[Li+].Cl>O1CCCC1.CO>[C:21]([O:20][C:18]([NH:17][C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]([F:14])([F:15])[F:16])[C:3]([OH:25])=[O:2])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](Cc1ccccc1OC(F)(F)F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1OC(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from Step 2 (5.65 g, 15.6 mmol) in tetrahydrofuran (60 mL), methanol (20 mL) and aqueous 1 N lithium hydroxide solution (20 mL) was stirred at room temperature for 18 hours. The mixture was then poured into 0.5 N aqueous HCl solution and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]([NH:8][CH:9]=O)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[CH:9]=[N:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CNc2nc(Br)cnc2NC=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cn2cnc3ncc(-c4ccc(F)cc4)nc32)cc1
Yield: 30.5 %

Procedure:
A mixture of N-[5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-formamide (160 mg, 0.47 mmol), 4-fluoro-phenyl boronic acid (200 mg, 1.44 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (118 mg, 1.41 mmol) in DME (1 mL) and water (0.2 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetontrile containing 0.1% trifluoroacetic acid to provide 6-(4-fluoro-phenyl)-1-(4-methoxy-benzyl)-1H-imidazo[4,5-b]pyrazine as a white solid (48 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[C:10]([NH:5][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 3,5dimethylaniline (20 g, 165 mmol), acetic anhydride (24 mL, 247 mmol) and triethylamine (70 mL, 495 mmol) in methylene chloride (300 mL is stirred at room temperature for 16 hours. The mixture is washed with water, dried (magnesium sulfate) and rotary evaporated. The residue is triturated with hexane and filtered to afford N-acetyl-3,5-dimethylaniline (25 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:7])[NH:5][N:6]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:3]1[C:4]([OH:7])=[N:5][N:6]2[C:19](=[O:20])[CH:18]=[C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[NH:1][C:2]=12
Reactant: NC1=NNC(=O)C1Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncc2)[nH]c2c(Cc3ccccc3Cl)c(O)nn12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-amino-4-[(2-chlorophenyl)methyl]-2,4-dihydro-3H-pyrazol-3-one (500 mg, 2.23 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (432 mg, 2.23 mmol). The reaction mixture was irradiated (microwave) and stirred at 140° C. for 60 minutes. Reaction mixture was cooled down, diluted with acetic acid (2 mL) and stood still for 2 hours. Precipitate was collected by filtration. The solid was washed with acetic acid (1 mL), ethanol (1 mL×2) and dried. The titled product was obtained. (177 mg, 22%); LC/MS: MS (ES+) m/e 353 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 6.06 (d, J=1.52 Hz, 1H) 7.02 (s, 1H) 7.23 (dd, J=5.94, 3.41 Hz, 2H) 7.45 (dd, J=5.68, 3.66 Hz, 1H) 7.75 (d, J=6.06 Hz, 2H) 8.76 (d, J=6.06 Hz, 2H) 12.05 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>CN(C)C=O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][CH2:19][O:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 15.0 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, 8.80 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 17 ml of 2-(2-bromoethyl)-1,3-dioxolane and 80 ml of dimethylformamide were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.67 g of the title compound, melting at 102-104° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[I:11]I.OO>O>[I:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: II
Reactant: c1ccc2c(c1)CCCN2
Agent: OO
Solvent: O
Product: Ic1ccc2c(c1)CCCN2
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a mixture of 1,2,3,4,-tetrahydroquinoline (0.34 g; 2.55 mmol) and I2 (0.32 g; 1.27 mmol) in H2O (10 ml), 30% H2O2 (0.26 ml; 2.55 mmol) was added at room temperature. The resulting mixture was vigorously stirred overnight at room temperature, and then extracted with Et2O (2×15 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2), to give the title compound (0.33 g; 50%) as a creamy syrup. 1H-NMR (CDCl3) 1.84-1.92 (m, 2H); 2.69 (tr, 2H, J=6.4 Hz); 3.27 (tr, 2H, J=6.4 Hz); 3.82 (broad s, 1H); 6.22 (d, 1H, J=8.2 Hz); 7.15-7.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]=[N:10][O:11][CH2:12][C:13]#[CH:14])[CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C(Cl)Cl.O>[CH3:15][NH:16][C:17](=[O:18])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]=[N:10][O:11][CH2:12][C:13]#[CH:14]
Reactant: C#CCON=Cc1cc(Cl)ccc1O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C#CCON=Cc1cc(Cl)ccc1OC(=O)NC
Yield: 75 %

Procedure:
A solution of 2.4 grams (0.011 mole) of 4-chloro-2-[(2-propynoxyimino)methyl]phenol (Example 1 product), 0.7 gram (0.013 mole) of methyl isocyanate and three drops of triethylamine in 50 ml of methylene chloride was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The residue was recrystallized from toluene-hexane to give a solid; mp 97°-100° . The solid was slurried in hot water and collected by filtration. A second recrystallization from toluene-hexane gave 2.2 grams of 4-chloro-2-[(2-propynoxyimino)methyl]phenyl methylcarbamate; mp 99.5°-100.5°.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>C(O)(=O)C>[CH3:19][C:20]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Solvent: CC(=O)O
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 91 %

Procedure:
15.12 g of 2-(theophyllin-7-yl)-acetamidoxime are heated on water bath for two hours with a mixture of 120 cm3 acetic acid and 8 cm3 of acetic anhydride. The solvent is distilled off and 16.06 g. (91%) of 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135° C. (methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][C:4]=1[O:16][S:17]([CH3:20])(=[O:19])=[O:18].C(Cl)CCl.[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:12][C:11](=[O:13])[CH2:10][S:9][C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[C:4]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 2-(4-methoxy-3-(methylsulfonyloxy)benzoylthio)acetic acid (0.150 g, 0.468 mmol) in dry DCM (12 ml), EDC (0.090 g, 0.468 mmol) and DMAP (0.057 g, 0.468 mmol) were added followed by (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.197 g, 0.468 mmol) and the reaction was stirred at RT for 48 hours. The mixture was partitioned between DCM and HCl 1N; the organic phase was washed with NaHCO3 sat. sol., and dried over Na2SO4. The solvent was removed and the crude was purified by preparative HPLC to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzoylthio)-acetoxy)ethyl)pyridine 1-oxide (0.080 g, 0.111 mmol, 23.64% yield, MS/ESI+ 722.38 [MH]+, [αD]=−34.72, c=0.5, DCM).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:25][C:26]([NH2:28])=[O:27].Cl>C(O)C.[OH-].[Na+].O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:25][C:26]([NH2:28])=[O:27])=[C:7]([NH:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:31]=[C:30]([F:32])[CH:29]=3)[CH:12]=2)=[CH:19][CH:18]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)c1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)Cc1cnc(Nc2ccc(C(=O)O)cc2)cc1NCc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 31.8 %

Procedure:
302 mg of 4-[(3,5-difluorobenzyl)amino]-6-[(4-ethoxycarbonylphenyl)amino]pyridine-3-carboxyamide (the compound of Example 321) was dissolved in 13 mL of ethanol, to which 2.5 mL of 2 mol/L sodium hydroxide in water was added, and stirred at 50° C. for 4 hours. After cooling, the reaction mixture was neutralized by adding 1 mol/L hydrochloric acid in water, extracted with chloroform, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 90 mg (yield 32%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:15]=[CH:14][C:13]3[N:12](COCC[Si](C)(C)C)[C:11]4[N:24]=[CH:25][CH:26]=[C:27]([O:28][C@@H:29]5[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]5)[C:10]=4[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[NH:31]1[CH2:32][CH2:33][CH2:34][C@@H:29]([O:28][C:27]2[C:10]3[C:9]4[CH:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[N:15]=[CH:14][C:13]=4[NH:12][C:11]=3[N:24]=[CH:25][CH:26]=2)[CH2:30]1
Reactant: Cn1cc(-c2cc3c4c(O[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)ccnc4n(COCC[Si](C)(C)C)c3cn2)cn1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(cn2)[nH]c2nccc(O[C@@H]4CCCNC4)c23)cn1
Temperature: 75 °C
Yield: 31.9 %

Procedure:
(R)-tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yloxy)piperidine-1-carboxylate (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (0.2 mL) and then treated with 48% HBr(aq) (0.2 mL) and heated at 75° C. for 5 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale yellow solid (10 mg, 30% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.77 (s, 1H), 8.39 (d, J=5.7, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 6.95 (d, J=5.9, 1H), 4.77-4.67 (m, 1H), 3.91 (s, 3H), 3.10-3.25 (m, 1H), 2.90-2.83 (m, 2H), 2.67 (m, 1H), 2.19 (m, 1H), 1.91-1.78 (m, 2H), 1.67-1.53 (m, 1H), piperidine NH not observed. LCMS (Method D): RT=5.567 min, M+H+=349.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)CC
Reactant: BrCCCCBr
Product: CCOC(=O)C(CC)(CC)CCCCBr

Procedure:
Using ethyl 2-ethylbutyrate and 1,4-dibromobutane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCNCC3)cc12
Reaction time: 3 h

Procedure:
A solution of Example 135A (0.955 g, 2.24 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1.73 mL, 22.4 mmol) and the mixture was stirred for 3 hours. After concentration, the residue was dissolved in 10 mL methanol and treated with 30 mL 1M hydrogen chloride in ether. After stirring for 15 minutes, the mixture was treated with ether and the solids were filtered, washed with ether and oven-dried to afford the title compound as a hydrochloride salt. MS (ESI+) m/z 326.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:19])[NH:28][CH3:27])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Product: CNC(=O)CCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O

Procedure:
Compound 754 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and methylamine using the method described for compound 751. The title compound was isolated as a white powder (0.0192 g, 18% yield). HRMS (M+H) calcd for C18H22N3Cl2O4: 414.09875. found: 414.0969.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1)[NH2:2].[C:18](/[N:20]=[C:21](\OC1C=CC=CC=1)/[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)#[N:19]>C(O)(C)C>[N:7]1[C:6]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=[C:3]([N:1]2[C:18]([NH2:19])=[N:20][C:21]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:28]=3)=[N:2]2)[N:8]=1
Reactant: N#C/N=C(/Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C

Procedure:
Diphenylcyanocarbonimidate (1.1 equiv) and 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (1 equiv) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with iso-propyl alcohol and dried to yield (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The precipitate which formed in the microwave vial was re-dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #1, as a yellow solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in dry DMSO (100 ml) was treated with sodium hydride (2.0 g of a 50% dispersion in oil, 42 mM). The reaction mixture was stirred for 1 hour then treated with 4-fluoronitrobenzene (5.65 g, 40 mM). After 24 hours the reaction mixture was poured on to water (500 ml) and extracted with ether (4×500 ml). The organic extracts were washed with brine, dried and the solvents removed under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (6.1 g) m.p. 136°-8°.