Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[OH:22][C@H:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](O)=[O:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.C(OCC)C>[OH:22][C@H:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:25]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@H](O)c4ccccc4)cc1c23
Yield: 55.8 %

Procedure:
Preparation of example 133 from the title compound of Example 7 (hydrochloride) (46 mg, 0.147 mmol), (2R)-hydroxy(phenyl)ethanoic acid (27 mg, 0.177 mmol), triethylamine (0.061 mL, 0.44 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67 mg, 0.177 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 3:1:1 hexane:ethyl acetate:ethanol), also in an analogous manner, followed by two successive triturations (ethyl acetate/diethyl ether then methanol/diethyl ether) afforded the title compound (34 mg, 0.082 mmol) as a yellow powder in 56% yield.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[NH:19]1)([O:15][CH2:16][CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49](/[CH:53]=[CH:54]/[CH2:55]O)[CH:48]=1.N1C=CC=C(/C=C/C(OC)=O)C=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:13]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:55]/[CH:54]=[CH:53]/[C:49]1[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Reactant: OC/C=C/c1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)/C=C/c1cccnc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)n1c2ccccc2c(=O)n1C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A solution of diethyl azodicarboxylate (1.6 g) in chloroform (5 ml) was added dropwise to a mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (1.5 g), triphenylphosphine (2 g) and trans-3-(3-pyridyl)-allyl alcohol [0.95 g; itself prepared from methyl trans-3-(3-pyridyl)-acrylate (J. Het. Chem., 1985, 22, 65) as an oil of satisfactory purity on reduction at 0° C. with a solution of di-isobutylaluminium hydride in toluene] in chloroform (20 ml). The mixture was stirred at ambient temperature for 16 hours and then evaporated to dryness. Diethyl ether was added, the mixture was filtered and the filtrate was evaporated The residue was chromatographed using an increasing gradient of ethyl acetate in petrol as eluant to give 1,2-dihydro-1-carboethoxy-2-[trans-3-(3-pyridyl)allyl]-3H-indazol-3-one (Ex. 213) as an oil (0.84 g) in 37% yield and of satisfactory purity as judged by NMR and mass spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:28])=[C:4]([NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([O:28][S:30]([CH3:29])(=[O:32])=[O:31])=[C:4]([NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-[(3-fluoro-2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)hydrazono]propanoate (4.95 g) in pyridine (50 mL) was added methanesulfonyl chloride (1.1 mL), and the mixture was stirred at 4° C. to room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous citric acid solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual light brown solid was washed with ethyl acetate-hexane to give the title compound (5.4 g, 92%) as a pale brown solid. MS 490 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:42]([NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:44])[CH3:43]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccccc1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-isopropylaniline (135 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), then quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-isopropyl-N-phenylamide. MS m/z 576.0 (M+H); 544.0 (M+H-MeOH).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([O-:21])(=O)=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].[K+].CN(C)C=O.S(Cl)([Cl:30])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:30])(=[O:21])=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCCc1cc(S(=O)(=O)[O-])c2ccccc2c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2ccccc2c1Br
Reaction time: 0.17 h

Procedure:
Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonate (17.75 g, 43.2 mmol) was added at room temperature to a stirred solution of N,N-dimethylformamide (0.334 mL, 4.31 mmol) in thionyl chloride (63 mL, 863 mmol). The resulting mixture was placed in an oil bath at 70° C. and stirred. After 10 minutes, additional thionyl chloride (20 mL) was added to facilitate stirring. After 40 minutes at 70°, the reaction flask was fitted with a distillation head and excess thionyl chloride was removed under vacuum. The residual brown solid was mixed with diethyl ether (300 mL) and added to an ice-cold, stirred mixture of water (100 mL) and ether (100 mL). The organic phase was separated, washed with water (200 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound (14.63 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CO.O>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1C(=O)O

Procedure:
Methyl cis-3-phenoxyacetamido-4-oxoazetidine-2-carboxylate is treated with K2CO3 in methanol-water as above to give cis-3-phenoxyacetamido-4-oxoazetidine-2-carboxylic acid, mp 150°-51° from ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1>[CH:27]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]4[N:16]([C:17]5[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=5)[N:15]=[CH:14][CH:13]=4)[CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (20 mg, 0.054 mmol), cyclopropylboronic acid (14 mg, 0.16 mmol), cupric acetate (20 mg, 0.11 mmol), triethylamine (0.038 mL, 0.27 mmol), pyridine (0.035 mL, 0.44 mmol), and tetrahydrofuran (2.0 mL) were added to a 10 mL sealed tube. The mixture was subjected to microwave radiation (300 watts, 140° C.) for 10 minutes. The solvent was removed and the residue was extracted with ethyl acetate (10 mL). The extract was washed with saturated sodium bicarbonate solution (2×50 mL). Concentration afforded 22 mg (40%) of 1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole. LC/MS (EI) tR 4.15 (Method A), m/z 407.1 (M++1). 1H NMR (CDCl3) δ 1.1 (m, 4H); 1.4 (t, 3H); 2.9 (m, 2H); 3.1 (s, 3H); 3.5 (m, 1H): 6.5 (s, 1H); 6.9 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 7.6 (d, 2H); 7.8 (s, 1H); 7.9 (d, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:15]>>[CH3:25][O:24][C:17]1[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:21][CH:20]=[C:19]([O:22][CH3:23])[N:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1ccc(C(=O)CBr)c(OC)n1
Product: COc1ccc(-c2cc3c(O)cc(O)cc3o2)c(OC)n1
Yield: 47 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(2,6-dimethoxypyridin-3-yl)ethanone: Yield 47% following procedures A.2 and A.5; m.p. 97° C. (dec.); IR 3434, 2958, 1587, 1471, 1319, 1265, 1084, 1020 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.77 (s, 1H), 9.30 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 6.51 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 6.16 (s, 1H), 4.08 (s, 3H), 3.92 (s, 3H); 13C-NMR (126 MHz, δ ppm, CD3OD) 163.3, 159.7, 157.8, 157.5, 152.3, 149.5, 138.2, 113.3, 107.8, 102.8, 102.6, 98.7, 90.7, 54.1, 54.1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncccc2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (183 mg, 0.77 mmol) in methylene chloride (4.30 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.28 g, 0.92 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.32 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 156 mg, 1.0 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1-2% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (21.9 mg, 7.6%); ES+-HRMS m/e calcd for C19H27N5O3 [M+H+] 374.2187 found 374.2187. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.72 (m, 9H), 1.05 (s, 3H), 1.06 (s, 3H), 1.92 (m, 1H, CH), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.94 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.42 (dd, Jo=9.4, Jo=3.8 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.00 (dd, Jo=3.8 Hz, Jm=1.5 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:9]#[N:10])=[C:4]([CH3:20])[CH:3]=1.[NH4+].[OH-]>C(O)C.O.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9][NH2:10])=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(C#N)CCOC1CCCCO1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)ccc1C(CN)CCOC1CCCCO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
2-(4-Fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile (4.5 g, 16 mmol) was dissolved in ethanol (40 mL) and concentrated NH4OH aq (20 mL). Raney® nickel suspended in water (one teaspoonful) was added and the mixture was alternately evacuated and flushed with H2. The mixture was then stirred under H2 at room temperature until the consumption of gas ceased. The catalyst was removed with a magnet and the mixture was then filtrated and the solvent was evaporated. There was obtained 4.1 g (90%) of [2-(4-fluoro-2-methylphenyl)-4(tetrahydro-2H-pyran-2-yloxy)butyl]amine as a pale blue oil. 1H NMR (500 MHz, CDCl3): 1.4-2.0 (m, 8H), 2.4 (d, 3H), 3.2-3.8 (m, 6H), 4.4-4.6 (d, 1H), 6.9 (d, 2H), 7.1-7.2 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.[Pd](Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of benzyl (cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate (900 mg) in methylene chloride (16.5 ml) was added palladium dichloride (30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2×0.395 ml) over 2 h. The reaction mixture stirred 1 h and 2 ml of trifluoroacetic acid was added. After 30 min the reaction was basified with 2 N NaOH, extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC chromatography was run on a biotage 40S column with 3-5% methanol/methylene chloride with 0.5% ammonium hydroxide to provide the title compound as an oil (501 mg, 74%): 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.33-7.26, 5.38, 4.54, 4.07, 3.68, 3.52, 3.22, 2.95, 2.71, 2.46, 1.29, 1.15; HRMS (FAB) calcd for C20H26Cl2N4O+H 409.1562, found 409.1567. Anal. Calcd for C20H26Cl2N4O: C, 58.68; H, 6.40; N, 13.69. Found: C, 58.42; H, 6.43; N, 13.50.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[C:22]=1[C:23](O)=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[C:22]=1[C:23]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:24]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.549 mmol), 2-fluoro-6-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)=[N:10][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 40.6 g (0.250 mole) of N-phenylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was taken up in 80 ml of hot methanol, from which the product crystallized, affording 7.8 g (68%) of product. Recrystallization from a hot solution of dichloromethane (25 ml) to which methanol (25 ml) was added, provided the analytical sample, mp 171°-173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)=[CH:19][CH:20]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Fc1ccc(Br)cc1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(F)cc3)cc21

Procedure:
6-(4-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 5 from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-4-fluorobenzene, as off-white crystals: mp 232–233° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 6.96 (d, 1H, J=8.9 Hz), 1.63 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=S)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.FC(F)(F)S(OC)(=O)=O.[CH3:27][O:28][CH2:29][CH2:30][C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:35]3[CH2:34][CH2:33][NH:32][C@@H:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:36]3)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Reactant: COCC[C@H]1CNCCN1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 90 °C

Procedure:
Suspend 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (500 mg, 1.9 mmol) in dichloromethane (30 ml), stir under nitrogen and cool in an ice/water bath. Add methyl trifluoromethanesulfonate (500 μl), and stir overnight. Concentrate the reaction mixture under reduced pressure, take up in pyridine (10 ml) and add (S)-2-(2-methoxyethyl)piperazine (400 mg, 2.78 mmol) and stir the reaction mixture under nitrogen and heat at 90° C. for three days. Concentrate the reaction mixture under reduced pressure and purify by flash column chromatography on silica gel (eluent dichloromethane/methanol) to give the desired as a yellow solid 727 mg: Mass Spectrum (FIA) 375 (M+1).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of methyl 2-(5-formyl-2-thienyl)acetate (3.88 g, 21.1 mmol) in methanol (4 mL) and tetrahydrofuran (16 mL) was added sodium borohydride (399 mg, 10.5 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 1 h. Sodium borohydride (399 mg, 10.5 mmol) was added and the mixture left to stir at 0° C. for 2 h. Acetic acid (1.2 mL) was added and the reaction solution concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-30% ethyl acetate in iso-hexane to give the title compound as a yellow oil (1.1 g, 28%).