Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:29]
Reactant: O=C(Cl)CCCCCl
Reactant: CCOC(=O)Cc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccccc1NC(=O)CCCCCl
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of ethyl 2-aminophenylacetate (5.60 g, 0.031 mole) and diisopropylethylamine (7.08 ml, 0.042 mole) in dry THF (75 ml) was treated with 5 chlorovaleryl chloride (4.00 ml, 0.031 mole) and left to stir for 1 h. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 ml) and washed with 1M HCl (100 ml), dried (Na2SO4) and concentrated in vacuo to afford a beige solid. This was washed with n-pentane/ether (1:1) and dried to afford the title compound as a light beige solid (8.1 g, 91%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[CH2:13]Br)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:22][CH2:23][CH2:24][NH:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([NH:10][CH:11]2[CH2:13][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N1CC1CBr
Reactant: CNCCNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccccc2)CC(NS(=O)(=O)c2ccccc2)C1
Reaction time: 5 h
Yield: 22.3 %

Procedure:
A mixture of 1-benzenesulfonyl-2-bromomethylethylenimine (27.2 g), N-benzyl-N'-methylethylenediamine (16.2 g), triethylamine (19.9 g) and chloroform (350 ml) is refluxed with stirring for 5 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography to give the title compound (7.9 g) as an oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=1.Br[CH2:26][C:27]([CH3:29])=[CH2:28].Cl>C1COCC1.C(OCC)(=O)C>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:28][C:27]([CH3:29])=[CH2:26])[C:16]([OH:18])=[O:17])[CH:10]=1
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
A solution of LDA (2.2 mL, 2.0 M in THF) in THF (20 mL) was cooled to 0° C. and then treated with biphenyl-3-ylacetic acid (0.212 g, 1.0 mmol). The mixture was stirred for 40 minutes, cooled to −78° C. and then treated with 3-bromo-2-methylpropene (135 μL, 1.3 mmol). The mixture was stirred for 1 hour, treated with 1 M hydrochloric acid (5 mL) and then diluted with ethyl acetate (50 mL). The organic layer was separated washed with water, brine, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 33% ethyl acetate in hexane to provide 2-biphenyl-3-yl-4-methylpent-4-enoic acid (250 mg, 0.93 mmol). 1H NMR (DMSO-d6): 1.71 (s, 3H), 2.52 (m, 2H), 3.68 (dd, 1H), 4.75 (m, 2H), 7.08 (d, 1H), 7.28-7.37 (m, 8H). LCMS: 267.1 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8][C:9]1[N:13]=[C:12]([NH2:14])[NH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:11]2[C:12]([NH2:14])=[N:13][C:9]([S:8][CH3:7])=[N:10]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CSc1n[nH]c(N)n1
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSc1nc(N)n(C(=O)c2ccc(Cl)cc2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
4.7 g of pyridine are added to a solution of 7.8 g of 3-methylthio-5-amino-1H-1,2,4-triazole [Monatshefte fur Chemie 106, 1291 (1975)] in 200 ml of dioxane, then 10.8 g of 4-chloro-benzoylchloride are added dropwise at -5° C. The reaction mixture is stirred for one hour at -5° C., then for a further one hour at room temperature, finally 100 ml of water are added at water-cooling and the entire mixture is extracted with chloroform. The chloroform layer is washed with water, dried, evaporated to dryness, yielding 13.46 g (83.5 percent) of 1-(4-chloro-benzoyl)-3-methylthio-5-amino-1,2,4-triazole, m.p. 175° to 177° C. (following boiling with alcohol).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:17]([O:30][CH3:31])=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[N+:13]([O-])=O.O.[Cl-].[NH4+]>O1CCCC1.CO.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Zn]>[F:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:17]([O:30][CH3:31])=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:13])=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1
Reactant: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3N)cc2OC)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101 %

Procedure:
To a stirred solution of N-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline (0.38 g, 0.70 mmol) in tetrahydrofuran (10 mL), methanol (5 mL), and water (1 mL) was added ammonium chloride (0.30 g, 5.64 mmol) and iron (II) sulfate heptahydrate (0.69 g, 2.47 mmol). The bright orange suspension was treated with zinc (0.16 g, 2.47 mmol). The mixture was gradually warmed to reflux. After 3.5 h, the color of the reaction mixture had turned from orange to olive-green. At this point the reaction mixture was allowed to cool to room temperature. The mixture was filtered through Celite, and the filtercake was washed with chloroform (250 mL). The filtrate was washed with 5N ammonium hydroxide solution (75 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to afford 0.36 g (100%) of N1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine as a tan solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:2].[Li+].[CH3:17][CH:18]([N-:20]C(C)C)C>C(#N)C>[CH2:14]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:17][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)[CH3:15]
Reactant: CC(C)[N-]C(C)C
Reactant: CCC(CC)COc1cccc(C=O)c1
Agent: [Li+]
Solvent: CC#N
Product: CCC(CC)COc1cccc(C(O)CC#N)c1

Procedure:
Reaction of 3-(2-ethylbutoxy)benzaldehyde with acetonitrile in the presence of LDA gave 3-(3-(2-ethylbutoxy)phenyl)-3-hydroxypropanenitrile. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J=7.2 Hz, 1H), 6.92-6.96 (m, 2H), 6.81-6.83 (m, 1H), 5.89 (brs, 1H), 4.83 (brs, 1H), 3.82 (d, J=6.4 Hz, 2H), 2.73-2.90 (m, 2H), 1.56-1.64 (m, 1H), 1.31-1.44 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1>CO>[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CSc1nccc(-c2ccc(/C=C/C(C)=O)s2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1nccc(-c2ccc(/C=C/C(C)O)s2)n1
Reaction time: 3 h

Procedure:
Solid sodium borohydride (25 mg, 0.66 mmol) was added to a solution of (E)-4-[5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-but-3-en-2-one (120 mg, 0.43 mmol) in 8 ml of MeOH. After stirring for 3 hours, the MeOH was evaporated and the residue was partitioned between water and EtOAc. The aqueous layer was separated and extracted once more with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give a yellow solid which was used without further purification. Yield: 112 mg (93%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH2:14].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]1[CH2:14][O:20]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1c(C)cc2ccccc2c1Cl
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C1CO1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-chloro-3-methyl-2-vinyl-naphthalene (3.0 g, 14.8 mmol) in CH2Cl2 (120 mL) was added 3-chloroperoxybenzoic acid (3.8 g, 22.0 mmol) at 0° C. and allowed to warm to room temperature overnight. The reaction mixture was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)oxirane. 1H-NMR: 400 MHz, (CDCl3) δ 8.26 (d, J=7.2 Hz, 1H), 7.74 (dd, J=7.2, 2.0 Hz, 1H), 7.57-7.48 (m, 3H), 4.13 (t, J=3.6 Hz, 1H), 3.34 (t, J=5.6 Hz, 1H), 2.97 (dd, J=5.2, 2.8 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2([C:21]#[N:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(I)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.95 g, 4.73 mmol) in CH2Cl2 (37.5 mL) at 0° C. was added TFA (12.5 mL). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×20 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation, dried under high vacuum for 1 h to yield 4-(4-iodo-phenyl)-piperidine-4-carbonitrile as a reddish solid (1.46 g, ˜4.7 mmol, ˜100%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H), 7.37 (dd, 2H), 3.25 (m, 4H), 2.15 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:34]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cncc(Br)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-bromo-nicotinic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](/[N:1]=[CH:23]/[C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)=[C:3]([NH:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Cc1ccc(N)c(NC(=O)c2ccccc2)c1
Solvent: CO
Product: COc1cc(/C=N/c2ccc(C)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-(2-amino-5-methylphenyl)benzamide (2 mmol) and 3,4,5-trimethoxybenzaldehyde (3 mmol) in methanol was stirred at room temperature for 12 h. The suspension was filtered and the solid was washed with methanol to afford (E)-N-(5-methyl-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][N:20]([CH:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 2 h

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-azetidin-3-ol (490 mg, 1.13 mmol), tetrahydropyran-4-one (158 mg, 1.58 mmol), AcOH (130 μL, 2.25 mmol) and 4 Å powdered molecular sieves (640 mg) in DCE (15 mL) was allowed to stir for 5 min before the addition of sodium triacetoxyborohydride (478 mg, 2.25 mmol) portion wise over 5 min. The resulting mixture was allowed to stir for 4 h at r.t before the addition of further tetrahydropyran-4-one (158 mg, 1.58 mmol) and sodium triacetoxyborohydride (478 mg, 2.25 mmol). The mixture was stirred for 2 h then diluted with DCM and washed with 1M NaOH. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, 2M NH3/MeOH:DCM, 0-15%) then (C18, MeOH:H2O, 7.5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 720 as a white foam (309 mg, 53%). LCMS (method I): RT 2.40 min, [M+H]+ 519.3. 1H NMR (MeOD, 400 MHz): δ 8.01-8.00 (1 H, m), 7.66-7.61 (1 H, m), 7.28-7.27 (2 H, m), 4.38 (4 H, s), 4.24 (2 H, d, J=8.76 Hz), 3.97-3.94 (2 H, m), 3.85 (7 H, s), 3.56 (2 H, d, J=8.75 Hz), 3.31-3.31 (5 H, m), 2.54-2.52 (1 H, m), 1.83-1.73 (2 H, m), 1.38 (5 H, t, J=7.49 Hz)
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:22])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:20]([N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11](=[O:12])[NH:10][C:9]2[C:8]([CH3:22])=[CH:7][C:6]([O:23][CH3:24])=[N:5][C:4]1=2)[CH3:21]
Reactant: CCNc1ncccc1C(=O)Nc1c(C)cc(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(OC)nc21
Yield: 47.6 %

Procedure:
Sodium hydride (0.14 g of a 50% dispersion in mineral oil) was added to a solution of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (0.54 g) in pyridine (4 ml), and the resulting mixture was refluxed for 1.5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The residue was washed with diisopropyl ether and hot ethyl acetate, and then crystallized from ethanol to provide 0.2 g of 5,11-dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 249°-251° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CS(=O)(=O)Cl
Product: CC(=O)c1c(NS(C)(=O)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
The product of Example 2 was reacted with methanesulfonyl chloride using the conditions of EXAMPLE 11 to afford the title compound. HPLC/MS: 549.9 (M+1), 551.9 (M+3); Rt=4.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3Cl)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1C=C(C)[N:5]=[C:4]([SH:9])[N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH2:5])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: CSc1nccc(C)n1
Product: CSc1nccc(-c2sc(N)nc2C)n1

Procedure:
This material is prepared by the procedure outlined for intermediate AC, replacing 4,6-dimethyl-pyrimidine-2-thiol in the first step (AC1) with 4-methyl-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[I:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]>>[Cl:1][S:2]([C:14]1[CH:15]=[C:7]([I:6])[C:8]([CH3:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:5])=[O:3]
Reactant: Cc1c(I)cccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Product: Cc1c(I)cc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with chlorosulfonic acid (3.80 mL, 57.2 mmol), and 3-iodo-2-methylbenzoic acid (5.00 g, 19.1 mmol) was added in portions at 0° C. The reaction was heated at 95° C. for two hours and then stirred at room temperature overnight. The reaction mixture was poured onto ice and the solids formed were collected and dried to afford the desired product as a white solid.
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:2]([CH2:3][CH2:4][C:5]#[CH:6])[C:1]([N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7]
Reactant: O=Cc1ccccc1
Reactant: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a stirred solution of 56.8 g (221 mmol) of (4S)-3-hex-5-ynoyl-4-phenyl-1,3-oxazolidin-2-one from step A above in 265 mL of anhydrous ethyl acetate at ambient temperature under an atmosphere of nitrogen was added 6.31 g (66.2 mmol) of anhydrous magnesium chloride, 61.5 mL (442 mmol) of triethylamine, 26.9 mL (265 mmol) of benzaldehyde and 42.3 mL (331 mmol) of chlorotrimethylsilane and the resulting mixture was stirred for 72 h. The heterogeneous reaction mixture was filtered through a 300 mL plug of silica gel eluting with an additional 1 L of ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue suspended in 265 mL of methanol and 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature under nitrogen for 5 h during which time the reaction became homogeneous. All volatiles were then removed in vacuo and the residue was purified by silica gel chromatography eluting with a 5-15% ethyl acetate in hexanes gradient to afford the title compound as a white solid (65.0 g, 81.2%). 1H NMR (500 MHz, CDCl3): δ 7.30-7.28 (m, 8H), 7.09-7.07 (m, 2H), 5.42 (dd, J=8.7, 3.7 Hz, 1H), 4.76-4.72 (m, 1H), 4.72-4.67 (m, 1H), 4.65 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 3.7 Hz, 1H), 3.05 (d, J=7.8 Hz, 1H), 2.24 (td, J=7.1, 2.5 Hz, 2H), 2.00-1.93 (m, 2H), 1.67-1.61 (m, 1H). LC-MS: m/z (ES) 346.1 (MH-H2O)+, 386.0 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=[O:9].C(O)(C(F)(F)F)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])(=[O:9])=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: CS(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1Cl
Product: CS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl

Procedure:
A solution of the product from step d) (73 mg) in TFA (3 ml) was stirred for 2 h. The solvent was removed in vacuo, water was added and the mixture was extracted with dichloromethane (three times). The organic extracts were dried (MgSO4), evaporated and triturated with ether to give the title compound (46 mg) as a white solid. M.p. 140-2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][C:16](OC3C=CC=CC=3)=[O:17])=[CH:13][C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:11]2)=[CH:6][CH:5]=1.[F:30][C:31]1[CH:36]=[C:35]([O:37][C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:34]=[CH:33][C:32]=1[NH2:45]>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH:15][C:16]([NH:45][C:32]3[CH:33]=[CH:34][C:35]([O:37][C:38]4[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=4)=[CH:36][C:31]=3[F:30])=[O:17])=[CH:13][C:12]([C:25]([CH3:26])([CH3:28])[CH3:27])=[N:11]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A solution of 4-(3-tert-butyl-5-phenoxycarbonylamino-pyrazol-1-yl)benzoic acid methyl ester (470 mg, 1.19 mmol) and 2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenylamine (260.69 mg, 1.19 mmol) was stirred at 40° C. overnight. The mixture was cooled to room temperature, and then evaporated at reduced pressure. The residue was purified by MPLC (eluting with 50:50 EtOAc/hexane) to afford the title compound (407 mg, 66%). 1H-NMR (DMSO-d6) δ 8.94 (s, 2H), 8.30 (d, J=5.7 Hz, 1H), 8.09 (m, 3H), 7.71 (d, J=5.7 Hz, 2H), 7.20 (d, J=14.7, 1H), 6.94 (d, J=5.4 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 6.72 (d, J=5.4 Hz, 1H), 6.42 (s, 1H), 3.87 (s, 3H), 2.38 (s, 3H), 1.27 (s, 9H); MS LC-MS [M+H]+=518.2, RT=2.94 min.