Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F-:13].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a solution of methyl 5-bromo-2-chloronicotinate (170 mg, 0.68 mmol) in 3 mL of DMSO was added CsF (152 mg, 1.0 mmol). The solution was stirred at room temperature for 2 d and then heated at 60° C. for 4 h. After cooling, the mixture was diluted with 30 mL of H2O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography to give the desired product (90 mg, 57% yield). MS (ESI+) m/z 234.06, 236.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: COc1cc(OCCN2CCCCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCCCC2)ccc1N
Yield: 81.4 %

Procedure:
A mixture of 1-[2-(3-methoxy-4-nitro-phenoxy)-ethyl]-piperidine (1.5 g, 5.4 mmol) and 5% Pd—C (0.5 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 18 hours. The mixture was filtered through Celite and evaporated, providing 1.1 g of the product, in 81% yield: 1H NMR (DMSO-d6) δ 1.45-1.53 (m, 6H), 2.35-2.41 (m, 4H), 2.59 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.93 (t, J=6.0 Hz, 2H), 6.28 (dd, J=8.3 Hz, J=2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17](OC)=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:2][NH2:3])=[O:18])[C:13]=1[CH2:14][CH3:15]
Reactant: NN
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: CCO
Product: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 70624 %

Procedure:
Hydrazine hydrate (520 μL, 10.9 mmol) was added to a solution of the ester (780 mg, 2.18 mmol) of Example 9 in ethanol (25 ml) and the resulting mixture was heated under reflux for 18 hours. After cooling, the precipitate was collected by filtration and washed with ether (50 ml) to afford the title compound (550 g) as a white solid, m.p. >250° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C(OCC)(=O)C>[CH3:34][Si:26]([CH3:33])([CH2:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[N:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: C[Si](C)(CCCCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)CCC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(CCCCOc1cnc(-c2ccc(O)cc2)nc1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 40 (0.321 g, 0.658 mmol), palladium on charcoal (0.0343 g, 0.033 mmol) in ethanol/ethyl acetate (6.5 ml, 1:2) was stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was filtered (celite), the solvent removed in vacuo and the residues recrystallized from acetonitrile to yield colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu][C:15]#[N:16]>CN(C)C=O.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Yield: 77.5 %

Procedure:
The product of Example 431A (0.581 g, 2.380 mmol) and copper (I) cyanide (0.426 g, 4.760 mmol) in N,N-dimethylformamide (5 mL) under a nitrogen atmosphere were heated in 160° oil bath for 1.5 hour. The reaction was cooled, treated with a solution of iron (III) chloride hexahydrate (2.48 g) in water (3.72 mL) and concentrated hydrochloric acid (0.62 mL), and then heated at 65° for 20 minutes. The cooled reaction mixture was extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed sequentially with 1N aqueous HCl (25 mL), 3N aqueous sodium hydroxide (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 20:80 ethyl acetate/hexanes afforded the title compound as a yellow liquid (0.351 g, 1.845 mmol, 58%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 2.82-3.47 (m, 1 H) 7.66 (dd, J=7.91, 1.29 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H); MS (DCI) m/z 208 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[CH3:27][NH2:28]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:28][CH3:27])[N:11]=1
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CCO
Product: CN=C(NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole (0.25 g.) in ethanol (1 ml.) was added ethanolic methylamine (33% w/v, 30 ml.). The mixture was allowed to stand overnight at room temperature and then evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylguanidino)pentyl]thiazole. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ):1.5 (multiplet, 6H); 2.7 (doublet, 3H); 3.1 (multiplet, 2H); 4.1 (multiplet, 2H); 6.4 (singlet, 1H).
Reaction SMILES: ClC1C=CC=CC=1C(=O)[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:8][CH:7]=1.CCOC(C)=O.[OH-].[Na+]>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([SH:5])=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Nc1ccc(SC(=O)c2ccccc2Cl)cc1)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S)cc1)c1ccccc1Cl
Temperature: 70 °C
Yield: 86.8 %

Procedure:
S-4-(2-chlorobenzamido)phenyl 2-chlorobenzothioate (305 g, 0.76 mol), EtOAc (325 mL), and water (65 mL) were charged to a flask fitted with a reflux condenser. A solution of NaOH (3 eq., 50% aq.) was added and the mixture heated to 70° C. for 30-40 minutes. EtOAc was removed by distillation at 100 mm Hg and the mixture was cooled to 5° C. The mixture was acidified with 6N HCl to pH 2. The solid was then collected by vacuum filtration and washed with water (390 mL). The solid was taken up in CH2Cl2 (520 mL) and washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to give the desired material (174 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].CN([CH:14]=[O:15])C.C[O-].[Na+]>O>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([O:15][CH3:14])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nc(C)c1Br
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(Br)c(C)n1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
3-bromo-6-chloro-2,4-dimethylpyridine obtained in Preparation Example 21 (200 mg) was added to DMF (1 mL). Sodium methoxide (28% solution in methanol, 0.741 mL) was added to the solution, and the mixture was stirred at 60° C. for 15 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (172 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].[C:23](#[N:26])[CH:24]=[CH2:25]>CC(C)=O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:25][CH2:24][C:23]#[N:26])[CH2:20][CH2:21]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Reactant: C=CC#N
Solvent: CC(C)=O
Product: N#CCCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 16.8 %

Procedure:
4-Piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate (0.180 g, 0.55 mmol) was dissolved in acetone (10 ml) and treated with acrylonitrile (0.040 ml; 0.61 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacua to an orange gum. The gum was purified by flash silica-gel chromatography with CHCl3 →2% MeOH/CHCl3 as eluant to yield the title compound as a colourless oil (0.035 g; 17%) which was converted to the oxalate salt, mp 101°-103° C.
Reaction SMILES: [CH3:1][C:2]1[S:14][C:5]2[C:6](=O)[C:7]3[S:8][C:9]([CH3:12])=[CH:10][C:11]=3[C:4]=2[CH:3]=1.C(O)COCCO.O.NN.[OH-].[K+]>O>[CH3:12][C:9]1[S:8][C:7]2[CH2:6][C:5]3[S:14][C:2]([CH3:1])=[CH:3][C:4]=3[C:11]=2[CH:10]=1
Reactant: Cc1cc2c(s1)C(=O)c1sc(C)cc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc2c(s1)Cc1sc(C)cc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 45 g (205 mmol) of 2,5-dimethyl-7H-thieno[3′,2′:3,4]cyclopenta[1,2-b]thiophen-7-one, 600 mL of diethylene glycol and 70 mL of hydrazine monohydrate was placed into the bulb. The mixture was warmed to 80° C. and kept at this temperature in 1 h at stirring. Then the mixture was intensively refluxed in 1 h, cooled to r.t. treated with solution of 70 g KOH in 230 mL of water. The resulting mixture was carefully heated and the gas started to bubble. The mixture was refluxed for 2 hours, then it was cooled to 70-80° C. and poured into 3 L water. The precipitate was decanted, filtered, washed 7 times with 200-300 mL of water and dried. Yield 32 g (78%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:10]1([C:16]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:24]3[CH:20]([CH2:21][NH:22][CH:23]3[C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19](=[O:34])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:27]1([CH2:26][C:25]([CH:23]2[CH:24]3[CH:20]([C:19]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([OH:34])[CH2:18][CH2:17][C:16]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:21][NH:22]2)=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C1NCC2C1C(c1ccccc1)(c1ccccc1)CCC2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of phenylmagnesium bromide (prepared starting from 3.14 g of bromobenzene and 0.48 [lacuna] of magnesium in 30 cm3 of ether) is added to a suspension of 4.09 g of (3aRS,7aRS)-7,7-diphenyl-2-phenylacetylperhydroisoindol-4-one in 50 cm3 of tetrahydrofuran. The reaction mixture is stirred at 25° C. for 1 hour and then heated under reflux for 2.5 hours, cooled and treated with 150 cm3 of a saturated solution of ammonium chloride. The organic phase is washed with water (2×100 cm3). The aqueous phases are extracted with 100 cm3 of ethyl acetate. The combined organic phases are washed with 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 30 cm3 of acetonitrile to give 2.9 g of (3aRS,4RS,7aRS)-2-phenylacetyl- 4,7,7-triphenylperhydroisoindol-4-ol in the form of white crystals which melt at 270° C.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:32][C:33]1([CH2:37][CH3:38])[CH2:36][NH:35][CH2:34]1>>[NH2:32][C:33]1([CH2:37][CH3:38])[CH2:36][N:35]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:34]1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CCC1(N)CNC1
Agent: CS(=O)(=O)O
Product: CCC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1
Yield: 68.9 %

Procedure:
8-(3-Amino-3-ethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid was prepared under the conditions of Example 15, but starting with 1.66 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.1 g of 3-amino-3-ethylazetidine dimethane-sulphonate. 1.46 g of 8-(3-amino-3-ethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 294° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:15]=[C:16]=[S:17])[CH:13]=[CH2:14].CCOCC>C(Cl)Cl>[CH2:12]([N:15]1[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:16]1[SH:17])[CH:13]=[CH2:14]
Reactant: C=CCN=C=S
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCn1c(S)nc2ccccc2c1=O
Temperature: 40 °C

Procedure:
To a stirred mixture of 50 g (0.33 mole) methyl anthranilate in 100 ml methylene chloride, 32.7 g (0.33 mole) allyl isothiocyanate in 50 ml methylene chloride was added dropwise. The reaction mixture was refluxed at 40° C. one hour, stirred over the weekend at ambient temperature, and refluxed at 40° C. for one hour. The reaction mixture was stripped. Additional methylene chloride (200 ml) was added; the resulting mixture was refluxed at 40° C. for 7 hours, and then stirred about 11/2 days at ambient temperature. The reaction mixture was stripped. Ether was added; a precipitate formed. The above-identified product was isolated by suction filtration.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSc3ccc(C)cc3)c(C)o2)cc1
Yield: 77.5 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6 g, 22.64 mmol, 1.00 equiv), 4-methylbenzenethiol (4.2 g, 33.87 mmol) and cesium carbonate (8.8 g, 26.99 mmol, 1.19 equiv) in N,N-dimethylformamide (120 mL) was stirred under nitrogen overnight at 50° C. The reaction mixture was diluted with 100 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with 2×50 mL of hexane. The solid was collected by filtration and dried in vacuum to yield 6.2 g (78%) of methyl 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 395 [M+CH3CN+H]+, 354 [M+H]+, 271, 203, 126, 120.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C1(C)C=CC=CC=1>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.C(O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(OC)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg), bis(triphenylphosphine)palladium(II) chloride (12.95 mg), potassium carbonate (128 mg) and 3-methoxyphenylboronic acid (33.6 mg) were added to a 2-5 ml microwave vial. Toluene (2 ml) and ethanol (2 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-5% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-8-(3-methoxyphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a cream solid (59.6 mg). LCMS (formate): MH+ 500/502, RT 1.09 min
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
7-Hydroxy-4-methylcoumarin (70.00 g, 0.397 mol), anhydrous K2CO3 (140 g, 1.01 mol), and allyl bromide (100 ml, 1.15 mol) were added to 2.0 L of reagent grade acetone. The milky mixture was refluxed for sixteen hours with overhead stirring, allowed to cool to room temperature, and filtered. Solids were washed once with reagent grade acetone (150 ml.), the filtrate and wash combined, and the resulting combined filtrate concentrated to dryness with a rotary evaporator to obtain 7-allyloxy-4-methylcoumarin (84.2 g, 98% yield). The crude product melted at 100.0°-101.5° C. (lit. 1 101° C.), showed only one spot in TLC, and was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: Cc1ccccc1-n1ccc(Cl)c(C=NO)c1=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(2-methylphenyl)pyridin-2(1H)-one obtained in Step C (6.36 g) in acetonitrile (60 mL) was added phosphorus oxychloride (2.93 mL) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration to give the title compound (3.15 g).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12](O)[CH3:13])[CH:11]=1.C(Cl)[Cl:31]>CN(C)C=O>[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12]([Cl:31])[CH3:13])[CH:11]=1
Reactant: ClCCl
Reactant: COc1c(C(C)O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 5 h
Yield: 80 %

Procedure:
Thionyl chloride (800 μL, 10 mmol) was added dropwise to a solution of 5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]N,N-dimethylpyridine-2-carboxamide (2 g, 6 mmol), methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 5 hrs and was complete by LC/MS. The reaction mixture was partitioned between EtOAc and water. The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give crude 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide as an oil (1.8 g, 80%). LCMS calculated for C18H18Cl2N3O2(M+H)+: m/z=378.1; found: 378.1.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:10][S:11]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccnc1F

Procedure:
A solution of (2-fluoropyridin-3-yl)methanol (400 mg, 3.1 mmol), methanesulfonyl chloride (0.37 mL, 4.7 mmol) and triethylamine (0.88 mL, 6.30 mmol) in dichloromethane (10 mL) was stirred at rt for 16 h. The mixture was then diluted with dichloromethane and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give (2-fluoropyridin-3-yl)methyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(CO)cc1
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: ClCCl
Product: COc1ccc(COC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzylalcohol (6.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.