Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[CH3:27][C:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH:9]=[CH:8][NH:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:33][CH:34]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2cccc3cc(Oc4ncnc5[nH]ccc45)ccc23)cc1
Reaction time: 14 h

Procedure:
THF (1.3 mL) was added to 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoyl chloride (84.0 mg, 0.259 mmol) in a 10 mL round bottom flask, followed by 4-t-butyl aniline (62.4 μL, 0.389 mmol) and Hunig's base (45.1 μL, 0.259 mmol). The resulting solution was stirred for 14 h and then transferred to a 50 mL flask. To this solution was added ˜5 g of silica gel. The resulting slurry was concentrated by reduced pressure. The impregnated silica gel was loaded into a dry pack column cartridge and the crude mixture was purified through Biotage chromatography (Hex:EtOAc). The collected product was repurified through trituration with DCM. MS (ESI, pos. ion) m/z: 437.1 (M+1). Mass Calc'd for C18H15NO3: 436.51.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH3:8][N:9]([CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:10]1[N:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[N:11]=1.C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:30]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:32][CH:33]=1)[C:10]1[N:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([NH2:20])=[CH:21][CH:22]=2)[N:11]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Yield: 69.5 %

Procedure:
A solution of 2,4-thiazolidinedione (120 mg) and 4-[2-(N-methyl-N-(6-(4-anilinyl)pyrimidinyl)amino)ethoxy]benzaldehyde (280 mg) in a catalytic amount of piperidinium acetate containing toluene (60 mL), was stirred under reflux on a Dean-stark device for 4 hours. The resultant mixture was cooled and filtered. The filtered solid was dried to give the title compound (250 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:17]([O:16][C:12](=[O:15])[CH:13]=[CH:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:18]
Reactant: Brc1ccc2ncccc2c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
A vial under nitrogen atmosphere was charged with 6-bromo-quinoline (1 g, 4.8 mmol) and dimethylformamide (15 mL), followed by ethyl acrylate (2.1 mL, 19.2 mmol), triethylamine (6.7 mL, 48 mmol), and palladium (II) acetate (32 mg, 0.142 mmol). The reaction mixture was stirred at 100° C. for 5 h, then the hot mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium bicarbonate, then brine. The organic layer was then adsorbed on silica gel. Purification on silica gel with 10-80% gradient of ethyl acetate in hexane provided 952 mg of product as a yellow oil. 1H NMR 500 MHz (DMSO) δ 1.28 (t, 3H), 4.20 (q, 2H), 6.82 (d, 1H), 7.58 (d, 1H), 7.84 (d, 1H), 8.01 (d, 1H), 8.16 (dd, 1H), 8.30 (d, 1H), 8.37 (dd, 1H), 8.93 (dd, 1H); MS (m/z) 228 [M+H+]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5](O)[CH:4]=1)#[N:2].[Li+].[BH4-].Cl.C1C[O:20]CC1>>[OH:8][CH2:7][C:6]1[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[C:4]([OH:20])[CH:5]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C#N)cc1O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Product: N#Cc1ccc(CO)cc1O
Temperature: 25 °C

Procedure:
Methyl 4-cyano-2-hydroxybenzoate (0.50 g, 2.82 mmol) was dissolved in dry THF (30 mL), treated with LiBH4 (2.0M solution in THF) (5.64 mL, 11.28 mmol), and heated at reflux for 18 hr. The reaction mixture was cooled to room temperature, poured into 1N HCl solution and extracted with EtOAc (2×). Organics combined and dried (MgSO4), filtered and concentrated to dryness to give the title compound which was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C(Cl)Cl.CO>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CO)cc3)c(=O)c2)nc1
Reactant: BrP(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.29 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1a) in 5.0 mL of DCM is added 21 μL (0.23 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT, diluted with DCM/MeOH and extracted twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+].CCOCC>CN(C=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1cccc(-c2c(C)[nH]c3ccc(OC)cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. mixture of the indole from Step 3 (285 mg, 0.96 mmol) and 4-bromobenzyl bromide (310 mg, 1.05 mmol) in DMF (5 mL) was added NaH (44 mg, 1.1 mmol). The mixture was warmed up to r.t. and stirred for 1.5 h after which time it was poured on a mixture of ice water and Et2O. The organic layer was washed with brine, dried with MgSO4 and the solvent removed to yield a residue which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][C:15]=3[CH:25]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:21][CH2:20]4)=[N:16][C:15]=3[CH:25]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.8 %

Procedure:
Intermediate 25 (80 mg, 0.24 mmol) was dissolved in DCM (10 ml) and added TEA (35 mg, 0.35 mmol). This mixture was stirred at rt for 15 mins Reaction mixture cooled to 0° C. and added propane-1-sulphonylchloride (33 mg, 0.23 mmol). Reaction mixture stirred at rt for 2 h. Work up (DCM/H2O) afforded the crude product. Crude was purified by column chromatography on 60-120 mesh silica gel using a gradient mixture of EtOAC and Petether (70:30) as eluent to afford the titled compound (8 mg) as a white solid. M.P.: 222-225° C. 1H-NMR NMR (δ ppm, DMSO-d6, 400 MHz): 8.09 (d, J 1.3, 1H), 7.82-7.72 (m, 3H), 7.71-7.61 (m, 4H), 3.67-3.58 (m, 2H), 3.30-3.22 (m, 2H), 3.09-2.99 (m, 2H), 2.25-2.16 (m, 2H), 1.92-1.79 (m, 2H), 1.69 (hextet, J 7.6, 2H), 0.98 (t, J 7.4, 3H).
Reaction SMILES: C([C:3]1[N:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[C:9]([CH3:17])[C:8]([F:18])=[C:7](F)[C:6]=2[F:20])C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:18][C:8]1[C:9]([CH3:17])=[C:10]2[C:5](=[C:6]([F:20])[C:7]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[N:4]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[CH:3]=[C:12]([C:13]([OH:15])=[O:14])[C:11]2=[O:16]
Reactant: CCc1c(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c2n1-c1ccc(F)cc1F
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 0.43 g (1.08 mmol) of ethyl 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.37 g (4.30 mmol) of anhydrous piperazine, and 20 mL of acetonitrile was refluxed overnight, cooled to room temperature, and concentrated in vacuo. The residue was taken up in 10 mL of 6N hydrochloric acid and refluxed for 2 hours. The mixture was cooled and the solids were collected by filtration. The crude product was suspended in water which was made basic (pH 12), and the resulting solution was filtered through a fiberglass pad, and neutralized (pH 6.5). The solids were collected by filtration, washed with water, ether, and dried to give 0.37 g of the title compound, mp 283°-284° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13](O)[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15].S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]([Cl:23])[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Yield: 74.9 %

Procedure:
A mixture of 14.3 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropanol, 11.9 g of thionyl chloride and 150 ml of anhydrous benzene is refluxed for 3.5 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (yellow oil) is purified by silica gel chromatography (Solvent: n-hexane-ethyl acetate (10:1). 11.4 g of 1-(2,3,4-trimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane are thereby obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)CC1
Yield: 89.4 %

Procedure:
To a solution of Example 11B (60 mg, 0.136 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (89 mg, 1.36 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (50 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-8.03 (m, 3H), 7.66 (s, 1H), 7.46-7.61 (m, 2H), 5.97-6.16 (m, 1H), 4.02-4.22 (m, 2H), 3.65-3.95 (m, 3H), 2.82-3.04 (m, 2H), 1.68-2.69 (m, 13H), 1.12-1.29 (m, 3H). MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:4][Si:3]([CH3:6])([CH3:5])[C:1]1[O:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cccnc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc2ncccc2o1
Temperature: 500 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Ethynyltrimethylsilane (32.5 ml, 0.2298 mol), copper(I)iodide (2.2 g, 0.0114 mol) and bis(triphenylphospine)palladium(II)chloride (4.1 g, 0.0057 mol) are added to a degassed solution of 2-Bromopyridine-3-ol (20 g, 0.1149 mol) in dioxane (20 ml). The mixture is stirred for 5 min under nitrogen and then triethyl amine (80 ml, 0.574 7 mol) is added. The mixture is heated to 500° C. for 18 h, cooled to RT, filtered through celite and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography by using petrolether and ethyl acetate (90:10) as an eluent to afford (22 g, 56%) of the title compound as a brown liquid. TLC: hexane/ethyl acetate: (9/1): Rf=0.50; LCMS (method B): 4.875 min (purity 98.4%); M+H+ 192.1; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.50-8.48 (1H, dd, J1=1 Hz, J2=4.6 Hz), 8.015-7.9923 (1H, dd, J1=1 Hz, J2=8.32 Hz), 7.352-7.350 (1H, d, J1=0.8 Hz), 7.314-7.280 (1H, m), 0.372-0.355 (9H, s).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8](N)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1.[BrH:17]>O>[Br:17][C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([F:5])[CH:7]=1
Reactant: Br
Reactant: Nc1cc(F)cc2c1OCCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(Br)c2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
NaNO2 (2.69 g, 39.9 mmol) in water (20 mL) was added slowly at 0° C. to a solution of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (4.5 g, 26 mmol) in aq. 47% HBr (20 mL) and continued stirring at same temperature for 30 min. The above diazonium salt solution was added slowly to a solution of CuBr (5.7 g, 39.9 mmol) in aq. 47% HBr (25 mL) at 0° C. and stirred at 25° C. for 30 min. Reaction mixture was quenched with ice water, extracted with ethyl acetate (3×50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was purified by column purification (using silica gel and 0-5% ethyl acetate in Hexane as eluent) to afford 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (5.9 g). 1H NMR (300 MHz, CDCl3) δ ppm 6.9-6.84 (1H, dd), 6.6-6.5 (1H, dd), 4.3-4.3 (4H, m).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:12][O:11][C:5]1[CH:10]=[CH:9][C:8]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylene chloride (300 ml) was added to aluminum chloride (185.6 g) and anisole (100 ml) was added dropwise thereto at 0° C. Succinic anhydride (100 g) was added thereto in 5 portions and the resulting mixture was warmed up to room temperature and stirred for 3 hours. The reaction solution was added to a 4N aqueous hydrochloric acid solution (2 L) and ethyl acetate (1 L) under ice-cooling, and the crystals precipitated were collected by filtration and dried to obtain 4-(4-methoxyphenyl)-4-oxobutanoic acid (160 g) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:47])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[CH:23][C:22]=2[F:46])=[CH:14][C:13]=1[C:48]([F:51])([F:50])[F:49])(C(C)(C)C)(C)C>Cl>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([CH3:52])([CH3:53])[CH2:9][OH:8])=[C:13]([C:48]([F:50])([F:51])[F:49])[CH:14]=3)=[O:47])=[C:22]([F:46])[CH:23]=2)[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A mixture of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (3 g, 3.97 mmol) and HCl (4 M in 1,4-dioxane, 20 mL) was stirred at 25° C. for 2 h. The mixture was concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) twice to give a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (1528.59 mg, 2.94 mmol, 73.9% yield): 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=2.0 Hz, 1H), 7.74-7.67 (m, 1H), 7.44-7.38 (m, 2H), 7.37-7.27 (m, 3H), 7.22 (d, J=2.0 Hz, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 2H), 3.32-3.30 (m, 2H), 2.77 (s, 2H), 1.45 (t, J=6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][CH:31]=[C:32]([F:34])[CH:33]=3)[CH:27]=2)OC1>>[F:34][C:32]1[CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]([C:35]#[N:36])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Yield: 46 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile as described in Example C to give 68.7 mg (46%) of 5,2′-difluoro-5′-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)biphenyl-2-carbonitrile as a yellow solid: mp 200-201° C.; 1H NMR (360 MHz, CDCl3) δ 7.25-7.34 (2H, m), 7.44 (1H, t, J 8.9 Hz), 7.87 (1H, dd, J 5.4, 8.6 Hz), 8.18-8.26 (2H, m), 8.63 (1H, s), 8.82 (1H, s); MS (ES+) m/z 401. Anal. Found: C, 55.98; H, 2.13; N, 17.49%. Required for C19H8F5N5.0.3H2O: C, 56.11; H, 2.13; N, 17.22%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19](O)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=3[O:24][CH3:23])[CH2:30]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 12 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 59 (12% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.97 (2t, 2H), 3.50 and 4.01 (2t, 2H), 3.68-3.81 (m, 6H), 4.42 and 4.92 (2s, 2H), 6.64 and 7.00 (2d, 1H), 6.82 and 7.07 (2d, 1H), 7.28-7.49 (m, 2H), 7.75-7.84 (m, 1H), 7.93-8.10 (m, 1H), 8.13-8.26 (m, 3H); MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.C1(C)C=CC=CC=1>[C:19]1([O:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)Oc2ccccc2)c2ccccc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and phenyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-phenyloxycarbonyl-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one was obtained.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:12]1([C:15](=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[O:19])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:15](=[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:16]=[CH:17][CH:18]([OH:19])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14]1
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 66 %

Procedure:
The dianion of 1,1-dimethylethyl acetoacetate (22 mL of 0.5M solution, 11 mmol) was added to a solution of 4-cyclopropyl-5,5-bis(4-fluorophenyl)-2,4-pentadienal (2.0 g, 9.7 mmol) in 30 mL tetrahydrofuran at -70° C. The mixture was stirred for 2.5 hours at -70° C. and quenched with saturated ammonium chloride solution. The mixture was extracted with diethyl ether; the extracts were dried over magnesium sulfate and concentrated in vacuo to give 3,0 g of the title compound as an oil. MS(CI): m/e =468 for M+ of C28H30F2O4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:24]1([C:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([C:30]([NH:31][S@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: CC(C)(C)S(=O)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)NC(c1ccccc1)(c1ccccc1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, 3-(pyridin-3-ylmethyl)pyridine (0.072 g, 0.42 mmol) was dissolved in THF (3 mL). The solution was cooled to 0° C. Lithium bis(trimethylsilyl)-amide (1 M solution in THF, 0.465 mL, 0.47 mmol) was slowly added and the reaction was stirred at 0° C. for 15 min. The reaction became dark red. A solution of N-(diphenylmethylene)-2-methylpropane-2-sulfinamide (0.121 g, 0.42 mmol) in THF (1 mL) was slowly added drop-wise. The reaction was stirred at 0° C. for 1 hr then removed from the ice bath. Sat. aq. NH4Cl (20 mL) was added and the reaction was stirred vigorously. The product was extracted with EtOAc (3×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford an oil which was purified by flash column chromatography (0-5% MeOH/CH2Cl2). The fractions were combined and concentrated in vacuo to afford the title compound as a white solid. (S) Enantiomer at Sulfur: 1H NMR (CD3OD) δ 8.49 (d, 1H, J=2.20 Hz), 8.46 (dd, 1H, J=1.46 Hz), 8.36 (dd, 1H, J=5.37 Hz), 8.30 (d, 1H, J=2.20 Hz), 7.49-7.33 (m, 11H), 7.25-7.23 (m, 3H), 5.78 (s, 1H), 1.08 (s, 1H ). HRMS m/z (M+H) found: 478.1920 (M+Na).