Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:18][C:19]([F:39])([F:38])[C:20]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)([OH:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:17][C:14]1[N:15]=[CH:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:20]([OH:22])([CH3:21])[C:19]([F:38])([F:39])[F:18])=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cn1
Reactant: CC1(C)OB(c2ccc(C(C)(O)C(F)(F)F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(O)(c1ccc(-c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 85.4 %

Procedure:
A 10 mL vial was charged with 5-((4-bromophenyl)sulfonyl)-2-pyridinamine (71 mg, 0.23 mmol), 1,1,1-trifluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (86 mg, 0.27 mmol, synthesized in manner analogous to Example 21 using 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (example 27)), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane complex (18 mg, 0.02 mmol, Sigma-Aldrich, St. Louis, Mo.), and cesium carbonate (222 mg, 0.68 mmol) were combined in DME (1.2 mL) and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 0 to 3% 2M NH3 in MeOH/CH2Cl2) to provide 2-(4′-((6-amino-3-pyridinyl)sulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol (83 mg) as an off-white solid.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.CN(C)C=O.[Na+].[CH3:31][S:32]([O-:34])=[O:33]>O>[CH3:31][S:32]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2)(=[O:34])=[O:33]
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(S(C)(=O)=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 120 h
Yield: 68.6 %

Procedure:
Reflux 1.4 gm. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate in 6 cc. of thionyl chloride for 10 minutes. Strip away excess thionyl chloride by evaporation and dissolve the chloro intermediate so produced in 14 cc. of N,N-dimethylformamide. Add 582 mg. of methanesulfinic acid sodium salt (10% excess). Stir at room temperature for 5 days. Dilute with water and separate the solids by filtration. Crystallize from 15 cc. of benzene to obtain the title product (yield 1.18 gm. 68.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (500 mg, 1.09 mmol, 1.00 equip), tert-butyl 4-aminopiperidine-1-carboxylate (326.8 mg, 1.63 mmol, 1.50 equip), Pd2(dba)3 (99.8 mg, 0.11 mmol, 0.10 equip), dppf (211 mg, 0.38 mmol, 0.35 equip), Cs2CO3 (882.35 mg, 2.71 mmol, 2.50 equip), and 1,4-dioxane (10 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield tert-butyl 4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-carboxylate as an off-white solid. (ES, m/z) 578 [M+H]+
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperazin-1-yl-1H-indole (71 mg, 0.18 mmol) in tetrahydrofuran is treated sequentially with benzyl bromide (21 μl) and triethyl-amine (75 μl ), shaken at room temperature for 16 hr and concentrated in vacuo to give a residue. The residue is purified by RP-HPLC to give the title product, 37 mg, identfied by HPLC and mass spectral analyses (2.81 min; 432 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]1[C:12]2[N:13]=[N:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:11]=2[N:10]=[CH:9]1)[CH3:7].[Br:24]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>CCOC(C)=O>[Br:24][C:19]1[CH:18]=[C:17]([C:16]2[C:11]3[N:10]=[CH:9][N:8]([CH2:6][CH3:7])[C:12]=3[N:13]=[N:14][CH:15]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCn1cnc2c(-c3ccc(F)cc3)cnnc21
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCn1cnc2c(-c3ccc(F)c(Br)c3)cnnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Concentrated sulphuric acid (66 g, 0.67 mol) was carefully added to 7-ethyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9, 2.3 g, 9.5 mmol) surrounded by an ice bath, and the resultant reaction mixture was gently stirred at room temperature until a homogeneous solution was observed. To this solution was added 1,3-dibromo-5,5-dimethylhydantoin (2.7 g, 9.5 mmol) portion-wise, and stirring was continued at 0° C. for 2 hours. The reaction mixture was poured carefully into aqueous sodium bisulphite (200 mL), and then basified with an aqueous sodium hydroxide solution (2 M) to pH=8 keeping the temperature below 20° C. EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether:CH2Cl2 1:1 followed by trituration with EtOAc to afford the title compound as a white solid in 41% yield, 1.25 g.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:5].[CH3:18][Mg]Br.O>C1COCC1.C(OCC)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:6]([C:4](=[O:5])[CH3:18])=[CH:7][N:8]=2)[CH:12]=1
Reactant: CON(C)C(=O)c1cnc(-c2cccnc2)s1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Yield: 98 %

Procedure:
A solution of N-methoxy-N-methyl-2-(3-pyridyl)thiazole-5-carboxamide (5.6 g, 21.9 mmol) in 150 ml of THF was cooled to 0° C. and treated with methyl magnesium bromide (8.4 ml of a 3M solution in diethyl ether, 24.1 mmol). The reaction was stirred at 0° C. and shown to be complete by LC/MS and TLC after 1 Hr. The mixture was hydrolyzed with 5 ml water and evaporated. The residue was taken up in 200 ml of ethyl acetate and washed with 2×80 ml water and 1×80 ml brine. The organic phase were dried over Na2SO4, filtrated and concentrated in vacuo to give the title compound (4.4 g, 98%) as orange crystals which were pure enough for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][PH:14](=[O:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][P:14]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:15])=[O:16]
Reactant: C[PH](C)=O
Reactant: COC(=O)c1cc(C)nc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)nc(P(C)(C)=O)c1

Procedure:
Intermediate I-50b was prepared from Intermediate I-50a following a similar procedure as described in WO2009/143389. A solution of methyl 2-bromo-6-methylisonicotinate (I-50a, 690 mg, 3 mmol) in DMF (12 mL) was treated with dimethylphosphine oxide (515 mg, 6.6 mmol), palladium acetate (39 mg, 0.05 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (104 mg, 0.18 mmol) and potassium phosphate (700.5 mg, 3.3 mmol). The mixture was purged with nitrogen and subjected to microwave irradiation (20 min, 150° C.). The reaction mixture was concentrated and purified by column chromatography (9:1:0.175N CH2Cl2/MeOH/NH3 in CH2Cl2, 0% to 100%) to afford methyl 2-(dimethylphosphoryl)-6-methylisonicotinate (I-50b) as an off-white solid. 1H NMR (400 MHz, DMSO) ∂ 8.14 (s, 1H), 7.87 (s, 1H), 3.93 (s, 3H), 2.64 (s, 3H), 1.67 (d, J=13.6 Hz, 6H); MS calculated for C10H15NO3P (M+H+) 228.07. found 228.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1
Reaction time: 4 h

Procedure:
In 100 ml of tetrahydrofuran were dissolved 4.6 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and 2.5 ml of benzyl alcohol, and under cooling at 0°-5° C. 2.4 ml of pyridine and 3.6 g of dicyclohexylcarbodiimide were added to the solution in that order. The mixture was stirred at the same temperature as above for 4 hours and then at room temperature for 18 hours. The precipitated dicyclohexylurea were filtered off and the filtrate was concentrated under reduced pressure. The residue was poured into a mixture of 300 ml of 2 N hydrochloric acid and 300 ml of ethyl acetate. The ethyl acetate layer was separated, washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure and the residue was dissolved in a small amount of ethyl ether. To this solution was added petroleum ether to give crystals. Yield 4.8 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([OH:32])=[O:31])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C=CC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.61 ml, 0.0049 mole) and acrylic acid (0.175 g, 0.0024 mole). The reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and sodium bicarbonate, dried over anhydrous sodium sulfate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.4 g, 61% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].O.CCOCC.C[N:38]1CCCC1=O>>[NH2:38][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:13]2[CH:12]=[CH:11][C:10](=[O:30])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CN1CCCC1=O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: O
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added NaNH2 (195 mg, 5 mmol, 5 eq) and the mixture was heated to 50°. After 1 h, H2O (20 mL) was added then Et2O (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 53% yield). 1H-NMR (CDCl3) δ 5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[N+](=[CH2:24])=[N-]>C(OCC)(=O)C.CCOCC>[C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([O:19][CH3:24])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)Sc1ccc(C(C)=O)cc1CC2

Procedure:
To a solution of 2-acetyl-10,11-dihydro-dibenzo[b,f]thiepin-7-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) (600 mg, 2.01 mmol) in ethyl acetate (10 mL), was added dropwise a solution of diazomethane in ether until the yellow coloration persisted. Evaporation of the solvent gave the crude title compound as a solid which was used as such.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH3:14])[CH3:13])[CH:8]([CH3:15])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH3:13][N:12]([CH3:14])[CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH:8]1[CH3:15]
Reactant: CCOC(=O)N1CCC(N(C)C)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1CNCCC1N(C)C
Temperature: 110 °C
Reaction time: 48 h

Procedure:
1-Carbethoxy-4-dimethylamino-3-methylpiperidine (3.5 g, 16.3 mmol) was suspended in 5 M NaOH solution (20 ml), stirred at 110° C. for 48 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-dimethylamino-3-methylpiperidine. Yield 1.0 g (43%), C8H18N2, m/z 143 (M+1), PMR (CDCl3): 0.96 (dd, 3H), 1.3 (m, 1H), 1.5 (m, 1H), 1.74 (m, 1H), 2.08 (m, 1H), 2.24 (s, 6H), 2.38 (m, 1H), 2.61 (bs, 1H, D2O exchangeable), 2.86 (m, 1H), 3.16 (m, 1H), 3.68 (m, 1H).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.N1C=CC=CC=1>O>[CH3:17][C:16](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCCCCc1ccc(C(C)=O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCc1ccc(C(C)=Nc2ccccc2)cc1

Procedure:
A solution of p-nonyl acetophenone (90 g), aniline (75 g), Toluene (125 ml) and pyridine (20 ml) was refluxed with continuous removal of water. N-(alpha-methyl-p-nonyl benzylidene) aniline (XXX) was obtained by fractional distillation. XXX had a boiling point of 200°-208° at 0.075 millimeter.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[N:6][C:7]=1[O:8][CH:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[CH:18]1([B-](F)(F)F)[CH2:20][CH2:19]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(PC12CC3CC(CC(C3)C1)C2)CCC>[CH:18]1([C:2]2[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[N:6][C:7]=2[O:8][CH:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:20][CH2:19]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CC(Oc1nc(C(=O)O)ccc1Br)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCPC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Temperature: 120 °C
Yield: 78.7 %

Procedure:
5-Bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (2 g, 6.37 mmol), potassium cyclopropyltrifluoroborate (952 mg, 6.43 mmol), cesium carbonate (6.22 g, 19.1 mmol) and palladium(II)acetate (28.6 mg, 127 μmol) were suspended in toluene (55 mL) and water (6.11 mL) under an argon atmosphere. Butyl-1-adamantylphosphin (68.5 mg, 191 μmol) was added, the reaction mixture was heated to 120° C. for 1 d, poured onto ice-water/1N HCl (150 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with ice-water/brine (150 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.38 g, 79%) as a yellow solid. MS (EI): m/e=276.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([O:12]C1CCCCO1)[CH3:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C@H:10]([OH:12])[CH3:11]
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C(=O)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
(2R)-2′,4′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (9.62 g, 35.6 mmol, synthesized according to the description in Chem. Pharm. Bull., Vol. 41(6), 1035-1042 (1993)) was dissolved in ethanol (99.5%, 50 mL), and pyridinium p-toluenesulfonate (0.89 g, 3.6 mmol) was added. The mixture was stirred at 50-60° C. for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to about 10 mL. Water (20 mL) was flown in and the mixture was extracted twice with ethyl acetate (50 mL). The layers extracted with ethyl acetate were mixed, washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After filtration, the filtrate (ethyl acetate solution) was concentrated. The obtained concentrate (about 9.5 g) was subjected to silica gel column chromatography (SiO2, 30 g) and eluted with n-heptane—ethyl acetate (10:1→5:1). The objective fraction was concentrated to give the title compound as a pale-yellow oil (6.00 g, yield: 91%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2=[CH:15][CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:13]2[N:12]=[C:11]1[CH3:27])[C:4]1C=CC=CC=1.[H][H].C(I)C>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([N:10]1[C:14]2=[CH:15][CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:13]2[N:12]=[C:11]1[CH3:27])[CH3:4]
Reactant: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C)nc2c(C(=O)OC)c(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Sodium hydride (1.38 g, 46.0 mmol, 80% oil dispersion) is added in portions to a solution of dimethyl 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylate (10.9 g, 43.8 mmol) in dry dimethylformamide at 0° C. After evolution of hydrogen ceases, ethyl iodide (3.68 mL, 46.1 mmol) is added. The reaction mixture is stirred at room temperature overnight, treated with ethyl acetate, and filtered. The filtrate is concentrated in vacuo; the resultant residue is recrystallized from 50% ethyl acetate:hexanes to yield the title product as a light yellow powder (3.84 g, 31.7%), mp 126.5°-128° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH:38]=2)O1.Br[C:47]1[N:52]=[C:51]2[C:53](=[CH2:57])[CH2:54][CH2:55][O:56][C:50]2=[CH:49][CH:48]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.[Pd](Cl)Cl.O.CCOC(C)=O>[CH2:57]=[C:53]1[C:51]2=[N:52][C:47]([C:34]3[CH:35]=[N:36][N:37]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[CH:38]=3)=[CH:48][CH:49]=[C:50]2[O:56][CH2:55][CH2:54]1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: C=C1CCOc2ccc(Br)nc21
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Reaction time: 8 h

Procedure:
137 mg (0.78 mmol) of palladium chloride, 948 mg (3.62 mmol) of triphenylphosphine, 356 mg (25.8 mmol) of K2CO3 and 3.54 g (11.89 mmol) of n-Bu4NCl in 30 ml of DMF were heated under 105° C. for 10 min under N2. 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-yl]pyridine (3.5 g, 12.92 mmol) and 6-bromo-4-methylene-2,3-dihydropyrano[3,2-b]pyridine (3.2 g, 14.16 mmol) in DMF (20 ml) were added to the above solution and stirred overnight. EtOAc and water were added to the reaction mixture. The aqueous phase was extracted with EtOAc for 3 times, the combined organic phase was washed with water for 3 times, dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica gel chromatography (petroleum/EtOAc=1/1) to get the title compound as red solid.