Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:2]1([CH3:1])[C:6]([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([F:17])=[CH:9][C:8]=2[C:29]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=2[F:27])=[CH:5][CH2:4][CH2:3]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(OS(=O)(=O)C(F)(F)F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(-c2cc(OC)ccc2F)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
To a stirred solution of 66.43F (1.05 g, 2.65 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.90 g, 5.32 mmol) (commercially available from Aldrich) and potassium carbonate (1.10 g, 7.96 mmol) followed by tetrakis(triphenylphosphine)palladium (0.31 g, 0.27 mmol). The mixture was heated to 90° C. After 17 hours, the mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to give 66.43G as a clear oil that was used without further purification (0.92 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=11.3 Hz), 6.99 (1H, t, J=9.0 Hz), 6.84 (1H, dt, J=8.7, 3.7 Hz), 6.78 (1H, dd, J=5.9, 3.1 Hz), 5.55 (1H, s), 3.96 (3H, s), 3.79 (3H, s), 2.27 (2H, td, J=7.1, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.84 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:15]3[O:14][CH:18]=[CH:17][CH:16]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1-c1ccco1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-c3ccco3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-furan-2-yl-benzylamine (111 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-furan-2-yl-benzylamino)-2H-phthalazin-1-one: 54 mg (26.5%): m/z (M+H)=351. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.93 (d, 1H), 7.82 (m, 1H), 7.70 (dd, 1H), 7.64 (m, 1H), 7.44 (m, 1H), 7.35 (m, 2H), 7.12 (dd, 1H), 6.76 (m, 2H), 6.63 (m, 1H), 4.56 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2=[O:9].[O-][Mn](=O)(=O)=O.[K+].O.CC1(C)[C@H]2C[C@@H]1CCC2=C.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]2=[O:9]
Reactant: CC1(C)C2C=CC(=O)C1C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)C2CCC(=O)C1C2

Procedure:
6,6-Dimethylbicyclo[3.1.1]hept-3-en-2-one—KMnO4 (5.71 g) was ground into a fine powder and combined with acidic alumina (22.55 g) and water (5.6 mL) for 5 minutes in order to form a homogenous mixture. (−)-β-Pinene (1.16 mL), and methylene chloride (200 mL) were placed in a 250 mL roundbottom flask; the moistened KMnO4/acidic alumina was added in small portions slowly to the solution. As the KMnO4/acidic alumina was added, the reaction turned into a dark purple color solution. The reaction was allowed to continue to stir until TLC indicated all starting material had reacted. The solution was filtered through fritted glass, and the residue was washed twice with 50 mL of methylene chloride. The filtrate was concentrated and yielded 6,6-dimethyl-bicyclo[3.1.1]heptan-2-one as a light yellow oil. The oil was purified via column chromatography (85:15, Hex:EtOAc) and like fractions were combined. 1H NMR (300 MHz, CDCl3): (ppm) 0.96 (s, 3H), 1.34 (s, 3H), 1.59 (d, 1H), 1.86-2.13 (m, 2H), 2.20-2.30 (m, 1H), 2.31-2.43 (m, 1H), 2.45-2.68 (m, 3H). (ESI, Pos) m/z 161.0 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13](C)[C:14](=O)C)[C:10]([N+:18]([O-:20])=[O:19])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][CH3:14])[C:10]([N+:18]([O-:20])=[O:19])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
A mixture of methyl 2-methoxy-4-(N-methylacetamido)-5-nitrobenzoate (2.1 g; 0.74 mmol), aqueous NaOH (29 mL; 1 M; 29 mmol) and EtOH (30 mL) was refluxed for 2 h. The mixture was thereafter concentrated and the remaining aqueous phase was acidified to strongly acidic pH with acetic acid, sonicated and filtered to give the sub-title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1C(OC(C)(C)C)=O>CO>[ClH:1].[ClH:1].[F:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C2CCCN2)c(F)c1)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of 4 N hydrochloric acid-dioxane solution was added to a methanol (50 ml) solution of 4.4 g of t-butyl 2-(2-fluoro-4-((pyrazin-2-ylcarbonyl)amino)phenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 1 hour. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](S(C)(=O)=O)=[N:14][N:15]=[C:3]12.[CH3:20][O-:21].[Na+]>>[CH3:20][O:21][C:13]1[N:4]2[C:3]([CH:2]([CH3:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH:6]=[CH:5]2)=[N:15][N:14]=1
Reactant: CC1c2ccccc2C=Cn2c1nnc2S(C)(=O)=O
Reactant: C[O-]
Agent: [Na+]
Product: COc1nnc2n1C=Cc1ccccc1C2C

Procedure:
The reaction of 11-methyl-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-11-methyl-11H-s-triazolo[3,4-b][3] benzazepine. Colorless prisms (as recrystallized from ether), melting point: 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]#[N:25])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>C(OCC)(=O)C.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)ccc(OCc3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetonitrile (0.10 g), sodium azide (0.026 g), ammonium chloride (0.022 g) and N,N-dimethylformamide (1.5 mL) was heated by microwave irradiation at 100° C. for 45 minutes. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous sodium chloride solution (20 mL). The resulting precipitate was collected by filtration, washed with water and ethyl acetate and dried to afford title compound as a white solid, 0.14 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C1C([N+]([O-])=O)=CC=C(O)C=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Chloro-2-fluoro-5-(trifluoromethyl)benzoic acid and an equimolar amount of p-nitrophenol are stirred with an equimolar amount of anhydrous potassium carbonate in dimethylsulfoxide at 110° C. for 24 hours and then left overnight at room temperature. The mixture is then poured into dilute hydrochloric acid and the solid is recovered and purified by dissolving, washing and drying to give 4'-nitrophenoxy ether at the 2-position of 3-chloro-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([N+:12]([O-])=O)=[C:8]([CH3:15])[N:7]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].[K+].[Br-]>>[NH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:21])[N:7]([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C:8]=1[CH3:15]
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(C)n(CCC(C)C)c1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCn1c(=O)c(N)c(C)n(CCC(C)C)c1=O
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure of example 18, step 3 except that 3-butyl-6-methyl-1-(3-methyl-butyl)-5-nitro-1H-pyrimidine-2,4-dione was used in place of 1-butyl-3,6-dimethyl-5-nitro-1H-pyrimidine-2,4-dione. Yield: 100%; mp: 68-70° C.; 1H NMR (300 MHz, CDCl3); δ 0.91-0.98 (m, 6H), 1.25 (s, 3H), 1.32-1.40 (m, 2H), 1.48-1.80 (m, 5H), 2.15 (s, 3H), 3.21 (m, 2H) 3.67-3.83 (m, 2H), 3.88-3.96 (m, 2H); IR (KBr, cm-1): 3435w, 3414w, 2959w, 2930w, 2869m, 1683s, 1644s, 1589m,1488m, 1359m; MS (ES) m/z (relative intensity): 268 (M+ +H). Anal. Calcd. for C14H25N3O2 : C, 62.89; H, 9.42, N, 15.72. Found: C, 62.76; H, 9.23; N, 15.59.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH:13]=[C:12]([N:24]3[CH2:30][CH:29]4[O:31][CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(NC1C=CC=CC=1)C>C(O)C.[Pd]>[CH:29]12[O:31][CH:26]([CH2:27][CH2:28]1)[CH2:25][N:24]([C:12]1[CH:13]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[N:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[N:11]=1)[CH2:30]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)cc(N3CC4CCC(C3)O4)n2)cc1
Agent: [Pd]
Solvent: CCNc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)cc(N3CC4CCC(C3)O4)n2)cc1
Reaction time: 16 h

Procedure:
In a 250 mL round-bottomed flask was placed 3,3′-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (20, 65 mg, 0.15 mmol) in ethanol (3 ml). A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give a quantitative yield of the title compound along with an impurity (the N-ethyl aniline product). The crude mixture was reacted in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N+:34]([O-:36])=[O:35])[N:19]=[CH:18][N:17]=1>CN(C=O)C>[N+:34]([C:23]1[CH:24]=[CH:25][C:26]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:27][C:22]=1[C:20]1[CH:21]=[C:16]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[N:17]=[CH:18][N:19]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: OCc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(OCc2cccc(C(F)(F)F)c2)ncn1

Procedure:
To a solution of 99 mg of 3-(trifluoromethyl)benzyl alcohol in 2 mL of DMF was added 27 mg of a 50% dispersion of sodium hydride in oil. After 15 min the solution was treated with 150 mg of intermediate 3.1b. After an additional 2 h the reaction mixture was partitioned between water and ethyl acetate. The organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated to give a yellow syrup that was used directly in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.CCN(CC)CC>C(Cl)Cl>[C:32]1([C:19]2([NH:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:4])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
Pb(NO3)2 (6.06 g, 18.3 mmol) was added over 1 min to a CH2Cl2 (80 mL) solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol), 9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et3N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient condition for 48 hr. The mixture was filtered and the filtrate was treated with MgSO4 and filtered again, and the final filtrate was concentrated. The resulting crude material was submitted to a Biotage purification (350 g silica gel, CH2Cl2 elution) to afford (S)-1-benzyl 4-methyl 2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorless oil (7.93 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partially overlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd. for [M+H]+ C31H28NO4: 478.20. found 478.19.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:30])[CH2:24][N:25]2[CH2:28][CH:27]([F:29])[CH2:26]2)=[CH:19][C:18]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]2[CH2:26][CH:27]([F:29])[CH2:28]2)=[CH:19][C:18]=1[C:31]([F:34])([F:32])[F:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CC(F)C1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CC(F)C3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 69 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-fluoro-azetidin-1-yl)-ethylamine hydrochloride to give the title compound. LC/MS [469 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (d, 1H), 9.01 (d, 1H), 8.57 (s, 1H), 8.39 (d, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.82 (m, 1H), 7.68 (m, 1H), 5.45 (m, 1H), 5.12 (m, 1H), 3.59 (m, 2H), 3.21 (m, 2H), 2.95 (m, 5.6 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:23][CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CCN(CCCOc1ccc(-c3csc4ccccc34)cc1)C2

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 1,2,3,4-tetrahydroisoquinoline, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=94%, [M+H]+=400.
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26]C3CCCCO3)[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1>CO>[Cl:34][C:2]([Cl:1])([Cl:35])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1
Reactant: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: CO
Product: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Yield: 88.8 %

Procedure:
Intermediate 20d (375 mg, 0.69 mmol) was dissolved in MeOH (5 mL) and loaded onto a 20 g SCX-2 SPE cartridge (pre-conditioned with MeOH). The cartridge was then washed with MeOH (2 column volumes) and the eluent concentrated in vacuo to afford the title compound as a colorless oil (283 mg, 89%). LCMS (Method 3): Rt 3.71 min, m/z 461, 463 [MH+].
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12](=[O:24])[N:13]([CH3:23])[C:14](=[O:22])[NH:15]2.[OH-].[K+]>>[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12](=[O:24])[N:13]([CH3:23])[C:14](=[O:22])[N:15]2[CH3:5]
Reactant: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)c(=O)n(C)c(=O)n2C

Procedure:
Dimethyl sulfate (2.5 ml, 3.33 g, 26.40 mM) was added to 5,6-dimethoxy-3-methylquinazolin-2,4(1H, 3H)-dione (2.0 g, 8.47 mM). The mixture was heated at 80°-85° C. (oil bath temperature) for five minutes. Aqueous KOH (7.9 ml of a 5N solution) was added gradually until the pH of the reaction mixture remained basic. The reaction mixture was cooled and the resulting solid filtered, washed with a small amount of H2O and dried to afford the title compound as a white solid; 1.74 g (80.6%); mp 136°-139° C.; CF3COOH(TMS) 7.75 (d, 1H, J7,8 =9.0Hz, 7-H), 7.33 (d, 1H, J8,7 =9.0Hz, 8-H), 4.28 (s, 3H, 5 or 6-OCH3), 4.07 (s, 3H, 5 or 6-OCH3), 3.80 (s, 3H, 1 or 3-N-CH3), 3.73 (s, 3H, 1 or 3-N-CH3); M+ 250.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[CH2:14](Br)[C:15]#[CH:16]>>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:16][C:15]#[CH:14]
Reactant: C#CCBr
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: C#CCN1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 76 %

Procedure:
Compound 2a is synthesized from (4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (Aldrich) according to general procedure F using 15 mmol (1.79 g) propargyl bromide (Aldrich).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:27]=[CH2:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH2:27][CH3:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Agent: [Pd]
Solvent: CCO
Product: CCc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 161.7 %

Procedure:
A solution of Intermediate 6a (120 mg) obtained in Example 9-1, Step A in ethanol (2 ml) was added with 10% palladium/activated carbon (90 mg, Wako Pure Chemical Industries), and the mixture was stirred at room temperature for 72 hours under a hydrogen gas atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (195 mg).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:21]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(O)[CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:32])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:12]([OH:32])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2CNCCC2(O)CCCc2ccccc2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)(C)c1ccc(C2=C(CCCc3ccccc3)CCNC2)c(O)c1

Procedure:
A mixture of 2.0 g. (4.57 mmols.) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-phenylpropyl)-4-piperidinol, 0.95 g. (5.0 mmols.) of p-toluenesulfonic acid monohydrate and 100 ml. of toluene is heated under reflux for 2 hours with a Dean Stark trap. The reaction mixture is cooled and added to 100 ml. of 20% potassium carbonate-200 ml. dichloromethane. The dichloromethane extract along with two additional 200 ml. dichloromethane extracts of the basic phase is dried over magnesium sulfate and evaporated. The residue is crystallized from ether-pentane to yield the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:22])[NH:18][C:19](=[O:21])[CH:20]=2)=[C:12]([F:23])[CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:2][CH:20]2[C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:12]([F:23])[CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1C=C(c2ccc(Br)cc2F)C(=O)N1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C1NC(=O)C2(c3ccc(Br)cc3F)CC12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsulfoxonium iodide (3.18 g, 14.5 mmol) in DMSO (15 mL) was added KOH (1.08 g, 19.3 mmol) at r.t. The reaction mixture was stirred at r.t. for 30 min followed by addition of 3-(4-bromo-2-fluoro-phenyl)-pyrrole-2,5-dione (2.60 g, 9.6 mmol). The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The title compound was obtained as brown solid in crude form (2.51 g, 92%) and was as such used in the next step.