Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:16]([NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1)([CH3:20])[CH2:17][OH:18]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CO)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g) in N,N-dimethylformamide (10 mL) was added 2-amino-2-methyl-1-propanol (1.18 g) at 0° C. The mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2-(1,1-dimethyl-2-hydroxyethylamino)-3-nitro-5-(trifluoromethyl)pyridine (1.23 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:13][CH2:14][CH2:15][OH:16].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:13][CH2:14][CH2:15][OH:16])=[O:8]
Reactant: NCCO
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)cc1C(=O)NCCO
Reaction time: 2 h

Procedure:
5-Chloro-2-methoxybenzoyl chloride (5.0 g) was added to a vigorously stirred mixture of 2-aminoethanol (10.12 g, 10 ml) and sodium hydroxide solution (1M, 100 ml). Stirring was continued for 2 hours at room temperature, then dilute hydrochloric acid (10% v/v, 100 ml) was added and the mixture extracted with dichloromethane (3×200 ml). The combined dichloromethane layers were dried (MgSO4) and evaporated, and the resulting oil chromatographed on silica gel with 1% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[NH:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:16]([OH:26])[C@H:15]([O:27][CH2:28][CH2:29][S:30][CH3:31])[C:14]=3[CH:13]=[CH:12][N:11]2[C:32]=1[CH3:33]>O.CO>[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[NH:18][C@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:16]([OH:26])[C@H:15]([O:27][CH2:28][CH2:29][S:30]([CH3:31])=[O:2])[C:14]=3[CH:13]=[CH:12][N:11]2[C:32]=1[CH3:33]
Reactant: CSCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc2c3c(ccn2c1C)[C@@H](OCCS(C)=O)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
130 mg of sodium metaperiodate, dissolved in 1 ml of water, is added to a solution of 200 mg of (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methylthioethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h]-[1,7]naphthyridine in 5 ml of methanol. After two hours stirring at room temperature, 50 ml of water are added. The mixture is extracted three times with dichloromethane, the organic phases are collectively washed with water and dried over sodium sulphate. The solvent is removed in vacuo and the remaining residue is purified by chromatography on silica gel (eluent: ethylacetate/methanol=10/1). 100 mg of the title compound of m.p. 105-106° C. are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O>COCCOC.O>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphoshine)palladium(0) (0.69 g, 0.60 mmol, 6 mol %) was added, under nitrogen, to a stirred solution of (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (3.16 g, 10.0 mmol) in DME (100 ml), and the resulting orange coloured solution stirred at room temperature for 10 min. Aqueous 2M sodium carbonate (30.0 ml, 60.0 mmol) was then added, the mixture stirred for 10 min, then furan-2-boronic acid (2.25 g, 20.11 mmol) was added, and the reaction mixture heated to 80° C. for 20 h, under reflux. The reaction mixture was cooled, diluted with water (100 ml) and the products extracted into ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product, which was purified by column chromatography on silica gel (3% diethyl ether in n-heptane eluent) to give the product, (E)-ethyl 3-(4-furan-2-yl-phenyl)-but-2-enoate as an off-white solid; 2.46 g (96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(N)CC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added 3-aminopentane (0.596 ml, 5.12 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl(aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 432.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.5 (2H, m), 1.6 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]1.[OH-:21].[K+]>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)c2Cl)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1Cl

Procedure:
A 15 g. portion of ethyl 1-(2,3-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was stirred under reflux overnight in 200 ml. of ethanol with 6 g. of potassium hydroxide. The reaction mixture was chromatographed over silica gel, and the product-containing fractions were combined and evaporated to dryness. The residues were recrystallized from ethanol-water to obtain 1.31 g. of the desired product, m.p. 228°-230°, which was identified by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:11].Cl[CH2:20][Li].BrCCl.C([Li])CCC>CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: [Li]CCl
Reactant: CC(C(=O)c1ccc(F)cc1F)c1ncccn1
Agent: ClCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1

Procedure:
Treatment of the product of part (ii) (3.10 g) with chloromethyllithium (prepared from bromochloromethane (1.78 g) and a 1.6M solution of n-butyllithium in hexane (8.20 ml)) according to the method of Example 11(iii) gave the title compound as a gun (2.25 g), which was used directly in the next stage.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12].[OH-].[Na+]>C(#N)C.CN(C=O)C.[Pd]>[NH:6]1[C:7]2[C:3](=[C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a mixture of 4-bromoindole (11.81 g, 60.26 mmol), and 3-carboxyphenylboronic acid (10.0 g, 60.6 mmol) in acetonitrile (100 mL) and DMF (100 mL) were added Palladium catalyst Pd(PPh3)4 (2.09 g, 1.81 mmol) and the freshly prepared sodium hydroxide solution (9.64 g, 241 mmol in 80 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under argon at 110° C. oil bath for 4 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, filtered through celite, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, dried over MgSO4, and concentrated. The crude product was purified by a silica gel column eluting with DCM: Hexanes: acetic acid (100:1:1) to provide 10.2 g (71%) of 3-(1H-indol-4-yl)-benzoic acid as a gray yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)([O-])=O.[N+](C1C=CC=C2C=1CCCC2)([O-])=O.[H][H]>CO.[Pd]>[CH:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCC2
Reactant: [H][H]
Agent: [Pd]
Agent: O=[N+]([O-])c1cccc2c1CCCC2
Solvent: CO
Product: Nc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 6-nitro-1,2,3,4-tetrahydronaphthalene and 5-nitro-1,2,3,4-tetrahydronaphthalene (5.5 g, 31.1 mmol) in MeOH (50 mL) was added 10% palladium on carbon (3.18 g, 3.0 mmol) under nitrogen, then replaced with hydrogen atmosphere (2 L). The resulting mixture was stirred at room temperature for 16 h, and filtered through Celite. The filtrate was concentrated, and the residue was purified by silica gel column (PE/EtOAc v/v 10:1) to give 5,6,7,8-tetrahydronaphthalen-2-amine as a white solid (2 g, 40% yield). ESI MS: m/z 148 [M+H]+. 1H NMR (400 MHz, CDCl1): δ 6.88 (d, J=8.0 Hz, 1H), 6.49 (dd, J=2.0 Hz, J=8.0 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 3.49 (s, 2H), 2.69-2.67 (m, 4H), 1.78-1.75 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[OH:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:11]1[CH:10]=[CH:9][C:8]2[O:15][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=1)#[N:14]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Chloroacetyl chloride (3.12 ml, 38 mmol) was added dropwise to a solution of 2-amino-4-cyanophenol (4.96 g, 37 mmol), triethylamine (10.98 ml, 78 mmol) and 4-(dimethylamino)pyridine (0.09 g, 0.74 mmol) in dry dichloromethane (40 ml) maintained at 0° C. The solution refluxed for 24 h. The reaction mixture was cooled, and the organic layer was washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water and brine, then dried with anhydrous magnesium sulfate. The organic layer was filtered, then evaporated to dryness. The residue was recrystalized from ethanol to afford 3.9 g (60%) of the titled compound. (mp 243–245° C.).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:25]\[CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](/[C:14]3[NH:36][C:17]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:16][CH:15]=3)=[CH:25]\[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)c1nccs1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(/C(=C\C2CCOCC2)c2ccc(-c3nccs3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 49.9 %

Procedure:
To a solution of (5E)-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-(1,3-thiazol-2-yl)hex-5-ene-1,4-dione (278 mg) in acetic acid (5 mL) was added ammonium acetate (750 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (133 mg, yield 50%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 441 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.BrC[CH:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:48][CH:47]=1)[OH:45]>C(Cl)Cl>[OH:45][CH:44]([C:46]1[CH:47]=[CH:48][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:50][CH:51]=1)[CH2:6][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@H]4CC(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (45.4 mg, 0.198 mmol) in DCM was added TFA. The reaction mixture was stirred for 1 hour followed by the removal of solvents in vacuo and drying of the solid material. Next, DMSO (2 mL) was added followed by the addition of tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol) and then 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 30-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((2S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)pyrrolidin-2-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.18 (4H, d, J=8.35 Hz), 7.77-7.84 (2H, m), 7.54-7.67 (5H, m), 5.92-6.01 (1H, m), 5.00-5.09 (2H, m), 4.26-4.42 (1H, m), 3.76-3.94 (1H, m), 3.00-3.11 (2H, m), 2.75-2.98 (2H, m), 2.18-2.34 (1H, m), 1.90-2.14 (2H, m), 1.60-1.85 (3H, t, J=7.25 Hz). MS (m+1)=503. HPLC Peak RT=3.50 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (1.0 g, 3.34 mmol) and morpholine (1.16 mL, 13.3 mmol) was added tetraisopropyl-orthotitanate (3.95 mL, 13.3 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (30.0 mL) and sodium cyanoborohydride (930 mg, 13.3 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with hexane/ethyl acetate/triethylamine 40:10:1 to give rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-morpholine (650 mg, 52%) as a yellow solid, MS: m/e=371.3 (M+H+).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:35].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2](=[O:35])[NH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:31][CH:30]=1
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 0.88 mmol.) was dissolved in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (6 mL) was added at 0° C. The reaction mixture was stirred at rt for 20 min. The reaction mixture was then treated with aqueous NaOH solution (8%), and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (350 mg, 0.78 mmol). 1H NMR (CDCl3): δ=1.10-1.25 (m, 8H), 1.37 (m, 1H), 1.42-1.55 (m, 2H), 1.78-1.93 (m, 2H), 2.10-2.38 (m, 2H), 2.87 (m, 2H), 3.52-3.58 (m, 1H), 3.31-3.97 (m, 1H), 4.12-4.19 (m, 1H), 5.53-5.63 (m, 1H), 6.85-7.15 (m, 3H), 7.35-7.55 (m, 1H), 7.75-7.89 (m, 1H), 8.10-8.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 72 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 3.26 (s, 4H), 3.77 (s, 3H), 4.08-4.18 (m, 4H), 6.78-6.90 (m, 3H), 7.15-7.38 (m, 3H), 7.56-7.64 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8](C3C=CC(F)=CC=3)[C:6]=2[N:7]=1.FC(F)(F)C1CCNC1>>[N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3][CH:2]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Agent: FC(F)(F)C1CCNC1
Product: c1ncc2c(n1)CCC2

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-trifluoromethylpyrrolidine to afford 2-chloro-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation Ht) as a mixture of 4 diasteriomers. LC-MS (M+H)+=386.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.05-7.11 (2H, m), 6.96 (2H, t, J=8.70 Hz), 4.14-4.20 (1H, m), 3.89-4.02 (2H, m), 3.75-3.86 (2H, m), 3.17-3.28 (1H, m), 3.06-3.16 (1H, m), 2.99 (1H, dq, J=15.95, 8.01 Hz), 2.50-2.61 (1H, m), 2.13-2.30 (2H, m), 1.95-2.06 (1H, m)
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1)=[O:2]
Reactant: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C

Procedure:
Formic acid (2.5 mL, 66.3 mmol) and acetic anhydride (5 mL, 52.9 mmol) were mixed, and stirred with heating at 50° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and cooled to 0° C. A solution of N-(3-aminophenyl)-3-(trifluoromethyl)benzamide (5.65 g, 20.2 mmol) in tetrahydrofuran (50 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 16 hr, during which the reaction temperature was allowed to gradually warm to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (50 mL) and ethyl acetate (250 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated aqueous ammonium chloride solution (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide as a yellow amorphous substance. To a solution of N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide produced above in tetrahydrofuran (100 mL) was added a 1.9M solution (21 mL, 39.9 mmol) of borane-dimethylsulfide complex in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hr. Since the starting materials were not completely consumed, a 1.9M solution (2 mL, 3.8 mmol) of borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was further stirred at room temperature for 1 hr. Methanol (30 mL) and acetic acid (10 mL) were added to the reaction solution, the mixture was stirred at room temperature for 14 hr, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (5.54 g, total yield of 2 steps 93%) as yellow crystals.