Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:14]I>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of sodium hydride (5.5 g, 137.50 mmol, 60%) in N,N-dimethylformamide (150 ml) was added quinolin-7-ol (8 g, 55.11 mmol). The reaction was stirred for 1 h at 0° C. in a water/ice bath. Then CH3I (7.84 g, 55.23 mmol) was added and the solution was stirred for an additional 1 h at room temperature. The reaction was then quenched by the addition of water/ice (700 ml) and extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by a silica gel column with 6% ethyl acetate in petroleum ether to afford 7-methoxyquinoline as a red oil (5.5 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[N:34][NH2:35])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:59][N:60]1[CH:64]=[C:63]([C:65](O)=O)[N:62]=[CH:61]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:65]([C:63]6[N:62]=[CH:61][N:60]([CH3:59])[CH:64]=6)[N:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=NN)NCC4)cc2)CCC1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2nnc3n2CCc2nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc2-3)c1
Temperature: 60 °C
Yield: 4.4 %

Procedure:
To a solution of tert-butyl(1-(4-(5-hydrazono-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (22 mg, 0.04 mmol) in dry DMF (1 mL) was added EDCI (11 mg, 0.06 mmol), HOBt.H2O (8 mg, 0.06 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (8 mg, 0.06 mmol) under nitrogen. The reaction mixture was heated at 60° C. overnight. After cooled down to room temperature, the mixture was partitioned between saturated NaHCO3 solution and ethyl acetate. The layers were separated and the organic phase washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (1 mg, 5%). 1H NMR (500 MHz, CDCl3): 8.49 (1H, s), 7.74 (1H, s), 7.54 (1H, s), 7.38 (2H, d), 7.31 (2H, d), 7.28-7.23 (5H, m), 5.01 (1H, br s), 4.94 (2H, t), 3.81 (3H, s), 3.49 (2H, t), 2.60-2.30 (4H, m), 2.10-2.01 (1H, m), 1.85-1.76 (1H, m), 1.45-1.20 (9H, br).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CCN(C(C)C)C(C)C>C(#N)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:22]=2[O:21][CH3:20])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
3-{[5-(Aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), 2,4-bis(methyloxy)benzoyl chloride (0.046 g, 0.25 mmol) and DIPEA (0.05 mL, 0.25 mmol) were dissolved in acetonitrile (3 mL) and stirred overnight. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized then EtOAc (25 mL) and saturated NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.045 g, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, 1H), 7.79 (s, 1H), 7.67-7.77 (m, 1H), 7.58 (d, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.22-7.26 (m, 1H), 7.12-7.22 (m, 1H), 6.59 (d, 1H), 6.62 (s, 1H), 4.46 (d, 2H), 3.83 (s, 3H), 3.80 (s, 3H). MS: m/z 457.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH2:23])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1)=O>>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH:23][CH2:26][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccccc1OCc1ccc(CCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Product: CC(C)(C)OC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(CCc3ccccc3)cc2)cc1

Procedure:
This compound was prepared analogously to Ex. I.1 from 2-(2-{[4-(2-phenylethyl)-benzyl]oxy}phenyl)ethylamine and tert-butyl 4-formylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][CH2:15][O:16][CH3:17])[O-:20]
Reactant: COCOCC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COCOCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.3 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (293.3 mg, 2.06 mmol), 2-methyl-2-nitro-1-(methoxymethoxy)propane (382.7 mg, 2.35 mmol) and zinc (266 mg, 4.07 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.46 ml, 8.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 19 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (361.9 mg; 56%).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1>CN(C)C=O>[N+:18]([C:14]1[CH:13]=[CH:12][C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[CH3:17])([O-:20])=[O:19]
Reactant: Sc1ccccc1
Reactant: Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (57% oil emulsion, 1.11 g) in dimethylformamide (30 ml) is added in small portions 2.48 ml (2.64 g, 24 mmoles) of thiophenol. The mixture is cooled in an ice bath while a solution of 5-bromo-2-nitrotoluene (4.32 g, 20 mmoles) in dimethylformamide (10 ml) is added dropwise. The mixture is stirred for an additional 30 minutes and then poured into ice water (200 ml). The partially crystalline product is extracted with dichloromethane and the combined extracts are washed with water and dried. The solvents are evaporated under high vacuum to remove DMF and the residue is covered with hexane. The resultant crystals are broken up and filtered to give pure product, 2-nitro-5-phenylthiotoluene, 3.78 g, m.p. 69°-75°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]2[O:20][C:23]([CH3:25])([CH3:24])[O:18][C:17]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Yield: 87.7 %

Procedure:
(S)-3-(4-Benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol), 2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was heated to reflux for 40 minutes under N2. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo to give crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford the title compound (2.01 g, 88%). 1H-NMR (400 MHz, CDCl3) δ 7.43–7.29 (m, 5H), 7.17 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.12 (dd, 1H, J=14.617 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES+) m/z calc'd for C19H20O4 (M+NH4) 330. Found m/z 330.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14](=[O:17])([O-:16])[O-:15].[Ca+2:18]>C(O)C>[C:14](=[O:15])([O-:17])[O-:16].[Ca+2:18].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Ca+2:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)O
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A mixture of 22 parts citric acid having a grain size between 0.4 and 0.6 mm and 43 parts citric acid of a grain size of about 0.1 mm were mixed, heated to 40° C., and mixed with 10 parts of a 50% ethanol solution. After five minutes of oscillating mixture, evacuation to 500 mbar was carried out and 20 parts of micronized calcium carbonate were introduced. Without agitation, evacuation was carried out again and when the pressure reached 500 mbar, mixing was carried out in an oscillating fashion and the valve to the vacuum pump was turned off. The resulting reaction permitted the pressure to rise slowly, and upon attaining a vacuum of 200 mbar pressure, full vacuum was applied. The difference in the overlying space pursuant to calculation of the pressure difference yields a conversion of approximately 4% of the quantity of calcium carbonate to monocalcium citrate.
Reaction SMILES: [CH:1](=[N:3][C:4]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:1]([NH:3][C:4]([CH2:11][CH2:12][CH3:13])([CH2:5][CH2:6][CH3:7])[CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CC=NC(CCC)(CCC)CCC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(CCC)(CCC)NCC
Temperature: 5 °C

Procedure:
Into a 500-ml three-necked flask, fitted with a mechanical stirrer and a condenser, were introduced 17.6 g (0.096 mol) of N-ethylidene-1,1-di-n-propyl-n-butylamine, prepared as described hereabove, and 150 ml of methanol. To this solution when cooled, 7.6 g (0.2 mol) of sodium borohydride were added slowly and while stirring. After this operation, the mixture was maintained at a temperature of 5° C for 30 minutes and then progressively heated under reflux. Thirty minutes later, the methanol was evaporated off under vacuum and 200 ml of water were added to the residue so obtained followed by 100 ml of a solution of sodium hydroxide (d = 1.38). The organic fraction was extracted with ether and the solution was distilled under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([O:32]CC)=[O:31])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].O.[OH-].[Li+]>CO.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([OH:32])=[O:31])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=S)[nH]c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product of step (ii) (0.55 g) and lithium hydroxide monohydrate (0.46 g) in methanol (10 ml) and water (10 ml) was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure to 10 ml and partitioned between 2M hydrochloric acid and ethyl acetate. The organic phase was dried (MgSO4) and the solvent evaporated under reduced pressure. Purification was by reverse phase chromatography eluting with 50% methanol in 0.1% aqueous ammonium acetate followed by lyophilisation.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[NH:7][C:6](=[O:13])[CH:5]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:6](=[O:13])[CH:5]=1
Reactant: CCCc1nc(COC)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(COC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A mixture of 6-(methoxymethyl)-2-propylpyrimidin-4(3H)-one (17 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (27 g) and potassium carbonate (25 g) in acetonitrile (300 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (15 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4].[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[CH:15][C:14]=2[C:20]([F:21])([F:22])[F:23])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:4]
Reactant: OCC(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 306, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 208 c) was treated with 2,2,2-trifluoroethanol and cesium carbonate to give a mixture of the title compound and starting material as yellow oil. MS (ESI): m/z=436.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:16](=[O:19])([O-])[OH:17].[Na+]>C(OCC)(=O)C>[O:19]=[C:16]1[O:17][CH:3]([C:4]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:5])[CH2:2][CH2:15]1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCC(C(=O)Nc2ccccc2C(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4.9 g of 5-oxotetrahydrofuran-2-carboxylic acid and 5.5 ml of thionyl chloride was subjected to reflux for 2 hours. Thionyl chloride was then distilled off under reduced pressure to leave 5-oxotetrahydrofuran-2-carbonyl chloride. This product was mixed with 5.0 g of 2-aminobenzophenone, 200 ml of ethyl acetate and 200 ml of a saturated aqueous solution of sodium hydrogencarbonate, which was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone (6.5 g) as needles, m.p. 100° C.-102° C.
Reaction SMILES: F[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14].[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:22][C@@H:20]1[CH2:19][N:18]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[F:14])[CH2:17][C@@H:16]([CH3:15])[O:21]1
Reactant: Cc1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@@H](C)O1
Product: Cc1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(C=O)cc12

Procedure:
Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].[OH-].[Na+]>O1CCCC1.CO>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCC/C=C/c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
(E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 160B as an intermediate.) was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 2 days. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC (mobile phase: 0-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 column to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.18 (d, J=9.21 Hz, 1H), 7.82-7.89 (m, 1H), 7.57-7.70 (m, 4H), 7.42-7.55 (m, 4H), 7.37 (t, J=7.67 Hz, 1H), 7.01-7.14 (m, 2H), 6.84 (d, J=7.67 Hz, 1H), 6.14-6.29 (m, 1H), 4.80 (t, J=7.83 Hz, 2H), 4.13 (t, J=5.68 Hz, 2H), 2.70-2.97 (m, 2H), 2.11-2.37 (m, 4H), 1.41-1.76 (m, 4H).
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.O=[C:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1>C1COCC1>[C:57]([O:56][C:54]([N:51]1[CH2:52][CH2:53][C:48](=[CH:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:49][CH2:50]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(=CCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of triphenyl(4-phenylbutyl)phosphonium iodide (975 mg, 1.87 mmol) in THF (8 mL) under Ar at −78° C. was added HMPA (1 mL) followed by n-BuLi (1.6 M in hexane; 1.28 mL, 2.05 mmol, 1.1 equiv.). After stirring at room temperature for 2 h, the mixture was cooled to −78° C. again, and tert-butyl 4-oxopiperidine-1-carboxylate (409 mg, 2.05 mmol, 1.1 equiv.) in THF (2 mL) was added. The mixture was allowed to warm to room temperature and to stand for 2 days. The reaction was quenched with H2O, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration, the residue was purified by CC (SiO2, hexane/EtOAc 10:1) to obtain 1-(tert-butoxycarbonyl)-4-(4-phenylbutylidene)piperidine (216 mg, 37%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.25 (m, 2H), 7.15 (m, 3H), 5.22 (t, 1H, J=7.2 Hz), 3.55 (m, 4H), 2.60 (t, 2H, J=8.0 Hz), 2.15 (m, 4H), 2.03 (m, 2H), 1.66 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=O)[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.Cl.[OH:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[N:24][OH:23])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C=NO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of (69) (11.66 g, 35.8 mmol), hydroxyamine hydrochloride (2.98 g, 42.96 mmol), and triethyl amine (7.48 ml, 53.7 mmol) in ethanol (100 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 4.5 g (37%) of a white solid. m.p. 185-187° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 6.94 (1H, s), 7.16 (1H, s), 7.28 (1H, s), 7.51 (1H, s), 8.10 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:8][C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:27][C:26]2=[O:32])=[N:22][C:21]=1[CH3:33])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3ccc(Cl)nc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 73 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-chloro-5-(chloromethyl)pyridine in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 73% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.9 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 7.95 (dd, J=8.3, 2.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.35-7.16 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.26 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 467.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].Br[Zn][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: Br[Zn]c1ccccn1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Temperature: 63 °C

Procedure:
A solution of 1-bromo-2-methoxy-4-nitrobenzene (7 g, 30.17 mmol), bromo(pyridin-2-yl)zinc (80 mL of 0.5M in THF, 40 mmol), tetrakis(triphenlyphosphine)palladium(0) (1.7 g, 1.47 mmol) in 70 mL THF was degassed with nitrogen for 10 minutes, then heated at 63° C. for 6 hr. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica (EtOAc/Hexane 3/7) to give 2-(2-methoxy-4-nitrophenyl)pyridine. MS (ESI) 231 (M++H).