Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C(N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)(=[O:3])[CH3:2].[CH2:39]([O:41][C:42](=[O:62])[CH:43]([C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:47][CH:46]=1)[OH:44])[CH3:40]>>[CH2:39]([O:41][C:42](=[O:62])[CH:43]([O:44][C:1](=[O:3])[CH3:2])[C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:47][CH:46]=1)[CH3:40]
Reactant: CCOC(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)C(OC(C)=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 83 %

Procedure:
According to the procedure described in Example 13 for the preparation of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-acetic acid ethyl ester was acylated to furnish in 83% yield 2-acetoxy-2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester which was used without purification. Flash column chromatography with 0-20% EtOAc/hex as eluant gave an analytically pure pink solid, mp 136-140° C. 1H NMR: δ 7.74 (d, 2H, J=8.5 Hz), 7.63 (d, 4H, J=8.5 Hz), 7.46 (t, 2H, 7.4 Hz), 7.36 (t, 1H, J=7.2 Hz), 6.68 (d, 1H, J=3.7 Hz), 6.58 (d, 1H, J=3.3 Hz), 6.57 (s, 1H), 4.29 (q, 2H, J=7.0 Hz), 2.21 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). Anal. Calculated for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.61; H, 5.63.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 4-hydroxy-3-methyl benzaldehyde (3 g, 22 mmol) and ethyl 2-bromo-2-methylpropionate (6.5 mL, 44 mmol) in DMF (100 mL) was added caesium carbonate (15.8 g, 48 mmol). The resulting mixture was heated at 40° C. for 42 h, then allowed to cool to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The organic solution was dried (MgSO4), filtered and evaporated. Purification by Biotage™ chromatography (Silica, 90 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (3.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>C1(C)C=CC=CC=1.C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)[N:3]=1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C#CC2CC2)nc1Cl
Yield: 31 %

Procedure:
Ethyl 2,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol), ethynylcyclopropane (1.6 mL of a 70% w/v solution in toluene, 13.63 mmol), copper(I) iodide (173 mg, 0.9 mmol), bis(triphenylphosphine) palladium(II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% EtOAc/hexane to give the product (0.7 g, 31%) as a brown oil. m/z=250 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=[O:12])=[CH:3]1.CC(=CC)C.[O-:18]Cl=O.[Na+]>C1COCC1.C(O)(C)(C)C.O>[CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]([C:11]([OH:18])=[O:12])=[CH:3]1
Reactant: [O-][Cl+][O-]
Reactant: Cn1cc(C=O)c2ccncc21
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: Cn1cc(C(=O)O)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (WO 05066132) (6.5 g, 40.6 mmol) was dissolved in a mixture solvent of THF (120 mL) and t-butyl alcohol (40 mL) under nitrogen. A 2M 2-methyl-2-butene solution in THF (120 mL, 46 mmol) was added followed by a solution of NaClO2 (11.02 g, 122 mmol) and NaH2PO4 (21.9 g, 183 mmol) in water (30 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents, and the residue was filtered. The precipitate contained the title compound as white solid in 57% yield, 4.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].[CH3:16][NH2:17].CCO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5]([NH:17][CH3:16])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 20 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of methyl 2-methoxy-5-nitrobenzoate (389 mg, 1.84 mmol) in THF (3.0 mL) was added 33% MeNH2/EtOH solution (2.0 mL, 16.0 mmol) and the mixture was stirred at 20° C. overnight. The solution was evaporated and the residue was chromatographed (SiO2 230-400 mesh) eluting with 7:3 hexanes/EtOAc to remove 2-(methylamino)-5-nitrobenzoate derivatives. Further elution with EtOAc provided the title compound (268.5 mg, 70% yield) as a yellowish solid: LCMS (ES) m/z 211 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)=CCSc1ccc(OCCN)cc1
Product: CCOC(=O)NCCOc1ccc(SCC=C(C)C)cc1

Procedure:
Following the procedure of Example 13, 2-[4-(3-methyl-2-butenylthio)phenoxy]ethylamine is prepared and is reacted with ethyl chloroformate to give ethyl N-{2-[4-(3-methyl-2-butenylthio)phenoxy]ethyl}carbamate (compound 43, Table A).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:1]([CH:8]1[CH2:10][N@@:9]1[S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1ccc(C[C@H]2CN2)cc1
Agent: CN(C)S(=O)(=O)[N@@]1CC1Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)[N@]1CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a cooled (−10° C.) solution of (S)-2-benzylaziridine (100 g, 0.751 mol) and N,N-dimethylsulfamoyl chloride (84.5 mL, 0.787 mol) in dichloromethane (100 mL) was added N,N-diisopropylethylamine (131 mL, 0.751 mol). The resulting yellow solution was stirred at −10° C. for a minimum of 16 hours. After this period, a 0.5M solution of citric acid (500 mL) was added and the phases were separated. The organic phase was then washed with 1.0 M sodium bicarbonate solution (500 mL). The organic phase was then solvent exchanged into tert-butyl methyl ether (500 mL). The solution was then cooled to 0° C., and heptane (100 mL) was added dropwise over a period of 2 hours. The mixture was then aged for an additional 2 hours at 0, and then cooled (−10° C.), to allowed compound IIa to precipitate out as a white, crystalline solid (27.8 g, 77%). Tlc assay: Rf: 0.53 (SiO2; 1:1 heptane:ethyl acetate, KMnO4). 1H NMR (400 MHz, CDCl3): δ 7.20-7.29 (m, 5H), 2.94 (dd, J=14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J=7 Hz, 1H), 2.14 (d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0.
Reaction SMILES: CC(O)(C[NH2:5])C.[CH3:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9].[C:19]1([CH3:25])[CH:24]=CC=C[CH:20]=1>>[CH2:10]([C:8]1([CH3:7])[NH:5][C:19]([CH3:25])([CH3:24])[CH2:20][O:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(O)CN
Reactant: Cc1ccccc1
Reactant: CCCCCCCCCC(C)=O
Product: CCCCCCCCCC1(C)NC(C)(C)CO1

Procedure:
The procedure of Example 1 was followed utilizing 1,1-dimethylethanolamine (22.3 grams; 0.25 mole) and methyl n-nonylketone (42.6 grams; 0.25 mole) in 250 mls of toluene. After removing the toluene, the residue was distilled to obtain 26.7 grams (44% of theoretical; b.p. 92°-94° C. at 0.3 mm.) of the desired product. This product was prepared for comparison with the compounds of Examples 1-3.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:21][NH:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: Cc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-methylbenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 163 mg of the title compound (80%) as a yellow solid in 99.99% purity by HPLC (Rt: 5.7, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][C@@H:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH2:28])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH:28][C:2]([O:4][CH3:5])=[O:3])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COC(=O)Cl
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC=Cc1c(NC(=O)OC)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
Methyl chloroformate (2.93 mL, 37.9 mmole) was added to a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methyl-benzenesulfonate (2.35 g, 6.30 mmole) in ethyl acetate (125 mL), followed by the addition of N,N-diisopropylethylamine (5.50 mL, 31.6 mmole) dropwise over a period of 20 minutes. The solution was stirred under nitrogen at room temperature over a period of 10 hours. This solution was then washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 0.2% methanol/methylene chloride gave the (R)-enantiomer of the title compound as a white foam (1.90 g, 70%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (3 H); doublet, 6.7 δ (1 H); broad singlet, 6.6 δ (1 H); multiplet, 6.1 δ (2 H); multiplet, 4.4 δ (1 H); multiplet 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.7 δ (3 H); singlet, 2.4 δ (3 H); doublet, 1.9 δ (3 H).
Reaction SMILES: Cl.O.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][CH2:14][C:15](O)=O)=[CH:11][C:6]=2[CH2:5][CH2:4]1>[Zn].C1(C)C=CC=CC=1>[O:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[C:10]3[C:9](=[CH:8][C:7]1=2)[CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: O=C(O)CCCc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: c1c2c(cc3c1CCO3)CCCC2

Procedure:
An amalgam of zinc and mercuric chloride (72 g Zn and 7.1 g HgCL2) is added to a mixture containing 120 ml of concentrated hydrochloric acid, 57 ml of water, 30 g of the compound of Example 1 and 71 ml of toluene, with stirring.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:9])[CH2:6][C:7]#[N:8])[CH3:3].Br.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14].CCN(C(C)C)C(C)C>CCO.C1COCC1>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([C:7]#[N:8])[CH2:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:3]
Reactant: O=C(CBr)c1ccncc1
Reactant: CCOC(=O)CC#N
Agent: Br
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of sodium metal (81 mg, 3.5 mmol) in 10 mL anhydrous EtOH, ethylcyanoacetate (0.37 mL, 3.5 mmol) was added at 0° C. The solution was stirred until sodium was completely dissolved. The solvent was evaporated to obtain a white solid that was added portionwise to a stirred solution of bromoacetylpyridine 1 (1.0 g, 3.5 mmol) in anhydrous THF (20 mL) and DIEA (0.6 mL, 3.5 mmol). The reaction mixture was stirred overnight at rt. The solvent was removed, the residue was suspended in water and extracted with DCM. The organic extracts were dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give 710 mg (87%) of 2-cyano-4-oxo-4-pyridin-4-yl-butyric acid ethyl ester as a reddish oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4](O)=[O:5].CN.C1C=CC2N(O)N=[N:25][C:23]=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([NH:25][CH3:23])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)O)c(Br)cc1C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
step 1—To a solution of 58 (150 mg) in DMF (10 mL) cooled to 0° C. was added MeNH2 (0.52 mL, 2.0 M in THF,), HOBt (140 mg) and EDCI (200 mg). The reaction mixture was then stirred overnight at RT then diluted with 1N aq HCl solution and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 140 mg of 2-bromo-4-tert-butyl-5-methoxy-N-methyl-benzamide (60) as a white solid.
Reaction SMILES: [K].CC(C)([O-])C.[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10]P(=O)(OCC)OCC.[C:23]1([CH3:45])[CH:28]=[CH:27][C:26]([N:29]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.Cl>O1CCCC1.O>[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]=[CH:44][C:41]1[CH:40]=[CH:39][C:38]([N:29]([C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)[C:26]2[CH:27]=[CH:28][C:23]([CH3:45])=[CH:24][CH:25]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
14.8 g of kalium-tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction reservoir having a mixer, a thermometer and a dropping funnel. Under a nitrogen stream, a solution wherein 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(di-para-tolylamino) benzaldehyde were dissolved in tetrahydrofuran was slowly dropped there in at a room temperature, and the reaction therein is further performed for 2 hrs at the same temperature. Then, water was added therein while cooling the reaction product with water, a hydrochloric acid solution having a normal concentration of 2 was added therein to acidize the reaction product, and the tetrahydrofuran was removed by an evaporator to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was further added thereto to dehydrate the toluene phase. After filtered, the toluene was removed therefrom to prepare an oily crude product, and the oily crude product was further column-refined with silica gel to crystallize 5.09 g of 2-hydroxy-4′-(di-para-tolylamino) stilbene in hexane at a yield of 72%, having a boiling point of 136.0 to 138.0° C.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.O1CCOCC1>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1c(CC(C)(C)C)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(C(=O)O)c(CC(C)(C)C)nc2cc(C(F)(F)F)ccc12
Temperature: 80 °C
Yield: 83.3 %

Procedure:
A 2M aq. LiOH sol. (10 ml) was added to a solution of 1.1 g (3.0 mmol) 4-methyl-2-neopentyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/1,4-dioxane mixture (in each case 10 ml) and the mixture was subsequently heated to 80° C. for 72 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with ether, adjusted to pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 0.8 g (2.5 mmol, 82%) 4-methyl-2-neopentyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=O)C.O.[NH2:30][NH2:31]>C(O)C>[NH:30]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=[O:3])[NH2:31]
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(=O)NN)cc1
Yield: 41.5 %

Procedure:
In this example, 4 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 30 ml of ethanol and 6.1 g of 85% hydrazine hydrate is added thereto. The mixture is heated under reflux for 2 hours. The solvent is distilled away from the reaction solution under reduced pressure. The residue is recrystallized from tetrahydrofuran-ether to obtain 1.6 g of 1-(4-hydrazinocarbonylmethylphenoxy) -3-(1-methyl-3-phenylpropylamino)-2-propanol. (Yield: 42%),
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19]Cl>CN(C)C=O>[Cl:17][CH2:18][CH2:19][N:5]1[C:4](=[O:9])[C:3]([CH2:1][CH3:2])([CH3:10])[NH:7][C:6]1=[O:8]
Reactant: CCC1(C)NC(=O)NC1=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(C)NC(=O)N(CCCl)C1=O

Procedure:
284.3 g of 5-ethyl-5-methyl-hydantoin (2.0 mols), 138.2 g of anhydrous potassium carbonate (1.0 mol), 791.7 g of 1,2-dichloroethane (8.0 mols) and 230 ml of dimethylformamide are subjected to an azeotropic circulatory distillation for 25 hours at 90° C to 107° C internal temperature (external temperature: 160° C), in the manner described under Example 1 (a). After completion of the reaction, the mixture is filtered whilst still hot and the filtrate is concentrated on a rotary evaporator at 90° C under a waterpump vacuum. The reaction mixture is then dried to constant weight at 90° C and 10-1 mm Hg. 392.5 g of a brown, clear, product (95.9% of theory) are obtained, and are purified by vacuum distillation (boiling point0.2 : 147° C). Yield of pure product: 327.3 g (80% of theory). A sample recrystallised from diethyl ether melts at 58.0° C to 59.0° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15]C(=O)[C@@H]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@@H:33]2[CH2:34]NCCN2[CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@H:33]([CH2:28][O:29][CH2:30][CH2:31]4)[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN2CCOC[C@@H]2CN1
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOC[C@@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (5)-octahydro-pyrazino[2,1-c][1,4]oxazine in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a pale yellow solid (210 mg, 90%).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[N:17]([O-])=O.[Na+].[OH-].[Na+].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[OH:29][C:23]1[CH:28]=[CH:27][C:26]([N:17]=[N:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)=[CH:25][CH:24]=1
Reactant: O=N[O-]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 58.4 %

Procedure:
35 g (0.17 M) of 4-octylaniline was cooled to 0° C. or below, 85 g of 10% aqueous hydrochloric acid solution was added, and then a solution of 12.0 g of sodium nitrite in 68 ml of water was added. During the addition, the mixture was cooled so as not to exceed 0° C. After the addition, the mixture was allowed to react for 30 minutes, transferred into a dropping funnel and added dropwise into 170 g of an 8% NaOH aqueous solution containing 16 g of phenol held at 5° C. or below. After the addition, the mixture was stirred for 1 hour, and then 10% hydrochloric acid aqueous solution was added thereto until a pH of 5-6 to precipitate the reaction product. The precipitate was separated by filtration, washed with water, overnight under reduced pressure. After the drying, the product was washed with 500 ml of petroleum ether and further dried under reduced pressure to obtain 30.8 g (0.10 M) of 4-hydroxy-4'-octylazobenzene. The yield was 59%.