Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.C(OC(N1CCNCC1C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:5][CH2:6][NH:7][CH:2]([CH3:1])[CH2:3]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Agent: CC1CNCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)CCN1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, using 2-methyl-piperazine-1-carboxylic acid tert-butyl ester in place of 2,6-dimethyl-piperazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (19.8 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH2:31][C:32]([OH:34])=[O:33])[CH:9]=[CH:10][C:11]=1[NH:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:5])[CH3:2].[CH2:35]([O:37][C:38](=[O:53])[C:39]([CH2:51]O)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH3:36]>>[CH2:43]([O:42][C:40](=[O:41])[C:39]([CH2:51][O:33][C:32](=[O:34])[CH2:31][C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][CH:22]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]([O:37][CH2:35][CH3:36])=[O:53])[CH3:44]
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Reactant: CCOC(=O)c1cc(CC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1cc(CC(=O)OCC(C(=O)OCC)(C(=O)OCC)c2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 64.5 %

Procedure:
The 3-ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid (0.532 g) obtained in Example 9-4e) and the 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (1.04 g) obtained in Example 1-2a) were treated in a similar manner to Example 1g) to give the title compound (0.524 g) (see Table 59).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:20])[CH3:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) suspension of 4-nitroaniline (10 g, 0.072 mol) and Et3N (10 mL) in CHCl3 (120 mL), was added dropwise ethyl chloroformate (6.9 mL) and the mixture was stirred under an argon atmosphere at room temperature overnight. CHCl3 was added and the resulting solution was washed with 1N HCl. The layers were separated, the aqueous phase was washed with CHCl3 and the combined organic extracts were dried and concentrated. The residue was chromatographed on silica gel (hexane:EtOAc, 30%) to afford N-(ethoxycarbonyl)-4-nitroaniline (1.7 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]2=[O:38])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[C:34]([CH3:37])([CH3:36])[CH2:35][NH:31][C:32]4=[O:38])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1.[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[C:34]([CH3:37])([CH3:36])[CH2:35][N:31]([CH2:30][C:29]5[CH:39]=[CH:40][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:38])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4(C)C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54 and by the reaction and treatment in the same manner as in Example 426, the title compound (56 mg) was obtained via 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (119 mg).
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2([CH3:32])[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([CH3:31])[C:22]([CH3:30])=[C:23]([OH:29])[C:24]=3[CH3:28])[O:19]2)=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:33][C:34](N)=[S:35].S1(CCCC1)(=O)=[O:38]>C(OCC)(=O)C>[OH:29][C:23]1[C:24]([CH3:28])=[C:25]2[C:20](=[C:21]([CH3:31])[C:22]=1[CH3:30])[O:19][C:18]([CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:2]3[S:35][C:34](=[O:38])[NH:33][C:3]3=[O:4])=[CH:10][CH:11]=1)([CH3:32])[CH2:27][CH2:26]2
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)cc1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCOc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 1(a) was repeated, except that 13.5 g of ethyl 2-chloro-3-{4-[2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)ethoxy]phenyl}propionate, 4.4 g of thiourea and 20 ml of sulfolane were reacted for 14 hours at 110° C. The crude product was dissolved in ethyl acetate and the solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the resulting residue was purified by column chromatography through silica gel. This was first eluted with a 4:1 by volume mixture of benzene and ethyl acetate, and from these fractions were obtained the desired 5-{4-[2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)ethoxy]benzyl}thiazolidine-2,4-dione, whose melting point and nuclear magnetic resonance spectra agreed with those of the product of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:28])[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:28][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)o2)cc1
Yield: 91.2 %

Procedure:
A solution of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (765 mg) and p-toluenesulfonic acid monohydrate (8 mg) in toluene (10 ml) was refluxed for 6 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure and the precipitate was triturated with methanol, collected by filtration, washed with methanol and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)furan-2-yl]benzoate (665 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CI>CC#N>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
To a solution of compound 6 (230 mg, 0.55 mmol) in CH3CN (15 mL) was added K2CO3 (304 mg, 2.2 mmol). After being stirred for 5 min, MeI (155 mg, 1.1 mmol) was added. The reaction mixture was stirred at 60° C. for 15 min in a CEM microwave reactor. The mixture was concentrated in vacuo, the residue was purified by prep-TLC to give compound 7 (120 mg, 50%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6](Cl)=[O:7])#[N:2].O[NH:18][C:19](=[NH:39])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[C:25]2[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:18]=[C:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:39]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)#[N:2]
Reactant: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(C#N)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
A solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D25; 54.2 mg, 0.23 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 68.9 mg, 0.219 mmol) and triethylamine (0.048 ml, 0.345 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (40 ml) and ethyl acetate (3×25 ml), and the combined organic layers washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil which was purified by flash chromatography on silica gel, eluting with 0-40% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (36 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.O.[OH-].[Na+]>C(O)(=O)C.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
5-bromo-2-methyl-3-nitropyridine (1.808 g, 8.33 mmol) was suspended in glacial acetic acid (16 ml) and water (4 ml) and iron powder (1.411 g, 25.3 mmol) was added in portions over 5 minutes. The reaction was stirred under nitrogen at room temperature for 70 minutes, using a water bath to cool the reaction flask. Then, the reaction was diluted with EtOAc (20 ml) and the suspension was poured into 5 N NaOH (50 ml). The emulsion was filtered through a pad of Celite® (diatomaceous earth), which was washed with water and EtOAc. Layers separated, and the aqueous phase was extracted with EtOAc (2×50 ml). The organic extracts and phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to afford 5-bromo-2-methylpyridin-3-amine.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:17])[C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[O:4].CCOCC.[Li+].[OH-].Cl>O.CO>[O:17]=[C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])[C:10](=[O:16])[C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (2S)-Methyl-1-(1,2-dioxo-3,3-dimethylpentyl)-azetidine-2-carboxylate from Reference Example 3 (0.64 g, 2.65 mmol) in a 1:1 mixture of ether:methanol (20.0 mL) was added LiOH in water (4.9 mL, 1N solution) at about 0° C. The mixture was stirred at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1N HCl, then the mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with brine and dried over sodium sulfate and then concentrated to give 0.40 g (67% yield) of the product as a yellow semisolid. 1H NMR (DMSO) δ 0.77-0.83 (m, 3H); 1.20-1.29 (series of s, 6H); 1.49-2.84 (series of m, 4H); 4.02-4.43 (series of m, 2H); 5.01-5.31 (series of dd, 1H); 6.10-6.80 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:23][CH3:22])=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Reactant: COc1ccc(NN)cc1
Product: COc1ccc(-n2nc3c4nc(F)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for synthesis for 5a using 4-methoxyphenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.25 (1H, ddd, J=7.14, 4.67, 1.10 Hz), 7.50 (1H, dd, J=8.79, 3.03 Hz),): 7.90 (1H, ddd, J=9.34, 7.42, 1.93 Hz), 8.14 (1H, brd, J=8.24 Hz), 8.28 (1H, ddd, J=9.06, 7.42, 7.14 Hz), 8.50 (1H, m), 8.84 (1H, s). m/z 282.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[C:19]#[N:20]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([C:19]#[N:20])[CH:21]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1cc(CBr)ccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1F
Temperature: 100 °C
Reaction time: 14 h
Yield: 21.1 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 5-(bromomethyl)-2-fluorobenzonitrile (0.29 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (71 mg).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH2:17]1COCC1>>[CH2:1]([N:3]=[C:4]([S:5][CH3:17])[N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCN=C=S
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CCNCC1
Product: CCN=C(SC)N1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl isothiocyanate (0.60 ml) was added to a solution of ethyl piperidine-4-carboxylate (1.02 g) in THF (20 ml), followed by stirring at room temperature for one hour. The reaction solution was concentrated and the resulting colorless oily product was made into an ethanol solution (20 ml), iodomethane (2.0 ml) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction solution was concentrated, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform, the organic layer was washed with saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain ethyl 1-[(ethylimino)(methylsulfanyl)methyl]piperidine-4-carboxylate (1.84 g) as a light yellow oily product.
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]=1)C1C=CC=CC=1>C(O)C.[OH-].[Na+].O>[CH3:30][S:27]([C:25]1[CH:24]=[CH:23][C:22]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:21]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[C:9]([OH:39])=[O:8])[CH:26]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)OCc4ccccc4)c3)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)O)c3)CCC2)c1

Procedure:
A solution of 3-{2-[5-methylsulfonyl-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid benzyl ester (30 mg, 0.059 mmol) in ethanol (5 ml) and 2M sodium hydroxide (1 ml) was left at room temperature for 20 hours then diluted with water, washed with ether and the aqueous phase separated, acidified with 2M hydrochloric acid and extracted with ether. The organic extract was dried (MgSO4), evaporated to dryness and the residue triturated with iso-hexane to yield the title compound as a white solid. (14 mg, 57%).
Reaction SMILES: CS(C)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)#[N:6].[NH2:14][OH:15].[OH-:16].[Na+]>O.C(Cl)(Cl)Cl>[OH:15][N:14]=[C:5]([NH2:6])[C:7]1[CH:12]=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: NO
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: NC(=NO)c1ccc(O)cc1
Reaction time: 14 h

Procedure:
To a dimethylsulfoxide (100 mL) solution of 10.0 g of 4-cyanophenol was dropwise added 12.9 mL of a 50% hydroxylamine aqueous solution at room temperature over a period of 6 minutes, which was then stirred at the same temperature for 14 hours. Chloroform, a 1 mol/L sodium hydroxide aqueous solution, and water were added to the reaction mixture. The aqueous layer was separated and washed sequentially with toluene, chloroform, and toluene, to which water was then added, followed by adjustment to pH 7.2 using 6 mol/L hydrochloric acid. After stirring this mixture at room temperature for 30 minutes, the precipitate was collected by filtration and washed with water to provide 8.88 g of N′, 4-dihydroxybenzamidine as white solid form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C@H:12]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@H]1c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1c1ccc(F)cc1
Yield: 87.4 %

Procedure:
To (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (0.55 g, 1.90 mmol) in tetrahydrofuran (20 mL) was added methanesulfonyl chloride (0.158 mL, 2.05 mmol), followed by dropwise addition of diisopropylethylamine (0.50 g, 3.9 mmol) and N,N-dimethylpyridin-4-amine (10 mg). After 30 minutes the reaction was diluted with ethyl acetate (50 mL) and washed with 0.1 M hydrochloric acid (25 mL) then saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 1:4) to give (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-(methylsulfonyloxy)piperidine-1-carboxylate (0.62 g, 88% yield). 1H NMR (400 MHz, CDCl3): 7.19 (dd, 1H), 7.05 (t, 2H), 5.38 (d, 1H), 5.14 (m, 1H), 4.14 (m, 1H), 3.25 (m, 1H), 2.68 (m, 1H), 2.59 (s, 3H), 2.21 9M, 1H), 1.93 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H](C(O)=O)CC(C)C)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:27]>C1COCC1.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:14](=[O:15])[C@H:12]([CH2:11][CH:6]([CH3:7])[CH3:5])[NH2:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](N)C(=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 10 mL of THF was charged with NH3 (29.6% water solution, 1.26 mL, 20 mmol) at room temperature. The reaction mixture was stirred for 30 min., then diluted with 100 mL of water and extracted with ethyl acetate (5×20 mL). The organic layers were combined, extracted with 10% potassium carbonate solution, washed with water, brine, dried and evaporated. Recrystallization of the product from ethanol afforded 1.26 g (36%) of N-(9-fluorenylmethoxycarbonyl)-L-leucine, amide as colorless solid, mp 79°-80° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][O-:10].[Na+].[CH3:12]O>O>[CH3:12][O:7][C:6]([CH2:5][CH2:4][CH2:3][CH:2]1[O:10][CH2:9]1)=[O:8]
Reactant: C[O-]
Reactant: CO
Reactant: O=C1CCC(CBr)O1
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCC1CO1

Procedure:
10.0 g 4,5-dihydro-5-bromomethyl-(3H)-furanone are refluxed with 3.0 g sodium methylate in 37 ml methanol for 5 hours. The solvent is eliminated in vacuum and the residue is dissolved in 20 ml H2O and then extracted with ether. The ethereal phase is dried through a molecular sieve and the ether eliminated in vacuum. The residue is distilled at 20 mm. 6.4 g 4,5-epoxypentane carboxylic acid methyl ester (boiling point at 20 mm, 85° C.) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>S(Cl)(Cl)=O.CC(C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: O=C(c1cc(Cl)ccc1[N+](=O)[O-])N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Dissolved in 20 ml of thionyl chloride were 5.0 g (24.8 mmol) of 2-nitro-5-chlorobenzoic acid, followed by heating for 1.5 hours under reflux. After the reaction, the reaction mixture was concentrated and the residue was dissolved in 10 ml of acetone. The thus-obtained solution was added dropwise to a solution of 4.7 ml (62 mmol) of morpholine in 20 ml of acetone, followed by stirring at room temperature for 2 hours. Subsequent to the reaction, the reaction mixture was concentrated and then extracted with ethyl acetate. The ethyl acetate layer was dried and then concentrated. The residue was recrystallized from ethyl acetate/n-hexane, whereby 5.64 g of the title compound were obtained as white powder (yield: 84%).