Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+].O=[Si]=O.[C:17](=[O:19])=[O:18]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:17]([OH:19])=[O:18])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C=O
Agent: O=[Si]=O
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 220 °C
Yield: 90 %

Procedure:
p-Acetaminophenol 15 g, potassium hydroxide 60 g, and quartz sand 90 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 5.0 MPa and heated to 220° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 97% and the yield is 90%.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4][O:3]1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[CH2:10]([O:9][C:7]([NH:6][C:5]([CH2:4][OH:3])([CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:31])([CH3:32])[C:28]([CH3:34])([CH3:33])[O:27]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1(CCCCB2OC(C)(C)C(C)(C)O2)COC(C)(C)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
While under an argon atmosphere, a solution of 3-benzyl 4-ethyl 2,2-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)oxazolidine-3,4-dicarboxylate (350 mg, 0.72 mmol) in dichloromethane (5 mL) was cooled to −40° C. and carefully treated with trimethylsilyltrifluoromethane sulfonate (1.09 g, 4.29 mmol, 0.94 mL). After stirring for 30 minutes the solution was warmed to 0° C. and stirred an additional 2 h, concentrated and purified using a combiflash system (12 g silica gel column, eluting with 20-100% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (180 mg, 56%). 1HNMR (CDCl3) δ 7.38-7.31 (m, 5H), 5.81 (bs, 1H), 5.10 (s, 2H), 4.25-4.23 (m, 3H), 3.84 (d, 1H), 2.84 (m, 1H), 1.76-1.68 (m, 1H), 1.41-1.35 (m, 2H), 1.28 (t, 3H), 1.23 (s, 12H), 1.11-1.03 (m, 1H), 1.29 (m, 4H), 0.75 (t, 2H). MS found for C23H36BNO7 m/z[450 (M+1)].
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:76])[C@@H:15]([NH:29][C:30]([C@H:32]1[NH:50][C:49](=[O:51])[C@H:48]([CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:47][C:46](=[O:63])[C@@H:45]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:44][C:43]2[CH:72]=[C:39]([CH:40]=[CH:41][C:42]=2[OH:73])[C:38]2=[CH:74][C:34](=[C:35]([OH:75])[CH:36]=[CH:37]2)[CH2:33]1)=[O:31])[CH2:16][CH2:17][NH:18]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>[Pd].C(O)(=O)C.O.C(O)C>[C:59]([O:58][C:56](=[O:57])[NH:55][CH2:54][CH2:53][CH2:52][C@@H:48]1[NH:47][C:46](=[O:63])[C@@H:45]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:44][C:43]2[CH:72]=[C:39]([CH:40]=[CH:41][C:42]=2[OH:73])[C:38]2=[CH:74][C:34](=[C:35]([OH:75])[CH:36]=[CH:37]2)[CH2:33][C@@H:32]([C:30]([NH:29][C@H:15]([C:14]([NH:13][CH2:12][CH2:11][NH2:10])=[O:76])[CH2:16][CH2:17][NH2:18])=[O:31])[NH:50][C:49]1=[O:51])([CH3:60])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)C(=O)NCCNC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCN)C(=O)NCCN)NC1=O
Reaction time: 15 h

Procedure:
29 mg (0.027 mmol) of benzyl(2-{[(2S)-4-{[(benzyloxy)carbonyl]amino}-2-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)butanoyl]amino}ethyl)carbamate (Example 191A) are added into 8 ml of a 4:1:1 acetic acid/water/ethanol mixture. 2.5 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated at RT under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr and washed with ethanol, and the filtrate is concentrated on a rotary evaporator in vacuo.
Reaction SMILES: C(=O)([O-])[O-].Cl.[NH:6]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[NH2:7].C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(Cl)Cl.CO>[NH2:23][C:22]1[N:6]([C:8]2[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[CH:18][C:19]=1[C:20]#[N:21]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ncccc1NN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncccc1-n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.4 %

Procedure:
MP-carbonate (2.64 mmol/g) (2.6 g, 6.80 mmol) was added to 3-hydrazinyl-2-methylpyridine hydrochloride (Intermediate V2) (362 mg, 2.27 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered and evaporated. 2-(Ethoxymethylene)malononitrile (277 mg, 2.27 mmol) was added to suspension of the above solid in MeOH (6 mL) under nitrogen cooled to −5° C. The reaction mixture was stirred at 0° C. for 30 mins and then allowed to warm to room temperature and heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (210 mg, 46.5%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.23 (3H, s), 6.65 (2H, s), 7.39-7.43 (1H, m), 7.74 (1H d), 7.79 (1H, s), 8.58-8.60 (1H, m), m/z (ESI+) (M+H)+=200; HPLC tR=1.21 min.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[CH:15][CH:14]=1.N12CCN(CC1)CC2>O1CCCC1>[O:25]=[C:20]1[CH2:21][CH2:22][C:23](=[O:24])[N:19]1[C:16]1[CH:15]=[CH:14][C:13]([O:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:18][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C1CCC(=O)N1c1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N2C(=O)CCC2=O)cn1)c1ccccc1
Yield: 84.5 %

Procedure:
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 1-(6-hydroxy-pyridin-3-yl)-pyrrolidine-2,5-dione (192 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 80:20) yielding the title compound (275 mg, 85% yield) as a white solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27](O)=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([NH2:37])=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(N)=O)c21
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of Example 598, (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165 mmol), and HOBt (0.023 g, 0.165 mmol) in DMF (1.5 ml) under N2 was added NH4Cl (0.009 g, 0.165 mmol) and diisopropylamine (0.046 ml, 0.33 mmol). The reaction was stirred overnight. The mixture was diluted with EtOAc, washed (1.0 N HCl saturated with NaCl), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc gradient) gave the title compound (0.024 g, 48%). MS(ES+) (m/z) 459.1 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg+].[Br-]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:15][C:16]([OH:18])([CH3:28])[CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 3-{[(2,4-dichlorobenzyl)-(3-oxo-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (190 mg, 0.46 mmol) in Et2O (4 mL) is added MeMgBr (3.0 M in Et2O, 0.92 mmol). The resulting mixture is stirred at room temperature for one hour. The reaction is quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 138 mg (70%) of 3-{[(2,4-dichlorobenzyl)-(3-hydroxy-3-methyl-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.49-7.47 (2H, m), 7.36-7.34 (1H, m), 4.0-3.96 (2H, m), 3.67 (2H, s), 3.57-3.53 (2H, m), 2.9-2.82 (1H, m), 2.75-2.73 (2H, m), 2.67 (2H, t, J=7.0 Hz), 1.69 (2H, t, J=7.3 Hz), 1.46 (9H, s), 1.1 (6H, s). Mass spectrum (ion spray): m/z=431.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:6][C:5]([NH:12]C(=O)C)=[C:4]([F:16])[CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[C:7]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:6][C:5]([NH2:12])=[C:4]([F:16])[CH:3]=1
Reactant: COC(C)c1cc(NC(C)=O)c(F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(C)c1cc(N)c(F)cc1Cl
Yield: 118.7 %

Procedure:
A mixture of 0.6 g (0.0024 mole) of N-[4-chloro-2-fluoro-5-(1-methoxyethyl)phenyl]acetamide, 0.14 g (0.0025 mole) of potassium hydroxide, 10 ml of water, and 10 ml of methanol was heated at reflux for 24 hours. This mixture was cooled and diluted with 50 ml of water. The resulting mixture was extracted successively with methylene chloride and diethyl ether. The combined extracts were dried, filtered, and the solvent was evaporated under reduced pressure, leaving 0.58 g of 4-chloro-2-fluoro-5-(1-methoxyethyl)aniline as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: COP(OC)OC
Reactant: Cc1cccc(CBr)c1
Product: COP(=O)(Cc1cccc(C)c1)OC

Procedure:
Following the procedure of Compound 11, 3-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [O:1]=[C:2]1[CH:23]=[CH:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([NH2:16])=[O:15])[CH3:13])=[CH:3]1.O=C1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(N)=O)C)=C1.O=C1C=C[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=C(C(N)=O)C)=C1>>[O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C:11]2=[C:12]([C:14]([NH2:16])=[O:15])[CH3:13])=[CH:3]1
Reactant: CC(C(N)=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C(N)=O)=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C(N)=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C(N)=O)=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
reacting the carbonyl halide formed in (a) in the presence of a source of ammonia in a sufficient amount, to form the 3-oxo-pregna-1,4-diene-20-carboxylic acid amide; 3-oxo-pregn-4-ene-20-carboxylic acid amide; 3-oxo-pregna-1,4,17(20)-triene-20-carboxylic acid amide; and 3-oxo-pregna-4,17(20)-diene-20-carboxylic acid amide and mixtures thereof thereby obtaining the desired amido-steroid.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([N:11]([S:22]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[C:27]([CH3:34])[C:26]=1[CH3:35])(=[O:24])=[O:23])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[Li].O.Cl>CO.O1CCCC1.O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([CH2:12][N:11]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[C:27]([CH3:34])[C:26]=3[CH3:35])(=[O:24])=[O:23])[C@H:4]([CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:36])=[O:2])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COC(=O)[C@@H](COC(C)(C)C)N(Cc1ccc2[nH]ccc2c1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3[nH]ccc3c2)[C@H](COC(C)(C)C)C(=O)O)c(C)c1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1H-indol-5-ylmethyl]amino}-3-tert-butoxypropionic acid methyl ester (1.0 g, 1.94 mmol) in 50% methanol/tetrahydrofuran (10 mL) was added a solution of LiOH.H2O (160 mg, 3.88 mmol) in water (1 mL). The reaction mixture was heated to 40° C. for 12 h and an additional amount of LiOH.H2O (160 mg, 3.88 mmol) in water (1 mL) was added. After 3 h, the aqueous solution was acidified to pH 3 using 2 N aqueous hydrochloric acid and the product was extracted into ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to afford 2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3-tert-butoxypropionic acid (0.90 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH:44]1([C:50]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH:10][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:9])=[CH:5][CH:6]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)CCCCC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Yield: 49.5 %

Procedure:
24 mg of (1S,2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine obtained in Example 115, 14 mg of monoethyl adipate and 10 mg of 4-dimethylaminopyridine were dissolved in 2 ml of methylene chloride, and 15 mg of 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide hydrochloride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then sequentially washed with a 10% citric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel™ C-200, 1 g, hexane/ethyl acetate=2/1), and 28 mg of the obtained amide compound was dissolved in 1 ml of methanol. Then, 0.5 ml of a 2N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and then subjected to liquid separation by an addition of ethyl ether and water. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off. The residue was treated with a liquid mixture of isopropyl ether and ethyl ether to obtain 16 mg (yield: 49%) of the above-identified compound as white crystalline powder having a melting point of from 123° to 124° C. and
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][NH:32][CH3:33].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:33][N:32]([O:31][CH3:30])[C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: O=C(O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-tritylpiperidine-4-carboxylic acid (7.0 g), O,N-dimethylhydroxylamine hydrochloride (2.0 g) and triethylamine (2.9 ml) in dichloromethane (70 ml) was added WSC (3.97 g), and the mixture was stirred at room temperature for 1 hour and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, dried (MgSO4) and concentrated. The resulting crystals (6.3 g) were washed with isopropylether.
Reaction SMILES: P(=O)(O)(O)O.Cl.O.[NH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[OH-].[NH4+]>C(O)(=O)C.CO>[NH:8]1[CH2:13][CH:12]=[C:11]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 100 °C

Procedure:
50 ml of aqueous N phosphoric acid and 39.3 g of the hydrochloride of 4-piperidone monohydrate were added under nitrogen with stirring to a solution of 10 g of indole in 200 ml of acetic acid at 95°-100° C. and the mixture was heated at 100° C. for an hour and was then cooled. The mixture was poured into ice containing 350 ml of concentrated ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, aqueous sodium chloride, dried over magnesium sulfate and evaporated to dryness to obtain 14.7 g of raw product. The latter was empasted with 75 ml of methanol under nitrogen and was vacuum filtered. The recovered precipitate was rinsed with methanol and ether to obtain 1.42 g of 3-(1,2,3,6-tetrahydro-4-pyridyl)-1-H-indole melting at 185°-186° C. The mother liquor was evaporated to dryness and the raw product was chromatographed over silica gel. Elution with a 6-3-1 chloroform-methanol-triethylamine mixture yielded 4.55 g of product with an Rf=0.15. The latter was empasted with ether to obtain 4.295 g of 3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole for a total yield of 5.715 g of product. The latter was crystallized from hot and cold isopropanol to obtain 3.56 g of 3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole melting at 190°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:8]=[C:9]([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C(=O)O)c2)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ccc(OC)c(CO)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
894 mg of 2-Methoxy-5-[3-(methoxycarbonyl)phenyl]benzoic acid was dissolved in 7 ml of tetrahydrofuran, 0.36 mg of triethylamine and 0.55 ml of ethyl chlorocarbonate were added successively, and the mixture was stirred at room temperature for 15 minutes. The precipitated crystals were filtered, and the filtrate was filtered. 2 ml aqueous solution of 180 mg sodium borohydride was added thereto, and the mixture was stirred at room temperature for 1 hour. 1 N hydrochloric acid was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by a silica gel column, to give 496 mg of the title compound in the 5:3 hexane-ethyl acetate fraction.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]>C1COCC1>[CH3:3][O:5][C:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]
Reactant: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride, 60% dispersion in mineral oil (0.322 g) and methyl iodide (1.00 mL) in 10 mL THF at room temp was carefully added portionwise benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate (1.49 g, 0.00537 mol) in 15 mL THF. The reaction was heated at 50° C. for 18 hours and then it was cooled down to 0° C. and carefully quenched by addition of sat NH4Cl solution, then extracted with EtOAc twice. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chrom to get 1.2 g benzyl 4-(2-methoxypropan-2-yl)piperidine-1-carboxylate as a colorless oil.