Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)N(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C(C)C)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isopropyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([SH:17])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:13][C:14]1[S:17][N:11]=[C:10]([CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: N=C(N)COc1ccccc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(COc2ccccc2)ns1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-phenoxyethanimidamide hydrochloride (2.00 g, 10.7 mmol) and perchloromethyl mercaptan (1.15 ml, 10.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.15 g, 53.7 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.66 g (68.3%) of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=5[CH3:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5c(C)cccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.96 min; Mass spectrum (ESI+): m/z=485 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]([CH2:49][NH2:50])[OH:48]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:50][CH2:49][CH2:47][OH:48])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: NCCO
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1[nH]cc(C(=O)NCCO)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added DIPEA (0.097 ml, 0.553 mmol), HATU (0.168 g, 0.442 mmol) and ethanolamine (0.033 ml, 0.553 mmol) and the reaction stirred at RT for 3 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.06 g, 53% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s., 1H) 7.78 (t, 1H) 7.52 (d, 1H) 4.28 (br. s., 1H) 3.80 (s, 3H) 3.56-3.68 (m, 1H) 3.46 (t, 1H) 3.25 (q, 1H) 3.07-3.21 (m, 1H). MS: m/z 247.0 (M+1).
Reaction SMILES: [CH:1]([O:5][C:6](=[O:26])[CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:3][CH3:4])[CH3:2].[Br-:27].[Li+]>CC(C)=O>[CH:1]([O:5][C:6](=[O:26])[CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:27])([CH2:3][CH3:4])[CH3:2]
Reactant: [Br-]
Reactant: CCC(C)OC(=O)CC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: CC(C)=O
Product: CCC(C)OC(=O)CC(C)CCCCCBr
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
A mixture of 337 mg of 3-methyl-8-(p-toluenesulphonyloxy)octanoic acid sec-butyl ester (prepared as described hereafter), 5 ml of acetone and 156 mg of lithium bromide was stirred at 70° C. for 1.5 hours. After evaporation under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as eluent to give 204 mg of the title compound having the following physical characteristics:
Reaction SMILES: N1C=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)C=1.[NH:18]1C(B(O)O)=CC=[N:19]1>>[NH:18]1[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=[N:19]1
Reactant: OB(O)c1ccn[nH]1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Product: O=Cc1ccc2c(-c3ccn[nH]3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 1H-pyrazole-5-boronic acid (25 mg, 0.22 mmol), the title compound was prepared as a beige solid (5.3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1H), 8.44-8.32 (br. m, 1H), 8.14 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H); MS ESI 213.0 (100) [M+H]+, calcd for [C11H8N4O+H]+ 213.07.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 60.3 %

Procedure:
The mixture of 2-hydroxy-4-fluorobenzaldehyde (10 g, 71.4 mmole), ethyl 4,4,4-trifluorocrotonate (15 mL, 100 mmole), and anhydrous potassium carbonate (14.8 g, 107.1 mmole) in 40 ml dry dimethylformamide was heated to 90° C. for five hours. LC-MS indicated that the reaction was done. After cooling to room temperature, to the reaction was added 500 mL of ethyl acetate. The organic phase was washed with brine (×3), and was then dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:18 EtOAc:hexane. It gave 12.5 g (60%) of a light yellow oil. LCMS(ES+) 291.0(M+1, 100), EIHRMS m/z 290.0586 (M−H, C13H9F4O3 calc'd 290.0566). 1H NMR (CDCl3/300 MHz) 7.73(s, 1H), 7.30-7.22(m, 1H), 6.79-6.73(m, 2H), 5.76(q, 1H, J=6.9 Hz), 4.38(m, 2H), 1.37(t, 3H, J=7.2 Hz). 13C (CDCl3/300MH) 167.2, 164.0, 163.9, 155.0(d, J=13.0 Hz), 136.3 (d, J=1.28 Hz), 131.0(d, J=10.4 Hz), 123.5 (q, J=287.5 Hz), 115.0 (dd, J=2.4, 7.3 Hz), 110 (d, J=22.5 Hz), 104.4(d, J=26.0 Hz), 71.0(q, J=33.2 Hz), 61.7 (d, J=10.4 Hz), 14.4. 19F(CDCl3/300 MHz) −79.0(d, J=6.5 Hz), −104.8 m).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:7]=1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[N:7]=[C:3]([N:2]=[CH:20][O:21][CH2:22][CH3:23])[S:4][CH:5]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Agent: Cl
Product: CCOC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Temperature: 130 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 2-amino-4-(4-cyclohexylphenyl)thiazole hydrochloride (1.0 g) and triethyl orthoformate (5 ml) was stirred at 130° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the remaining crystals was added hexane, followed by filtration. The filtrate was concentrated to give crystals of 4-(4-cyclohexylphenyl)-2-ethoxymethyleneaminothiazole (1.02 g, yield of 95.6 %). Recrystallization from diethyl etherhexane produced yellowish prisms, mp of 84° to 85° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:21][C:10]3=[CH:11][C:12]4[C:13]([CH3:20])([CH3:19])[C:14](=[O:18])[NH:15][C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[CH3:20][C:13]1([CH3:19])[C:12]2[CH:11]=[C:10]3[NH:21][C:7]([C:3]4[C:2]([NH:1][C:22](=[O:24])[CH3:23])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[NH:15][C:14]1=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CC(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.53 mmol) and acetic anhydride. The title compound was obtained as white powder (73 mg).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:17][C:18]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:5][CH2:9][CH:10]([NH:17][C:18]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1-c1ccc(C(=O)NC(CN(C(=O)[O-])C(C)(C)C)c2ccccc2)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)c2ccccc2)s1
Reaction time: 4 h
Yield: 107.6 %

Procedure:
1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate (56 mg, 0.131 mmol) was dissolved in MeOH (2 mL) and treated with excess 4M HCl in dioxane (656 μL, 2.62 mmol). After 4 h, the solution was concentrated affording the title compound (46 mg, quant.) as a yellow solid: LC-MS (ES) m/z 327 (M+H)+, 1H NMR (d6-DMSO, 400 MHz) δ 9.46 (d, J=8.2 Hz, 1H), 8.27 (bs, 1H), 8.20 (d, J=4.0 Hz, 1H), 7.48-7.75 (m, 3H), 7.37-7.40 (m, 2H), 7.31-7.33 (m, 1H), 6.58 (d, J=1.9 Hz, 1H), 5.21-5.30 (m, 1H), 3.97 (s, 3H), 3.36-3.41 (m, 1H), 3.19-3.25 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=[C:6]([OH:13])[N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:10]([C:8]1[C:9]([N+:19]([O-:21])=[O:20])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([OH:13])[N:7]=1)([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cc(C(C)C)nc(O)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(O)nc(C(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49 %

Procedure:
Compound 4 (20 mg) was suspended in a mixture of concentrated sulfuric acid (1 mL) and chloroform (1 mL). To the resulting mixture, fuming nitric acid (166 μL: d=1.50) was added while being stirred and cooled with ice at 5° C. or below. The resulting mixture was allowed to slowly warm to room temperature (20-30° C.), and subsequently kept stirred at room temperature (20-30° C.) overnight. The reaction mixture was poured into ice and neutralized with a 10N aqueous sodium hydroxide solution to a pH of approx. 5 (at 20° C. or below). The mixture was extracted twice with chloroform and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 to 10:1) to give 17.8 mg (49% yield) of the desired product as a brown amorphous.
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:22][C:21](S(C)=O)(SC)[CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl(O)(=O)(=O)=[O:29]>CCOCC.O>[Si:5]([O:18][CH:19]1[CH2:22][C:21](=[O:29])[CH2:20]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CSC1(S(C)=O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1CC(=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of tert-butyl {[3-(methylsulfinyl)-3-(methylthio)cyclobutyl]oxy}diphenylsilane (17.05 g, 40.7 mmol, from Step 2) in ether (350 mL) cooled to 0° C. was treated with a solution of 6 M perchloric acid in water (10 mL) that was pre-diluted with water (7 mL). The bath was removed and stirred overnight. The mixture was poured into pH 7 buffer, and the product was extracted with diethyl ether. The combined extracts were dried over sodium sulfate, decanted and concentrated. The reaction was performed again on the same scale and the two batches were combined for purification. Flash chromatography, eluting with a gradient from 0-5% ethyl acetate/hexanes afforded desired product (15.7 g, 59%). 1H NMR (300 MHz, CDCl3): δ 7.75-7.62 (m, 4H), 7.49-7.33 (m, 6H), 4.59 (tt, 1H), 3.22-3.03 (m, 4H), 1.07 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15]Br>C(Cl)Cl>[Br:15][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 1-(4-methyl-3-nitrophenyl)propan-1-one (6.6 g, 34.1 mmol) in CH2Cl2 (200 mL) is added bromine (34.1 mmol) dropwise over 20 minutes. The reaction is stirred for 4 hours at room temp. and then washed with sat. aqueous NaHCO3 (100 mL), organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness to afford 9.0 g (97%) of the title compound as an orange oil: Rf 0.53 (1:1 CH2Cl2:hexanes).
Reaction SMILES: C(O)(C)(C)C.[C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19])C(O)=O)#[N:7].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH2:35][C:10]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:8]([CH:9]=1)[C:6]#[N:7]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1C#N
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(N)cc1C#N
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To tert-butyl alcohol containing 3-cyano-4-isobutylbenzoic acid (8.5 g) and triethylamine (4.2 g) was added diphenylphosphoryl azide (11.5 g) at room temperature and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added 6N hydrochloric acid (10 ml) and methanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (6.0 g), melting point: 68° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCCN1CC(Cc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CC(Cc2ccc(Cl)cc2)C1
Reaction time: 1.25 h

Procedure:
A solution of {3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-carbamic acid tert-butyl ester (0.48 g, 1.43 mmol) in DCM (5 ml) is treated with trifluoroacetic acid (2 ml) and the reaction mixture stirred for 1.25 hours. The solvent is evaporated and the crude product partitioned between 1 M sodium hydroxide solution and 20% isopropanol in DCM. The organic phase is evaporated to afford 3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propylamine. [M+H] 239.13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:15][CH:14]=1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
α-(1-t-Butoxyformamido)-p-toluic acid and β-alanine benzyl ester are coupled to give N-[α-(1-t-butoxyformamido)-p-toluoyl]-β-alanine benzyl ester, m.p. 113°-116° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10](=[O:19])[C:9](=[N:20]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1>O>[C:9]([CH2:8][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]=1[C:10]([OH:19])=[O:29])#[N:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOc1cc2c(cc1OC)CC(=NO)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(C(=O)O)c(CC#N)cc1OC
Temperature: 50 °C
Yield: 44.4 %

Procedure:
To a solution of NaOH (5.15 g, 129.2 mmol) in H2O (100 ml) was added 5-Methoxy-6-(2-methoxy-ethoxy)-indan-1,2-dione 2-oxime (9.0 g, 34 mmol), and the mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (8.5 g, 44.2 mmol) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooling to room temperature, the precipitate (a little) was filtered. The filtrate was acidified by concentrated HCl to PH=3-4, and the precipitate was collected and dried to give product (4.0 g, 44.1%). LC-MS: m/e 265 (M−1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile (5.00 g, 18.7 mmol), methyl bromoacetate (3.25 mL, 37.5 mmol), and Cs2CO3 (12.2 g, 37.3 mmol) in acetonitrile (50 mL) was held at reflux, under N2, for 2 h and cooled to rt, and solids were removed by filtration. The filtrate was adsorbed onto a minimal amount of silica gel, filtered through a short pad of silica gel (EtOAc/hexanes) and concentrated to dryness. Recrystallization from EtOAc/hexanes afforded 4.72 g of the title compound as fine needles, mp 144-145° C.: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.9 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 6.88 (dd, J=2.6 Hz, 1H), 4.24 (s, 2H), 4.06 (q, J=8.5 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:15][OH:16])[NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18]=O>CO>[CH3:1][O:2][C:3](=[O:17])[CH:4]([N:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:18])[CH2:15][OH:16]
Reactant: COC(=O)[C@H](CO)NCCCc1ccccc1
Reactant: C=O
Solvent: CO
Product: COC(=O)C(CO)N(C)CCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-(3-phenylpropyl)serine methyl ester (6.4 g, 0.027 mol) in methanol (150 ml) is added with 10% Pd-on-carbon (0.7 g) and 40% formic aldehyde (3.0 ml 0.04 mol) dissolved in methanol (50 ml). The mixture is stirred at room temperature under hydrogen atmosphere, under a slight pressure (40 psi) until the absorption ceases. The mixture is filtered and the filtrate is evaporated under vacuum. The residue is taken up in ethyl ether (300 ml), washed with water (2×200 ml), dried over sodium sulfate and evaporated under vacuum. Yield: 6.6 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]2[CH:16]=[C:17]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH:12]=1)[C:5]([OH:7])=O.[CH3:26][NH2:27].O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]2[CH:16]=[C:17]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH:12]=1)[C:5]([NH:27][CH3:26])=[O:7]
Reactant: CN
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)cc4Cl)c3c2)o1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)c(Cl)c1
Yield: 21 %

Procedure:
In the same manner as in Example 117 and using 3-chloro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and using 2M methylamine-tetrahydrofuran solution instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 21%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[C:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(C#Cc2sccc2S(C)(=O)=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
450 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulfonyl)-2-thienyl]-1-ethynyl]piperidine and 250 mg of 10% palladium-carbon powder (water-containing product) were suspended in 10 ml of ethanol. After replacing the atmosphere of a container with hydrogen, the mixture was stirred at room temperature under normal pressure for 8 hours. The reaction solution was filtered, and the filtrate was evaporated, to give the title compound as a yellow oil (quantitatively).