Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2]/[C:3](/[NH:12][C:13]([NH2:15])=[O:14])=[C:4](\[C:10]#[N:11])/[C:5](OCC)=[O:6].Cl>[OH-].[Na+]>[C:10]([C:4]1[C:5](=[O:6])[NH:15][C:13](=[O:14])[NH:12][C:3]=1[CH2:2][Cl:1])#[N:11]
Reactant: CCOC(=O)/C(C#N)=C(/CCl)NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(CCl)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Dissolved in 17 ml of a 2N aqueous solution of sodium hydroxide were 3.88 gof the ethyl 4-chloro-2-cyano-ureidocrotonate (22) obtained in Referential Example 5. The resulting mixture was stirred at room temperature for 1 hour and under ice cooling, was neutralized with 2N hydrochloric acid. A crystallized matter was collected by filtration, whereby 1.16 g of the title compound were obtained (yield: 37%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35]C)=[O:34])[CH2:30]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].[OH-].[Na+].C(O)(=O)C.C(O)(=O)C(O)=O>O1CCOCC1.CO.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1
Yield: 75.4 %

Procedure:
To a solution of methyl 1-[(4-ethyl-5-{5-[4-(2-methoxyphenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (86 mg, 0.17 mmol) that was obtained in Example 21 (21c) in dioxane (3 ml) was added a 1N aqueous solution of sodium hydroxide (0.51 ml, 0.51 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, acetic acid (29 μl, 0.51 mmol) was added to the reaction mixture to quench the reaction, and the resulting mixture was evaporated in vacuo. Subsequently, to the residue obtained were added successively methanol (2 ml) and water (1 ml) with stirring, and furthermore a solution of oxalic acid (8 mg, 0.09 mmol) in methanol (0.5 ml) was added, and then the resulting mixture was stirred for 30 minutes. The white solid precipitated was collected by filtration using a Kiriyama funnel, washed with a mixed solvent of water and methanol (3:7) and dried in vacuo to afford the title compound (63 mg) in a yield of 69% as a white crystalline solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:15][NH:16][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:21]5[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=5)[CH:25]=4)[CH2:13][CH2:14]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 49 %

Procedure:
This compound was synthesized from (1-(4-phenylthiazol-2-yl)cyclopropyl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (47 mg, yield 49%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.23 (m, 2H), 8.09-8.07 (m, 1H), 7.90-7.88 (m, 2H), 7.63-7.59 (t, J=7.9 Hz, 1H), 7.41-7.38 (m, 2H), 7.35-7.33 (m, 1H), 7.32 (s, 1H), 3.93 (d, J=5.5 Hz, 2H), 1.42-1.39 (m, 2H), 1.23-1.20 (m, 2H). MS (ESI) m/z: Calculated for C23H17F3N4O2S: 470.10. found: 471.0 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]#[N:13])[O:7]1)(=O)C.CCN(CC)CC>CO>[OH:4][CH2:5][C@H:6]1[O:7][C@@H:8]([C:12]#[N:13])[CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)OC[C@@H]1CCC[C@H](C#N)O1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#C[C@H]1CCC[C@@H](CO)O1
Temperature: 23 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To ((2S,6R)-6-cyanotetrahydro-2H-pyran-2-yl)methyl acetate (3.90 g, 21.29 mmol) in methanol (300 mL) was added Et3N (30 mL). The reaction mixture was stirred at 23° C. for 18 h. The solvents were evaporated in vacuo. The residue was redissolved in methanol the solvent removed in vacuo (2×20 mL). The crude material was then purified on a silica gel column (Biotage flash chromatography system) eluting with a gradient mixture ethyl acetate (100%) to ethyl acetate:methanol (8:2) to afford 2.20 g (73% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 4.31 (1 H, dd, J=11.6, 2.5 Hz), 3.58-3.63 (2 H, m), 3.51-3.57 (1 H, m), 2.06 (1 H, s), 1.94-2.03 (2 H, m), 1.79-1.90 (1 H, m), 1.53-1.65 (2 H, m), 1.36-1.47 (1 H, m).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[S:37][C:38]([CH2:42]O)=[C:39]([CH3:41])[N:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:42][C:38]3[S:37][C:36]([CH3:35])=[N:40][C:39]=3[CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(C)c(CO)s1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c(COc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)s1
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (2,4-dimethylthiazol-5-yl)methanol (22.92 mg, 0.160 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (17.7 mg, 0.031 mmol, 58.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.29-7.21 (m, 1H), 7.14-7.01 (m, 3H), 5.84 (s, 1H), 5.36-5.15 (m, 2H), 3.27 (d, J=7.7 Hz, 1H), 2.79 (t, J=11.9 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.18 (d, J=12.5 Hz, 1H), 2.06 (s, 3H), 1.96-1.87 (m, 1H), 1.49 (br. s., 1H), 1.36-1.25 (m, 1H), 1.18 (d, J=12.8 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=11.7 Hz, 1H), 0.85 (br. s., 3H), 0.59 (br. s., 3H). LCMS (M+H)=566.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.N>O>[C:7]1([N:5]2[N:6]3[C:16](=[O:15])[CH:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:1]=[C:2]3[CH:3]=[CH:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccn(-c2ccccc2)n1
Agent: N
Solvent: O
Product: O=c1cc(-c2ccccc2)nc2ccn(-c3ccccc3)n12
Reaction time: 1.5 h

Procedure:
A mixture of 10 g. of 5-amino-2-phenylpyrazole (0.063 mol.), 12.1 g. of benzoylacetic acid ethyl ester (0.063 mol.) and 50 g. of polyphosphoric acid is heated at 110°-120° with stirring for 90 minutes. After cooling, 200 ml. of water and then concentrated aqueous ammonia is added under external cooling to adjust the mixture to pH 9. The collected 1,5-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one is washed with water and dried at 70°, yield: 17 g. (94%); m.p. 194°-200°. A sample, recrystallized from absolute ethanol, melts at 205°-207°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:16]([OH:18])=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8]([CH2:7][CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:16]2=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)NC1Cc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of N-methoxycarbonyl-O-methyl-L-tyrosine (0.5 g) in dichloromethane (2 ml) was added thionyl chloride (0.29 ml). After stirring for 1 hour at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and treated with 0.9M ethylaluminum dichloride in dichloromethane (4.4 ml) in an ice-bath. The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured into concentrated hydrochloric acid containing crashed ice and extracted once with dichloromethane. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; 10:1 dichloromethane-ethyl acetate) gave 6-methoxy-2-(methoxycarbonylamino)indan-1-one (0.12 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:31])([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>>[ClH:32].[CH3:29][C@@H:24]1[C:23](=[O:30])[NH:22][N:21]=[C:20]2[N:25]1[C:26]1[CH:27]=[C:28]3[N:12]([C:10]4([CH3:31])[CH2:9][NH:8][CH2:11]4)[CH2:13][CH2:14][C:15]3=[CH:16][C:17]=1[O:18][CH2:19]2
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CN(C(=O)OC(C)(C)C)C1)CC4
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CNC1)CC4
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of 3-methyl-3-((R)-1-methyl-2-oxo-1,2,3,5,8,9-hexahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, 0.04 g, 0.094 mmol) in HCl (4M in EtOAc, 5 mL) was stirred at ambient temperature for 20 min. The solvent was removed in vacuo to give (R)-1-methyl-10-(3-methyl-azetidin-3-yl)-3,5,9,10-tetrahydro-8H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloride (0.026 g, 0.079 mmol, 85%). 1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H), 6.78 (s, 1H), 5.80 (s, 1H), 4.98 (m, 1H), 4.45 (s, 2H), 4.11 (m, 4H), 3.30-3.20 (m, 2H), 2.74 (m, 2H), 1.39 (s, 3H), 1.20 (d, J=6.4 Hz, 3H). LC/MS (Table 1, Method 41) Rt=2.422 min; MS m/z: 328 [M+H]+. SFC (Table 1, Method 37) Rt=10.675 min.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])(=[O:6])=[O:5].[Cl:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[C:19](Cl)[N:18]=[C:17]([S:25][CH3:26])[N:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[Cl:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[C:19]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=2)[N:18]=[C:17]([S:25][CH3:26])[N:16]=1
Reactant: CSc1nc(Cl)c(C(N)=O)c(Cl)n1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)n1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 mL), a mixture of 3-(methylsulfonyl)aniline (1.44 g) and THF (20 mL) were added under ice cooling and stirred for 30 minutes under ice cooling. After dropwise addition of a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxamide (2.0 g) and DMF (30 mL) over 15 minutes, the reaction liquid was further stirred under ice cooling for 15 minutes. After addition of 10% aqueous citric acid (300 mL) and extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was concentrated, and the precipitated solid was collected by filtration and dried to give 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (1.95 g) as a light yellow solid.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][N:5]2[CH2:4][CH2:3][S:2][CH2:7][CH2:6]2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1CCSCC1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCSCC1
Yield: 37.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-thiomorpholinoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 83, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-thiomorpholinoacetyl)pyrrolidine-2-carboxamide (13.9 mg, 37.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.54 (d, 2H), 7.27 (m, 2H), 7.21-7.16 (m, 7H), 6.93 (m, 2H), 4.44 (m, 1H), 3.71 (m, 1H), 3.28 (m, 1H), 3.13 (m, 2H), 2.87 (m, 4H), 2.63 (m, 3H), 2.55 (m, 4H), 1.85 (m, 2H). MS (EI) for C30H32FN3O3S. found 534.7 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=S)[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[NH3:18]>>[NH2:18][C:10]1[CH:9]2[CH2:15][CH2:16][CH2:17][CH:8]2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=2[N:11]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NC(=S)C1CCCC21
Reactant: N
Product: NC1=Nc2cc([N+](=O)[O-])ccc2C2CCCC12

Procedure:
7-Nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (47 mg, 0.19 mmol) is stirred in 7N methanolic ammonia (10 ml) for 15 hours at room temperature. The batch is concentrated by evaporation in a vacuum. The residue is purified on silica gel with dichloromethane-2-propanol/methanol: 21 mg (48%) of product.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)N1CC(Oc2ccc(Cl)cc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cl)ccc1OC1CN(C(=O)CCC(=O)O)C1
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a stirred solution of methyl 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutanoate (236 mg, 0.67 mmol) obtained in Example 188 in THF (5.0 ml) was added lithium hydroxide (1.0M aqueous solution, 5.0 mL, 5.0 mmol) at room temperature. After 3 hr, the reaction mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (222 mg, 98%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/OC(=O)COCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol) and benzyloxyacetylchloride (0.029 ml, 0.18 mmol) were added into dichloromethane (5.0 ml). Then, at 0-5° C. triethylamine (0.026 ml, 0.18 mmol) was added, stirred for 15 minutes so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using diisopropylether. As a result, 40.7 mg of the present compound (productive yield 56%) was obtained as a white solid crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10]([C:19]([F:22])([F:21])[F:20])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:19]([F:22])([F:20])[F:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O)CC(C(F)(F)F)=NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 65 °C
Yield: 77 %

Procedure:
Sulfuric acid (concentrated, 2 drops) was added to ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) and the mixture was warmed to 65° C. for about 1 hour. The mixture was allowed to cool to 25° C. and most of the acetic acid was removed under reduced pressure. The mixture was partitioned between saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL). The combined organic extracts were dried and evaporated to give the product as an oil (0.66 g, 77% yield).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:14])[CH:12]=[CH2:13]>O1CCCC1>[C:4]1([CH:3]=[CH:2][CH2:1][NH:14][CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCN
Reactant: BrCC=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCNCC=Cc1ccccc1
Reaction time: 20 h
Yield: 82 %

Procedure:
A solution of cinnamyl bromide (10 g, 50.7 mmol) in 250 mL tetrahydrofuran was added dropwise to a solution of allyl amine (38 ml, 507 mmol) in 50 mL tetrahydrofuran at 0° C. the mixture was allowed to slowly come to room temperature then stirred 20 hours. The tetrahydrofuran was removed in-vacuo, and the residue was partitioned between 500 mL of ethyl acetate and 200 ml of water. The layers were separated, the organic phase was washed with water followed by brine, then dried over sodium sulfate and concentrated to an amber oil. The oil was purified by flash chromatography on an 8×15 cm silica column, eluting with 5% methanol/chloroform followed by 10% methanol/chloroform. Obtained 7.2 g of an amber oil as product. Yield=81%. NMR (300 MHz, CDCl3) δ7.39-7.20 (m, 5H), 6.54 (d, 1H, J=16 Hz), 6.35-6.26 (m, 1H), 6.01-5.87 (m, 1H), 5.24-5.14 (m, 2H), 3.43 (d, 2H, J=7 Hz), 3.31 (d, 2H, J=6 Hz).
Reaction SMILES: [O:1]1[C:5]([C:6]2[O:7][C:8]([CH3:13])=[C:9]([CH2:11]Cl)[N:10]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:20]=1>>[O:1]1[C:5]([C:6]2[O:7][C:8]([CH3:13])=[C:9]([CH2:11][O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:23][CH:24]=3)[N:10]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: Cc1oc(-c2cc3ccccc3o2)nc1CCl
Reactant: N#CCCCc1ccc(O)cc1
Product: Cc1oc(-c2cc3ccccc3o2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 2-(benzo[b]furan-2-yl)-4-chloromethyl-5-methyloxazole was allowed to react with 4-(4-hydroxyphenyl)butyronitrile to give 4-[4-[2-(benzo[b]furan-2-yl)-5-methyl-4-oxazolylmethoxy]phenyl]butyronitrile. Recrystallization from dichloromethane--isopropyl ether gave colorless prisms, m.p.118°-119° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([I:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])=[O:5].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[I:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[NH:1][C:18](=[O:20])[N:6]([CH2:7][CH2:8][CH2:9][S:10][CH3:11])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSCCCNC(=O)c1cccc(I)c1N
Solvent: ClCCl
Product: CSCCCn1c(=O)[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Yield: 319 %

Procedure:
To a 100 mL round-bottomed flask was added 2-amino-3-iodo-N-(3-(methylthio)propyl)benzamide (1.25 g, 3.57 mmol) and triphosgene (0.185 mL, 1.25 mmol, Sigma Aldrich) in DCM (20 mL). The reaction was heated to reflux for 15 h, and then cooled to RT. The solvent was removed to give the crude product 1.5 g. MS (ESI, pos. ion) m/z: 376.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>CC(O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([O:13][CH:24]([CH3:29])[CH3:25])[CH2:11][CH3:12])[C:7]([C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCC(OC(C)C)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 312 h
Yield: 38.5 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (394 mg, 1.23 mmol) in 2-propanol (2 mL) at room temperature was treated with p-toluenesulfonic acid monohydrate (75.3 mg, 0.39 mmol) and the reaction was stirred for 13 d at r.t. The reaction mixture was diluted with water and EtOAc and basified to pH 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20 g of silica gel, EtOAc/hexanes (0:1→3:7)) to give the title product (48 mg, 12%). as colorless crystals. m.p.: 54-56° C., ESI-MS: m/z 320 [M+H]+.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[N:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:14]=[N:15][CH:16]=1
Reactant: N#Cc1cccnc1F
Reactant: Oc1cncc(Cl)c1
Product: N#Cc1cccnc1Oc1cncc(Cl)c1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 5-chloro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 232 (M)+, 234(M+2)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS:559.6 (M+H)+