Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[OH:32][CH2:31][CH2:30][CH2:29][NH:28][S:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: NCCCO
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCCO)c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 4-({4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)benzenesulfonyl chloride (0.10 g, 0.25 mmol) in 2 ml of ethyl acetate is added 3-amino-1-propanol (0.19 g, 2.5 mmol) with stirring, at 0° C. The mixture is stirred at room temperature for 1 hr and then quenched with water (10 ml). The ethyl acetate is evaporated, the resulting suspension is filtered, and the precipitate is washed with water, and hexanes, and then dried in vacuo to give 0.10 g of a white solid; mp 204-205° C.; HRMS: calcd for C20H19F3N4O3S, 452.1130; found (ESI-FTMS, [M+H]1+), 453.12161.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4](=[O:24])[CH2:3]1.C[Li].[CH2:27](OCC)C>C1COCC1>[OH:24][C:4]1([CH3:27])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:10]=2[C@H:2]([CH3:1])[CH2:3]1
Reactant: CCOCC
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li]C
Solvent: C1CCOC1
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.120 mmol; see Example 3, Step 8) in THF (4 mL) was added to a 1.5M solution of methyllithium in diethyl ether (0.088 mL, 0.132 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and quenched by saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×). The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a solid (29 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 349.1; Retention time: 2.49 minutes.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[N:12][CH:13](Cl)[C:14]([Cl:17])([Cl:16])[Cl:15])[C:10](=[O:19])[N:9]([CH3:20])[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)C>C(#N)C>[C:1]1([N:7]2[C:11](=[N:12][CH:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([Cl:17])([Cl:16])[Cl:15])[C:10](=[O:19])[N:9]([CH3:20])[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)(Cl)Cl)N(c2ccccc2)C1=O
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN1C(=O)C(=NC(Nc2ccccc2)C(Cl)(Cl)Cl)N(c2ccccc2)C1=O
Reaction time: 5 h

Procedure:
In this Example 1-phenyl-3-methyl-5-(1,2,2,2-tetrachloroethyl)imino-1,3-diazolidine-2,4-dione (0.02 mol) was dissolved in 20 ml of acetonitrile and 0.02 mol of aniline then added. A mild exothermic reaction was observed. After ten minutes, triethylamine was added causing a very exothetmic reaction, which subsided within an hour to occur. The mixture was stirred for five hours and then 20 ml of ethyl ether added to assist precipitation of salts. The mixture was filtered and the filtrate evaporated off under high vacuum affording 1-phenyl-3-methyl-5-(1-phenylamino-2,2,2-trichloroethyl)imino-1,3-diazolidine-2,4-dione oil (Anal. calcd. for C18H15Cl3N4O2 --C50.79, H3.55, Cl24.98, N13.16 found C51.6, H3.8, Cl26.54, N12.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].ClCCCN(CC)CC.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:22][CH3:21])[CH2:18][CH3:19])[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Agent: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
The N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea (150 mg) synthesized in Example 142 was dissolved in dimethylformamide (2.5 ml), and then potassium carbonate (150 mg) and 1-chloro-3-(diethylamino)propane (80 mg) were added and the mixture was heated and stirred at 60° C. for 2 hours. After cooling, water was added, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (10 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:7]=1
Reactant: Nc1cc(Br)nc(Cl)c1OC(F)F
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COc1c(Cl)ccc(-c2cc(N)c(OC(F)F)c(Cl)n2)c1F
Yield: 84.2 %

Procedure:
6-Bromo-2-chloro-3-(difluoromethoxy)pyridin-4-amine (368 mg, 1.346 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (395 mg, 1.615 mmol), PdCl2(PPh3)2 (47.2 mg, 0.067 mmol), and CsF (409 mg, 2.69 mmol) were combined in DME (2 mL) and H2O (2 mL) and heated in a Biotage microwave reactor at 110° C. for 15 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried, concentrated onto silica gel, and purified by flash chromatography (SiO2, EtOAc/hexane gradient). This process yielded the title compound as a white solid (0.4 g, 84%): mp 152-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.50 (m, 1H), 7.42 (dd, J=8.7, 1.6, 1H), 7.16 (d, J=1.8, 1H), 7.02 (t, J=73.4, 1H), 6.70 (s, 2H), 3.93 (d, J=0.8, 3H); ESIMS m/z 354 ([M+H]+), 352 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[C:5](=[S:13])[NH:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2S[C:25]([CH:27]=O)=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].NCCC(O)=[O:33].CO.C(Cl)Cl>C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2[O:33][C:25]([CH:27]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[C:5](=[S:13])[NH:4]3)=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCC(C(=O)O)N1C(=O)CNC1=S
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)s1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCC(C(=O)O)N1C(=O)C(=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.130 g, 0.643 mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.155 g, 0.643 mmol) in acetic acid 5 mL is added β-alanine (5.72 mg, 0.064 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060 g, 0.141 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.97 (d, J=2.1 Hz, 1H), 7.68 (dd, J=8.4, 2.1 Hz, 1H), 7.49 (d, J=4.8 Hz, 1H), 7.02 (m, 2H), 6.48 (s, 1H), 5.31 (dd, J=11.1, 5.4 Hz, 1H), 2.32 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS (ES−, m/z): 423.3 (M−, 100.0).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[NH3:12].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][S:8]([NH2:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)CCc1cccs1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)CCc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of crude 2-thiophen-2-yl-ethanesulfonyl chloride (25 g) in THF (400 ml) was treated with sat. aq. ammonia (60 ml) at 0° C. The mixture was stirred at rt for 16 h before it was neutralised with 25% aq. HCl (60 ml). Bulk of the THF was evaporated. The aq. solution was extracted twice with EA. The organic phase was washed with water and evaporated. The remaining oil was purified by chromatography on silica gel eluting with heptane:EA 1:1. The product was further purified by recrystallisation from diethyl ether/pentane to give 2-thiophen-2-yl-ethanesulfonic acid amide (8.46 g) as off-white crystals. 1H-NMR (300 MHz, CDCl3): 3.36–3.50(m, 4H), 4.54(s br, 2H), 6.89–6.92(m, 1H), 6.95(dd, J=3.5, 5.1, 1H), 7.20(dd, J=1.1, 5.0, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:31])([CH2:25][N:26]1[CH:30]=[N:29][N:28]=[N:27]1)[C:10]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][O:22][CH2:23][CH3:24])=[CH:15][N:14]=1)([F:12])[F:11]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:31])([CH2:25][N:26]1[CH:30]=[N:29][N:28]=[N:27]1)[C:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:15][N:14]=1)([F:11])[F:12]
Reactant: CCOC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1-(5-(3-ethoxyprop-1-en-1-yl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (51; 80 mg, 0.21 mmol) in EtOH (10 mL) was added 10% Pd/C (8 mg), and the mixture was stirred under hydrogen atmosphere for 2 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of Celite®, and the Celite® cake was washed thoroughly with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexanes) afforded 53 (65 mg, 0.14 mmol, 68%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.36 (s, 1H), 7.88 (s, OH, 7.64 (dd, J=8.0, 2.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.37-7.32 (m, 1H), 6.77-6.73 (m, 1H), 6.67-6.63 (m, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.09 (d, J=14.0 Hz, 1H), 3.46 (q, J=7.0 Hz, 2H), 3.39 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 1.90-1.85 (m, 2H), 1.20 (t, J=7.0 Hz, 3H). MS (ESI): m/z 440 (M+H)+. HPLC: 95%.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:29]1[NH:30][C:31]2[C:27]([C:28]=1[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:32]=2
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: COc1ccc2c(CCNC(C)=O)c[nH]c2c1
Product: COc1ccc2c(CCNC(C)=O)c(C(C3=C(O)C(c4ccccc4)CC3=O)c3ccccc3)[nH]c2c1

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(6-methoxy-1H-indol-3-yl)-ethyl]-acetamide (Lit. 7) to give the title compound as a pale red solid. MS: 495.5 ([M+H]+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCOc1ccc(CCCCCC(=O)O)cc1
Yield: 94.2 %

Procedure:
This compound was synthesized from 6-(p-butoxyphenyl)-5-hexenoic acid (2.62 g, 10 mmol) by a hydrogenation reaction using Pd/C (260 mg). Crystallization (petroleum ether) afforded the product (2.49 g, 94%) as white crystals (mp 39-40° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 0.96 (t, 3H), 1.35 (m, 2H), 1.50 (m, 2H), 1.62 (m, 4H), 1.75 (m, 2H), 2.35 (t, 2H), 2.52 (t, 2H), 3.92 (t, 2H), 6.95 (q, 4H), 10.30 (bs, 1H). Anal. Calcd. for C16H24O3 : C, 72.69, H, 9.15%; Found: C, 72.78, H, 9.18%.
Reaction SMILES: [Li]CCCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.O=[C:14]1CC[CH2:16][CH:15]1[C:19]([O:21][CH3:22])=[O:20].CI>C1COCC1.COCCOC>[CH3:22][O:21][C:19]([C:15]1[CH2:16][CH2:12][CH:10]([CH3:11])[CH:14]=1)=[O:20]
Reactant: COC(=O)C1CCCC1=O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1=CC(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
The intermediate 3-methyl-cyclopent-1-enecarboxylic acid methyl ester was prepared as described below: n-BuLi (40.00 mL, 2.5 M in hexane, 100.00 mmol) was added to diisopropylamine (15.00 mL) in THF at 0° C. After 10 minutes, commercially available methyl 2-oxocyclopentanecarboxylate was added. The reaction mixture was stirred at 0° C. for another 10 minutes, then methyl iodide was added. The resulting reaction mixture was allowed to warm to room temperature over 20 minutes, then quenched with 2N HCl (50 mL). The mixture was extracted with ether, and the combined ether layers were washed with brine, then dried over magnesium sulfate and concentrated. 5.43 g of the methylated ester was dissolved in ethylene glycol dimethyl ether (DME) and cooled to −78° C., then Li(TMS)2N (42.00 mL, 1.0 M in THF, 42.00 mmol) was added. After 60 minutes, the reaction mixture was transferred to Cp2ZrHCl in DME at 0° C. Stirring was continued for another 60 minutes and then the reaction mixture was concentrated. Chromatography (5% EtOAc/hex) gave 1.40 g (29%) of 3-methyl-cyclopent-1-enecarboxylic acid methyl ester. This ester was converted to the final thiourea in accordance with General Procedure G. The intermediates 3-methyl-cyclopent-1-enecarboxylic acid methyl ester and 1-azidomethyl-3-methyl-cyclopentene were isolated and characterized as follows:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:37])[CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)CCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxy-phenyl)-3-phenyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C28H30O6 [M+NH4]+: 485 [M+H]+: 463.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 61.0 mg, 0.141 mmol) was dissolved in methylene dichloride (2 mL), methanesulfonyl chloride (26 μL, 0.34 mmol) and triethylamine (92 μL, 0.66 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (58.0 mg) as a pale pink solid. (Yield 82%)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18]([Cl:22])[CH:19]=2)[CH:14]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[ClH:22].[ClH:22].[Cl:22][C:18]1[CH:19]=[C:20]2[O:21][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:14][C:15]2=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1cnc2cc([C@@H]3CCCN3)oc2c1
Reaction time: 1 h

Procedure:
To a 2 g sample of the compound from step 7b above in 10 mL of CH2Cl2 at 0° C. was added 10 mL of TFA, and the reaction mixture was stirred for 1 hour, poured into saturated aqueous Na2CO3 and extracted with CH2Cl2. The organic extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 99:1 to 95:5 CHCl3 :MeOH. The product was treated with HCl/ether, and the salt was recrystallized from EtOH/EtOAc to give 1.2 g of title compound: 1H NMR (D2O, 300 MHz) δ 2.18-2.50 (m, 3H), 2.54-2.65 (m, 1H), 3.51-3.36 (m, 2H), 5.06 (t, 1H, J=8 Hz), 7.26 (d, 1H, J=0.7 Hz), 8.24 (dd, 1H, J=0.7, 1.8 Hz), 8.60 (d, 1H, J=1.8 Hz); MS m/z: 223 (M+H)+, 240 (M+NH4)+ ; Anal. Calcd for C11H11N2OCl.2.0 HCl: C, 44.69; H, 4.43; N, 9.47. Found: C, 44.57; H, 4.31; N, 9.33.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of benzyl chloride was added to the mixture and the liquid was refluxed for 4 hours. Then, 1.2 g of sodium hydroxide was further added to the mixture, the liquid was refluxed for 2 hours, and the reaction liquid was put into 1N hydrochloric acid, and the precipitate was recovered by filtration, washed with water, methanol and n-pentane in succession and recrystallized from a mixed solvent of benzene and tetrahydrofuran to obtain 2.7 g of 4-benzyloxy-3-chlorobenzoic acid. Then, 15 g of thionyl chloride was added to 2.7 g of this 4-benzyloxy-3-chlorobenzoic acid, and the mixture was reacted under reflux and reacted for 3 hours. Unreacted thionyl chloride was removed by distillation under reduced pressure. Thus, 4-benzyloxy-3-chlorobenzoic acid chloride was quantitatively obtained.
Reaction SMILES: O[Li].O.[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[CH:11]2)#[N:5]>O.C1COCC1>[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2)#[N:5]
Reactant: CCOC(=O)Cn1ccc2cccc(C#N)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc2ccn(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of LiOH.H2O (1.4 g, 34.06 mmol, 3.0 equiv.) in water (10 ml) was added at 0° C. to a solution of ethyl 2-(7-cyano-1H-indol-1-yl)acetate (2.6 g, 11.37 mmol, 1.0 equiv.) in THF, and the mixture was stirred for 2 h at RT. When the reaction was complete (TLC monitoring), the mixture was concentrated under vacuum and the residue was taken up in water (50 ml). Extraction with ethyl acetate (50 ml) was carried out, and then the aqueous phase was adjusted to pH≈3-4 with 10% HCl solution. Extraction with DCM (2×50 ml) was then carried out, and the combined organic phases were washed with sat. NaCl solution, dried over Na2SO4 and concentrated under vacuum. The desired product was isolated in the form of a light-yellow solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:25])[C:20]=1[S:21](Cl)(=[O:23])=[O:22])=[O:15])[CH3:12]>C(#N)C>[OH-:1].[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:25])[C:20]=1[S:21]([NH:3][C:2]([N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:1])(=[O:23])=[O:22])=[O:15])[CH3:12]
Reactant: N#C[O-]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)[n+]1ccccc1
Product: [OH-]
Temperature: 40 °C

Procedure:
1.08 g (16.6 mmole) of anhydrous sodium cyanate, 1.25 g (15.8 mmole) of dry pyridine and 20.0 g of dry acetonitrile were mixed together and the resulting mixture was then stirred under nitrogen atmosphere while maintaining the temperature of 40° C. To this mixture was added 3.80 g (15.0 mmole) of 4-ethoxycarbonyl-1-methylpyrazole-5-sulfonylchloride over one hour. The reaction mixture was then stirred for further 2 hours while maintaining the temperature of 40° to 45° C. to complete the reaction. After the reaction was completed, the reaction solution was filtered under nitrogen atmosphere. The solvent and the remaining pyridine were removed from the filtrate at normal temperature by means of a vacuum pump to obtain the crude product which was then washed with 10.00 g of dry ethyl ether and dried to obtain 4.68 g (Yieid 92%) of the title compound as the white solid.