Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=C[C:40]([O:43]C)=CC=2N=1>>[CH3:40][O:43][C:4]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc2sc(I)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: COc1ccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc2c1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5-methoxy-1,3-benzothiazole and conducting the Suzuki coupling at 55° C. for 4 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.75 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.21 (dd, J=2.4, 8.8 Hz, 1H), 4.67 (m, 1H), 3.94 (s, 3H), 3.59-3.62 (m, 2H), 3.25-3.27 (m, 2H), 2.34-2.39 (m, 4H). MS(ES+): m/z=407.13 [MH+]. HPLC: tR=1.12 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Ca+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[CH:10]([CH:22]1[CH2:27][C:26](=[O:28])[O:25][C:23]1=O)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC>O.C(O)(C)C>[C:26]([O:25][CH:23]=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:28])[CH2:27][CH2:2][C:1]([O-:4])=[O:3].[Ca+2:5].[CH:23]([O:25][C:26](=[O:28])[CH2:27][CH2:7][C:6]([O-:9])=[O:8])=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCC=COC(=O)CCC(=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 113.2 %

Procedure:
A solution of 313.5 g (1.98 mol) calcium acetate in 1000 ml water was added to a solution of 570 g (1.98 mol) dodecenyl succinic anhydride in 1000 ml isopropanol. The mixture was then heated to 90° C., left at that temperature for 1.5 h and then concentrated in a water jet vacuum. The residue was dried in vacuo in a drying cabinet at 100° C. 680 g of the calcium soap were obtained in the form of a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Fc1ccc(Cl)nc1
Solvent: O
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
2-chloro-5-fluoropyridine (5.00 g, 38.01 mmol) was combined with hydrazine monohydrate (15 mL, 303.0 mmol) in a Teflon® lined reactor. The reaction was purged with argon gas and sealed, then heated to 200° C. overnight. Following overnight heating, the reaction mixture was evaporated to solids under reduced pressure, and then dissolved in water containing NaHCO3. The mixture was transferred to a separatory funnel, and extracted 4 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to residue under reduced pressure, followed by purification by flash column chromatography eluting with 5% MeOH 0.5% NH4OH in DCM to give the desired 5-fluoro-2-hydrazinylpyridine (1.50 g, 31% yield). MS APCI (+) m/z 128.0 (M+1) detected.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>>[C:16]([NH:12][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:8][C:9]([OH:11])=[O:10])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A 0° C. slurry of 50.0 g (300 mmole) of DL-3-amino-3-phenyl propionic acid in 300 mL of 1N aq NaOH (300 mmole) was treated simultaneously with 48.0 mL (340 mmole) of benzyl chloroformate and 300 mL of 1N aq NaOH (300 mmole). The reaction was stirred at ambient temperature for 18 h at which time the reaction was acidified to pH 2 with conc. aq HCl and extracted with EtOAc (4×200 mL). The combined organic fractions were dried over Na2SO4 and evaporated in vacuo to give 73.4 g (250 mmol; 82%) of N-Cbz-3-amino-3-phenyl propionic acid as an off white solid.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8](=[O:13])([O:11][CH3:12])OC.[Br:14][C:15]1[S:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][CH:19]=1>>[Br:14][C:15]1[S:16][C:17]([C:20](=[O:22])[CH2:21][C:8]([O:11][CH3:12])=[O:13])=[CH:18][CH:19]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(Br)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a 500 mL round bottom flask was added a suspension of sodium hydride (1.950 g, 48.76 mmol) in tetrahydrofuran (250.00 mL, 3082.3 mmol). Dimethyl carbonate (8.218 mL, 97.53 mmol) was added followed by 2-bromo-5-acetylthiophene (5.000 g, 24.382 mmol) which was added in portions. The reaction mixture was heated to 60° C. and allowed to stir for 18 hours. The reaction was cooled to ambient temperature and quenched by the dropwise addition of water (100.0 mL). The mixture was acidified to pH 2 with 6N HCl (8.00 mL) and extracted with diethyl ether (150.00 mL×3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was split in half and dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 25% EtOAc over 30 min) to afford the title compound (5.547 g, 82%) as a brown oil. LC/MS (AA) ES+ 263, 265. 1H NMR (dmso-d6, 400 MHz): δ 7.87 (d, 1H), 7.45 (d, 1H), 4.13 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:30])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([N+]([O-])=O)[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[CH3:31][O-:32].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:30])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([O:32][CH3:31])[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Reactant: C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: COc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)=O)[nH]n3)n2)ccc1C#N
Reaction time: 144 h
Yield: 5 %

Procedure:
(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (0.27 g, 0.663 mmol) was added to a flask and flushed with nitrogen. Dry THF was added and tetrabutylammonium methoxide solution in methanol (1.219 ml, 0.729 mmol) was added dropwise through a septum. During the reaction 1.754 ml of tetrabutylammonium methoxide solution in methanol was added and after reacting for 6 days the reaction was stopped. The crude product was evaporated and dissolved in DCM. The mixture was washed with water, dried and evaporated. Evaporation residue was dissolved in 20% methanol/DCM-solvent and filtered through silica wetted with the same solvent. The product was triturated using a small amount of DCM. Yield 5.00%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.5 (s, 3H), 3.94 (s, 3H), 4.31 (s, 2H), 4.40-4.50 (m, 1H), 6.88 (d, 1H), 7.31 (s, 1H), 7.46-7.54 (m, 2H), 7.71 (d, 1H), 7.80 (d, 1H), 8.49 (s, 1H), 14.12 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
53 mg of (R)-methyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 1.5 mL of tetrahydrofuran, and 0.5 mL of water were added to 25 mL flask and the resulting reaction solution was cooled to 0° C. 7.32 mg of lithium hydroxide was added to the reaction solution and stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, 5 mL of ethyl acetate and 5 mL of water were added to the reaction solution and stirred for 10 minutes. An aqueous layer was isolated, cooled at 0° C., and 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 40.8 mg of a title compound.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:31][C:28]([F:29])([F:30])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:20][CH:21]=1)(=[O:26])=[O:27]
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CCNC3)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine (270 mg, 0.55 mmol) was dissolved in anhydrous chloroform (10 mL) and 1-chloroethylchloroformate was added (0.18 mL, 1.65 mmol). After stirring for 30 min, N,N-diisopropylethylamine was added (0.24 mL, 1.65 mmol) and the mixture was stirred for an additional 2 h. The chloroform was removed under vacuum and 30 ml of methanol was added and the mixture was heated for 30 min. Upon reaction completion, the methanol was removed and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product (163 mg, 83%). The crude material was used for the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:26]1([NH:25][C:16](=[O:24])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)Nc3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), salicylanilide (213 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (86 mg, yield 86%).
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[S:6]1[CH2:7][CH2:8][C:3]2([O:9][C:13]3[C:14]4[C:19]([C:10](=[O:21])[C:11](=[O:20])[C:12]=3[S:1][CH2:2]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][CH2:5]1
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: OC1(CS)CCSCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCSCC1)O2

Procedure:
The crude 4-(mercaptomethyl)tetrahydro-2H-thiopyran-4-ol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione. The crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione was purified by flash column chromatography (SiO2, 25% EtOAc in hexanes) to afford the product as a purple solid. M.p.=221-223° C., 400 MHz 1H NMR (CDCl3) δ 8.05 (dd, d, J=7.4 Hz, 1.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.67 (dt, J=6.2 Hz, 1.1 Hz, 1H), 7.50 (dt, J=6.2 Hz, 1.1 Hz, 1H), 3.10-3.03 (m, 1H), 2.64-2.60 (m2, 2H), 2.47-2.43 (m, 2H), 1.99-1.92 (m, 2H); LCMS: 319 [M+H].
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:30]([C:23]1[CH:22]=[N:21][N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=12)=[O:31]
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Yield: 85.1 %

Procedure:
To a solution of (3R)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 10) (80.0 mg, 0.259 mmol) in DMF (4 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42.3 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at rt for 1.5 hours. The DMF was evaporated in vacuo then DCM (5 ml) was added and the whole washed with saturated aq. NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP to give the title compound (100 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:4]=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:11]=[CH:10][N:9](COCC[Si](C)(C)C)[C:7]=2[N:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CN(C)c1nc(-c2ccco2)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Yield: 21.2 %

Procedure:
A solution of N,N-dimethyl4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (370 mg, 0.97 mmol) in THF (3 mL) was treated with tetrabutylammonium fluoride (1 ml, 1-M in THF, 1 mmol), refluxed for 36 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9, alumina) to give the title compound (47 mg, 21%) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][S:8][CH3:9])[C@@H:3]([OH:6])[CH2:4][OH:5].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.CCOCC>[C:10]([O:5][CH2:4][C@H:3]([OH:6])[C@@H:2]([CH3:1])[CH2:7][S:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CSC[C@@H](C)[C@@H](O)CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CSC[C@H](C)[C@@H](O)COC(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred, ice-cooled solution of (B) (3.7g.,0.025m.) in dried pyridine (30 ml.) was added dropwise over ca. 5 minutes under a nitrogen atmosphere a solution of benzoyl chloride (3.0 ml., 0.026m.) in dry ether (5 ml.). The mixture was stirred for an additional 5 minutes, the ice-bath removed, and the mixture allowed to stir at ambient temperatures. After ca.1.5 hr., tlc analysis indicated that the reaction was complete and the mixture was transferred to a separatory funnel with ether (300 ml.). The mixture was washed IX with water (100 ml.), 4 X with saturated copper sulfate solution, lX with saturated sodium chloride solution and dried over sodium sulfate. Concentration of the filtered solution followed by chromatography on silica gel (200g.; 1% methanol/methylene chloride as eluant) yielded 5.4g (C) as an oil. N.m.r. was consistent with the structure [α]D =30 9.1 (c=0.75, CDCl3).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[CH:10][CH:9]=1)[OH:7].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH:6]([OH:7])[C:5]([OH:41])=[O:4])=[CH:13][CH:12]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.7 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.070 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)hydroxy-acetic acid methyl ester (Example 155-(2); 17.5 mg, 0.0330 mmol) in methanol (0.47 mL) at room temperature, and the mixture was stirred at room temperature for 5.5 hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (17.0 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:35])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21]CN1C(OCC1C=CC=CC=1)=O.BrCCC1CCC[N:41]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:40]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:35])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:41]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:40]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from phenylmethyl 3-(2-bromoethyl)-1-piperidinecarboxylate and 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:30])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[Cl:29])=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:44](OC(=O)C)([F:46])[F:45]>O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:44]([F:46])[F:45])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][C:20]=1[Cl:29])[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(=O)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.34 g), N,N-dimethylformamide (15 mL), potassium carbonate (0.58 g) and acetic acid chlorodifluoromethyl ester (0.4 mL) was stirred at 70° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and then the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (7:3 by volume) gave title compound, 0.37 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:15]([F:14])([F:24])[F:25])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: FC(F)(F)c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccccc1C(F)(F)F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: [N+](C1C=CC(O[C:11](=O)[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])=CC=1)([O-])=O.[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)=[O:27].CO>C1(C)C(C)=CC=CC=1>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH:33][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])[S:31][CH:32]=1)=[O:27]
Reactant: COc1cc(O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NCc2cc(OC)c(OC)cc2O)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
In 1 mL of xylene were suspended 200 mg of 2-hydroxy-4,5-dimethoxybenzoic acid 4-nitrophenyl ester and 119 mg of 2-amino-1,3-thiazole-4-carboxylic acid methyl ester in a stream of argon, which was then stirred at 130° C. for 12 hours. The reaction mixture was allowed to stand to cool, to which 1 mL of methanol was then added, followed by heating to reflux for one hour. The resultant reaction mixture was allowed to stand to cool, followed by collecting the precipitated crystal by filtration at 30° C. or lower before drying under reduced pressure to provide 180 mg of the title compound (5a) at a yield of 80%.