Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][N:6]=1.Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH:3]([CH3:12])[C:2]([F:1])([F:13])[F:14])[CH:10]=2)[N:17]=[N:18][CH:19]=1
Reactant: COc1cnnc(Cl)c1
Reactant: CC(Oc1cc(O)ccn1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1cnnc(Oc2ccnc(OC(C)C(F)(F)F)c2)c1
Yield: 43.1 %

Procedure:
2-(2,2,2-Trifluoro-1-methylethoxy)-4-pyridinol (0.64 g, 3.09 mmol), 3-chloro-5-methoxy-pyridazine (0.44 g, 3.09 mmol), potassium carbonate (0.85 g, 6.18 mmol) and CuBr (0.89 g, 6.18 mmol) were stirred under nitrogen in diglyme (5 mL) at 100° C. for 6 days. The mixture was then poured in water and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated in-vacuo. The crude product was purified by flash chromatography to give 5-methoxy-3-[[2-(2,2,2-trifluoro-1-methylethoxy)-4-pyridinyl]oxy]pyridazine (0.42 g, 43% yield, Compound No. 10) as a white solid, mp=100° C. -102° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4Cl)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-chlorophenylisocyanate (0.00669 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.6 Hz, 3H), 2.59 (br. s., 2H), 3.78 (t, J=5.8 Hz, 2H), 4.28 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.45-6.55 (m, 1H), 7.08-7.17 (m, 1H), 7.18-7.32 (m, 2H), 7.36-7.46 (m, 2H), 7.60 (dd, J=8.1, 1.5 Hz, 1H), 7.69 (s, 1H), 8.23 (br. s., 1H). MS (ES+): m/z 575.03/577.01 (98/100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Methyl 5-hydroxypyridine-2-carboxylate (Intermediate 224, 0.610 g, 3.59 mmol) was dissolved in DMF (5 mL), cesium carbonate (1.40 g, 4.31 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 g, 4.31 mmol) were added and the mixture stirred at room temperature for 18 h. The mixture was partitioned between EtOAc (50 mL) and water (15 mL) and the aqueous layer extracted with further EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude material was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to afford the title compound as a white solid (0.652 g, 77%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.40 (1H, d), 8.09 (1H, d), 7.27 (1H, dd), 4.41 (2H, q) and 3.93 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[N:16]([CH2:17][CH2:18][CH3:19])[CH:15]=[N:14][CH:13]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH2:17]([N:16]1[C:12]([CH2:11][S:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:13][N:14]=[CH:15]1)[CH2:18][CH3:19]
Reactant: CCCn1cncc1CSc1ccc([N+](=O)[O-])cn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cncc1CSc1ccc(N)cn1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
5-nitro-2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]pyridine (2.9 g) was dissolved in 85% ethanol solution (87 ml), calcium chloride (0.58 g) and reduced iron (2.9 g) were added to the mixture, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 6-[[(1-propylimidazol-5-yl)methyl]sulfanyl]pyridine-3-amine (2.0 g).
Reaction SMILES: C[Si](Br)(C)C.[OH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:40])[CH:10]=[C:11]([C:18]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([CH3:39])=[CH:33][C:19]=1[C:20]([NH:22][CH:23]([P:25](=[O:32])([O:29]CC)[O:26]CC)[CH3:24])=[O:21])[C:12]2=[O:17]>>[OH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:40])[CH:10]=[C:11]([C:18]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([CH3:39])=[CH:33][C:19]=1[C:20]([NH:22][CH:23]([P:25](=[O:26])([OH:29])[OH:32])[CH3:24])=[O:21])[C:12]2=[O:17]
Reactant: CCOP(=O)(OCC)C(C)NC(=O)c1cc(C)cc(OC)c1C1=CC(=O)c2c(O)cccc2C1=O
Agent: C[Si](C)(C)Br
Product: COc1cc(C)cc(C(=O)NC(C)P(=O)(O)O)c1C1=CC(=O)c2c(O)cccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Trimethylsilyl bromide was added to diethyl 1-[2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzamido]ethylphosphonate (500 mg) as obtained in Example 9 and the mixture was stirred at room temperature for 2 hours. The excess trimethylsilyl bromide was distilled off, water was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The resultant crude crystals were recovered by filtration and recrystallized from methanol. The above procedure gave yellow crystals (200 mg) of 1-[2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzamido]ethylphosphonic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (1.0 g, 0.0044 mole) in 140 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (0.2 g) at room temperature for 4 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. To this stirred solution was added triethylamine (0.6 g, 0.0059 mole) and benzoyl chloride (0.62 g, 0.0044 mole). The reaction mixture was allowed to stir at room temperature overnight. The triethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue was taken up in ether-methylene chloride solution. Sodium sulfate was added to adsorb an immiscible dark oil. The filtrate was evaporated to dryness to give a residue which was recrystallized from ether. The precipitate was collected, washed with a solution of 75% hexanes/25% ether, and dried at room temperature under high vacuum to yield 1.1 g, of title compound, m.p. 115°-16° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.BrC1C=C(C(F)(F)F)C=CC=1N.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[S:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: Nc1ccc(C(F)(F)F)cc1Br
Agent: [K+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Sc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a stirred solution of tris(dibenzylidene)dipalladium(0) (Pd2dba3, 0.183 g, 0.2 mmol) and bis(2-diphenylphosphinophenyl)ether (DPEphos, 0.215 g, 0.2 mmol) in toluene (80 mL) was added 3-bromo-4-iodobenzotrifluoride (7.02 g, 20 mmol; prepared from 2-bromo-4-trifluoromethyl-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753), 4-chlorothiophenol (2.89 g, 20 mmol) and potassium tert-butoxide (2.46 g, 22 mmol) at room temperature (rt). The reaction mixture was stirred for 2.5 h at 100° C. and then cooled to room temperature (rt) and filtered through celite. The solvent was evaporated off and the crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8) to produce 4.53 g (81%) of 1-bromo-2-(4-chloro-phenylsulfanyl)-5-(trifluoromethyl)-benzene as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1cccc(C(=O)Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09 mmol, Example 1, Step H), 3-methoxybenzoyl chloride (389 mg, 2.28 mmol), and triethylamine (757 μL, 5.43 mmol) were placed in DCM (5 mL) and stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was added. The reaction was stirred for 10 minutes and then poured onto water. The mixture was then filtered and washed with DCM and water to provide solid N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide (219 mg, 55% yield).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:26][CH:27]1[C:47](=[O:48])[N:29]2[C:30]([C:44]([OH:46])=[O:45])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][CH:42]=[CH2:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([NH:26][CH:27]2[C:47](=[O:48])[N:29]3[C:30]([C:44]([OH:46])=[O:45])=[C:31]([CH2:34][S:35][C:36]4[N:40]([CH2:41][CH:42]=[CH2:43])[N:39]=[N:38][N:37]=4)[CH2:32][S:33][C@H:28]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 33.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid (syn isomer, 1.86 g.) and 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.77 g.) were treated in similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:16]([CH3:27])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10]>CO.[Pd]>[OH:19][C:17]1[C:16]([CH3:27])=[CH:15][C:3]([O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:13])([CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[CH:18]=1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(O)cc1C
Yield: 107 %

Procedure:
A solution of 1.85 g (5 mmol) of 5-[2,5-dimethyl-4-(phenylmethoxy)phenoxy]-2,2-dimethylpentanoic acid, methyl ester (Example 13) in 100 mL of methanol and 0.2 g of 20% palladium on carbon is shaken under a hydrogen atmosphere of 50 pounds per square inch (psi) for 14 hours. The catalyst is removed and the solvent is evaporated to afford the title compound as a colorless oil (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[C:4]([OH:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Br)cc1O
Solvent: c1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1O
Yield: 70.7 %

Procedure:
To 1-(4-bromo-2-hydroxyphenyl)ethanone (35.8 g, 167 mmol) in dry benzene (800 mL) was added N,N-dimethylformamide dimethylacetal (44 mL, 333 mmol) and the solution was heated at reflux for 4 hrs and concentrated to dryness. The resulting residue was dissolved in dichloromethane (300 mL) and filtered over SiO2. The organic layer was concentrated to afford (E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one as a bright yellow solid (31.9 g, 71%). LCMS 270 (M+H); 1H NMR (DMSO-d6) 14.96 (s, 1H), 7.86-7.94 (m, 2H), 6.96-7.02 (dd, 2H), 5.92-5.96 (d, 1H), 3.32 (s, 3H), 3.20 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@@H:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@@H:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: CCN(CC)[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCN(CC)[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[cis-4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (31 mg, 0.070 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (14.1 mg, 39%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.25 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 4.77 (s, J=12.7 Hz, 1H), 3.98 (s, 3H), 3.50-3.41 (m, 1H), 3.23 (q, J=7.2 Hz, 4H), 2.97-2.88 (m, 1H), 2.22 (d, J=12.9 Hz, 2H), 2.09-1.85 (m, 6H), 1.35 (t, J=7.3 Hz, 6H), 1.24-1.17 (m, 2H), 1.18-1.09 (m, 2H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC 98.3% (AUC), tR=11.07 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Yield: 94.1 %

Procedure:
A mixture of 9.7 g (37 mmol) of the above ester and 200 ml of 1 N sodium hydroxide is heated on the steam bath for 11/4 hours. The resulting suspension is poured over ice and acidified with 250 ml of 1 N hydrochloric acid. The solid is collected by filtration and washed with water and ethanol to give 8.15 g the title acid, mp>310°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.55 (m, 10H), 4.75-2.75 (m, 5H), 1.75-0.65 (m, 8H).
Reaction SMILES: [C:1]1([CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:36])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]([CH3:35])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+].CO>O1CCCC1>[C:1]1([CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:36])[NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]([CH3:35])[CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCc3cc(C(C)CC(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of ethyl (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate [0.55 g, Reference Example 4(b)], aqueous sodium hydroxide solution (5.5 ml, 1M), methanol (5.5 ml) and tetrahydrofuran (11 ml) was stirred at room temperature overnight then evaporated to low bulk. The residue was diluted with water and the mixture was acidified by the addition of hydrochloric acid. The precipitate was collected by filtration, washed with water and then dried to give the title compound (0.41 g) as a white powder. LC-MS: RT=3.77 minutes (100% total area by ELS); MS (ES+) 472 (MH+), 494 (MNa+).
Reaction SMILES: [CH2:1]1[CH2:36][O:35][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:4][CH2:5][C:6]23[CH2:13][CH:12]([O:14][C:15](=[O:28])[C:16]4C=CC(C5C=CC=CC=5)=CC=4)[CH2:11][CH:10]2CC(=O)O3)[O:2]1.C(=O)([O-])[O-:38].[K+].[K+].C(O)(=O)C>CO>[CH2:36]1[CH2:1][O:2][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:4][CH2:5][C@H:6]2[C@H:10]([OH:38])[CH2:11][C@H:12]3[C@@H:13]2[CH2:16][C:15](=[O:28])[O:14]3)[O:35]1
Reactant: CCCCCC1(CCC23CC(OC(=O)c4ccc(-c5ccccc5)cc4)CC2CC(=O)O3)OCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)OCCO1

Procedure:
To a solution of (1S,5R,6R,7R)-6-(3,3-ethylenedioxyoctyl-7-(4-pheny1benzoyloxy)-2-oxabicyclo[3.3.0]octan-3-one (5a) (8.20 g) in methanol (200 ml)was added potassium carbonate (1.15 g) and the resultant mixture was stirred overnight, and acetic acid (1 ml) was added thereto. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (6a).
Reaction SMILES: CCOC(C1C=CC(C#C[C:14]2[CH:15]=[CH:16][C:17]3[S:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:18]=3[CH:19]=2)=NC=1)=O.CC1(C)C2C(=CC=C(C#C)C=2)SCC1.C1(S)C=CC=CC=1.BrCC=C(C)C.[OH-].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>CC(C)=O.C1(C(SC(C2C=CC=CC=2)C=C(C)C)C=C(C)C)C=CC=CC=1.C1C=CC=CC=1>[CH3:24][C:20]1([CH3:25])[C:18]2[C:17](=[CH:16][CH:15]=[CH:14][CH:19]=2)[S:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Agent: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: CC(C)=CC(SC(C=C(C)C)c1ccccc1)c1ccccc1
Agent: CC(C)=CCBr
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CC1(C)CCSc2ccccc21

Procedure:
A key intermediate in the preparation of tazarotene, 4,4-dimethyl-6-ethynylthiochroman (II), is prepared as shown in Scheme I: Thiophenol (1) and 1-bromo-3-methyl-2-butene (2) are heated at reflux with sodium hydroxide in acetone resulting in phenyl-3-methylbut-2-enylsulfide (3). The phenyl-3-methylbut-2-enyl sulfide (3) is cyclized by refluxing with phosphorus pentoxide and phosphoric acid in benzene to yield 4,4-dimethylthiochroman (4). The 4,4-dimethylthiochroman (4) is reacted with acetyl chloride catalyzed by tin (IV) chloride (SnCl4) in benzene resulting in 4,4-dimethyl-6-acetylthiochroman (5). The 4,4-dimethyl-6-acetylthiochroman (5) is dehydrated with lithium diisopropylamide (LDA) and diethyl chlorophosphate in tetrahydrofuran (THF) results in the initial 6-ethenyl phosphonate intermediate (6). This intermediate undergoes further reaction with two equivalents of LDA to give 4,4-dimethyl-6-ethynylthiochroman (II).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[OH:15][C:6]1([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:13](=[O:14])[N:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)c2cccnc2C1=O
Reactant: Clc1cccc([Mg]Br)c1
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccnc2C1(O)c1cccc(Cl)c1
Temperature: -65 °C

Procedure:
6-(n-Butyl)-pyrrolo[3,4-b]pyridine-5,7-dione (20 g, 98 mmole) was dissolved in toluene (500 mL) and cooled to -65° C. To this mixture was added 3-chlorophenylmagnesium bromide (prepared by heating under reflux 2.5 g magnesium metal, 20 g of 3-chlorobromobenzene and 100 mL of tetrahydrofuran for 1 hour) at such a rate that the temperature of the reaction remain below -40° C. After the addition was complete, the cooling bath was removed and the mixture was allowed to warm to 0° C. The reaction mixture was quenched with aqueous ammonium chloride (25 mL) diluted with ethyl acetate (250 mL) and water (250 mL). After separating the resulting 2 layers, the organic fraction was dried with sodium sulfate (50 g). Filtration, followed by solvent removal gave 7-hydroxy-7-(3-chlorophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one as an oil, which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21](=[O:25])([O:22][CH2:23][CH3:24])[O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 127.9 %

Procedure:
To a mixture of tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (53.93 g) obtained above and ethyl acetate (350 mL) were added pyridine (53.78 mL) and ethyl chlorocarbonate (70.57 g) under ice-cooling, and the mixture was stirred at room temperature for 96 hrs. Ethyl acetate (500 mL) was added to the reaction mixture, and the mixture was washed with water (500 mL), an aqueous copper sulfate solution (200 mL), water (300 mL) and saturated brine (300 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate (93.19 g) as a colorless oil.