Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=1)[C:11](=[O:30])[CH2:12][C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=2[S:15](=[O:29])(=[O:28])[N:14]=1)=O.[O-]CC.[Na+]>C(O)C>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[CH2:31][N:10]1[C@@H:6]2[C@@H:5]([CH2:9][CH2:8][CH2:7]2)[C:3]([OH:2])=[C:12]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][C:16]=3[S:15](=[O:29])(=[O:28])[N:14]=2)[C:11]1=[O:30]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)c(Cl)c3)C1=O)N2
Temperature: 60 °C
Yield: 61.7 %

Procedure:
(1R,2S)-2-{(3-Chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (crude from Example 11b, 0.252 g, 0.42 mmol) was dissolved in ethanol (8.4 mL), followed by addition of a 21% w/w solution of sodium ethoxide in ethanol (0.545 mL, 1.68 mmol), and heated to 60° C. for 1 h. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (2 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and dried in vacuo. Recrystallization from 10-20% ethyl acetate in hexanes afforded the desired product, (4aR,7aS)-N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.147 g, 0.259 mmol, 61%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.51-1.58 (m, 3H), 1.99-2.00 (m, 3H), 3.06 (s, 3H), 3.30 (bs, 1H), 3.88 (bs, 1H), 4.47 (d, 1H, J=15.0 Hz), 4.89 (d, 1H, J=15.4 Hz), 7.36 (d, 2H, J=7.3 Hz), 7.50 (dd, 1H, J1=8.6 Hz, J2=2.4 Hz), 7.57-7.59 (m, 3H), 10.17 (bs, 1H). LC-MS (ESI) calcd for C23H22ClFN4O6S2 568.07, found 569.03 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COc1cnc(Cl)n(C)c1=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cnc(-c2ccc(Cl)c(C(F)(F)F)c2)n(C)c1=O
Temperature: 130 °C
Yield: 68.6 %

Procedure:
To a solution of 500 mg (2.86 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 10 ml THF was added 233 mg (0.286 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 0.965 g (4.29 mmol) 4-chloro-3-(trifluoromethyl)benzeneboronic acid, and 1.87 g (5.73 mmol) Cs2CO3. The reaction mixture was heated to 130° C. for 15 min in the microwave, then diluted with 10 ml water, extracted with 30 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (25 g silica gel, 40-100% hexane/EtOAc) gave 625 mg (68% yield) of 2-[4-chloro-3-(trifluoromethyl)phenyl]-5-methoxy-3-methylpyrimidin-4(3H)-one. LCMS [M+H]+=319.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of 4-methoxy-2-nitrobenzoic acid (12 g; 61 mmol; 1 eq; commercially available from Aldrich) in MeOH (200 mL) is added thionyl chloride (13 mL, 178 mmol, 2.9 eq) and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum and the residue is diluted with EtOAc (150 mL) and washed with a 10% aqueous solution of sodium bicarbonate, water, and then dried over MgSO4. The solvent is removed under reduced pressure to afford 11 g (85%) of the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.81-7.79 (m, 1H), 7.27-7.25 (m, 1H), 7.13-7.11 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(F)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(F)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(3-fluoro-4-methoxyphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethyl benzyl bromide.
Reaction SMILES: [CH2:1]([CH:8]([NH2:13])[C:9]([F:12])([F:11])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:1][CH:8]([C:9]([F:10])([F:11])[F:12])[N:13]=1
Reactant: NC(Cc1ccccc1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC1=NC(C(F)(F)F)Cc2ccccc21

Procedure:
(The starting material N-(1-benzyl-2,2,2-trifluoro-ethyl)-acetamide is obtained by reacting 1-benzyl-2,2,2-trifluoro-ethylamine with acetic anhydride.)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:31][N:30]=4)=[CH:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98 mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 8 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (84 mg, 40%) as a yellow film: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.33 (s, 1H), 7.26 (s, 1H), 7.07-7.02 (m, 2H), 4.73-4.64 (m, 2H), 3.76-3.67 (m, 5H), 2.99-2.98 (m, 2H), 2.05-2.04 (m, 2H), 1.44-1.38 (m, 9H); ESI MS m/z 539 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([O:15]C)=[O:14])(=[O:3])[CH3:2].[OH-].[Na+].Cl.O>C(O)C>[C:1]([N:4]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(C)cccc1COCCCCN(Cc1ccc2ccccc2n1)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N(CCCCOCc1cccc(C)c1C(=O)O)Cc1ccc2ccccc2n1
Temperature: 90 °C

Procedure:
Methyl 2-[4-(acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benzoate (375 mg, 0.86 mmol, EXAMPLE 40a) is dissolved in ethanol (7.5 mL). 10 N NaOH (860 μL, 8.6 mmol) is added, and the contents are heated to 90° C. overnight. The reaction is cooled to r.t. and 2 N HCl (4.3 mL) is added, followed by dropwise addition of 2 N HCl to adjust the pH to ˜4-6. The contents are poured into water (100 mL) and extracted with dichloromethane (3×75 mL). The organic fractions are pooled and washed with brine (3×100 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 6% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) Rotamers 2:1 δ 8.37 (d, 0.5H), 8.28-8.15 (m, 1.5H), 7.88-7.83 (m, 1.25H), 7.80-7.73 (m, 1.75H), 7.65-7.57 (m, 1.25H), 7.43 (d, 0.25H), 7.33-7.10 (m, 3H), 5.24 (s, 1.33H), 5.01 (s, 0.66H), 4.67 (s, 1.33H), 4.63 (s, 0.66H), 3.55-3.45 (m, 2.66), 3.39-3.32 (m, 1.33), 2.58 (s, 2H), 2.55 (s, 1H), 2.31 (s, 1H), 1.95-1.82 (m, 2H), 1.77-1.62 (m, 2H). MS (ESI) 421 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.CCOCC>C(O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: Cc1cc(Cl)cc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(Cl)cc(CC#N)c1
Temperature: 70 °C
Yield: 75.5 %

Procedure:
To a flask equipped with additional funnel, was placed potassium cyanide (29.6 g, 0.45 mol) and distilled water (55 ml). The mixture was heated up to 70° C. in an oil bath. With stirring, 1-Bromomethyl-3-chloro-5-methyl-benzene (46) (35 g, 0.16 mol) in ethanol (180 ml) was then dropwise added over 1 hr through the addition funnel. After completion of addition, the mixture was refluxed for 8 hr. After cooling to room temperature, ether was added to the mixture. The mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 20 g (77%) of a pale brown oil. 1H NMR (200 MHz, CDCl3) δ: 2.31 (3H, s), 3.66 (2H, s), 7.02 (1H, s), 7.09 (2H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[O:24]([C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[CH3:12])[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)c1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-dimethylaminobenzoic acid (23.1 g), N,N'-carbonyldiimidazole (22.7 g) and 2-amino-7-phenoxy-1,8-naphthyridine (23.7 g). The product produced by precipitation in water (44 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (1000 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×50 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-dimethylaminobenzamide (32 g) is produced (m.p. 120° C.).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:27][CH2:26][C:9]2([N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)[NH:11][C:10]2=[O:25])[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].Br[C:29]1[C:41]([CH3:42])=[CH:40][C:32]([O:33][CH2:34][CH2:35][CH:36]([OH:39])[CH2:37][OH:38])=[CH:31][C:30]=1[CH3:43].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CN(C1CCCCC1)C1CCCCC1.[NH4+].[Cl-]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CN1C(=O)CCC1>[OH:39][CH:36]([CH2:37][OH:38])[CH2:35][CH2:34][O:33][C:32]1[CH:31]=[C:30]([CH3:43])[C:29](/[CH:2]=[CH:1]/[S:3]([N:6]2[CH2:7][CH2:8][C:9]3([N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=4)[NH:11][C:10]3=[O:25])[CH2:26][CH2:27]2)(=[O:5])=[O:4])=[C:41]([CH3:42])[CH:40]=1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(c1ccc(F)c(C(F)(F)F)c1)NC2=O
Reactant: Cc1cc(OCCC(O)CO)cc(C)c1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(OCCC(O)CO)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1ccc(F)c(C(F)(F)F)c1)NC2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 49.1 %

Procedure:
8-Ethenesulfonyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (57.6 mg, 0.142 mmol), 4-(4-bromo-3,5-dimethyl-phenoxy)-butane-1,2-diol (49.3 mg, 0.170 mmol), bis(dibenzylideneacetone)palladium(0) (8 mg, 0.014 mmol) and tri-tert-butylphosphine tetrafluoroborate (4 mg, 0.014 mmol) were placed in a vial. NMP (0.5 ml) and N-methyldicyclohexylamine (36.1 μl, 0.170 mmol) were sequentially added in a nitrogen atmosphere, and the mixture was heated with stirring at 100° C. for 2.5 hours. A saturated aqueous NH4Cl solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (ethyl acetate:dichloromethane:methanol=10:10:1) to give 8-{(E)-2-[4-(3,4-dihydroxy-butoxy)-2,6-dimethyl-phenyl]-ethenesulfonyl}-2-(4-fluoro-3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (42.8 mg, 49%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH:15]=[C:14]([CH3:26])[C:13]=1[CH3:27]>C1COCC1>[F:24][C:22]1[CH:23]=[C:18]([C:16]2[CH:15]=[C:14]([CH3:26])[C:13]([CH3:27])=[C:12]([CH2:11][NH:10][C:3]3[C:2]([F:1])=[C:7]([OH:8])[CH:6]=[CH:5][C:4]=3[F:9])[CH:17]=2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Temperature: 60 °C
Yield: 44.4 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3,5-difluorophenyl)-2,3-dimethyl-benzamide (46 mg, 0.12 mmol, 1.0 eq) in THF (5 mL) under N2 was added dropwise a solution of BH3 (1M in THF, 0.72 mL, 0.72 mmol, 6.0 eq). The reaction mixture was heated at 60° C. overnight. After cooling, the resulting mixture was quenched with water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 40:1 to 20:1) to give the title compound as a colorless oil (20 mg, 45%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](OC)=O)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.CO[C:19](=[O:22])[O:20][CH3:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([C:19]([O:20][CH3:21])=[O:22])[C:19]([O:20][CH3:21])=[O:22])=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)OC
Reactant: COC(=O)Cc1ccc(C(=O)C2CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OC
Reaction time: 72 h
Yield: 21.1 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, methyl ester (1.5 g, 6.0 mmol) and dimethylcarbonate (930 mg, 10.3 mmol) in tetrahydrofuran (10 mL). Add 20 mL (20 mmol) of a 1.0 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 3 days. Add iodomethane (5.3 g, 35 mmol). Stir 24 hours. Add water and ethyl acetate. Wash organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (50 g silica gel, ethyl acetate/heptane as eluent) to give the title compound (315 mg, 16%).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
4-Fluoro-2-methyl-5-nitrophenol (D16) (0.85 mmol, 145 mg) in dimethylformamide (5 mL) under argon was treated with K2CO3 (0.85 mmol, 117 mg, 1 eq) then methyl iodide (1.7 mmol, 242 mg, 2 eq). The mixture was allowed to stir at room temperature for 1.5 h, concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted 3 times with ethyl acetate. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a bright yellow solid (0.79 mmol, 146 mg, 93% yield). Rt=2.84 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:17]#[N:18])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[N+:14]([O-])=O)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=2)[NH:14][C:17]=1[NH2:18])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C#N)c1cc(OC)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)[nH]c2ccc(OC)cc12
Temperature: 55 °C
Yield: 19.1 %

Procedure:
A solution of cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (13.2 g, 46.3 mmol, 93-95% pure) in glacial acetic acid (185 mL) is treated with a single charge of zinc dust (12.1 g, 185 mmol). The mixture is heated at 55° C. for 45 min, then treated with more zinc (4 g). After heating for another 105 min, the brown mixture is filtered through a pad of flash silica gel. The pad is washed well with acetic acid and the filtrate is concentrated to a residue that is distributed between dichloromethane and H2O. The organic phase is washed with 5% aqueous sodium bicarbonate and concentrated to a residue that shows about a 1:1 mixture of products by silica gel thin layer chromatography (dichoromethane:EtOAc, 3:1). The residue is purified by flash silica gel chromatography eluting sequentially with 100:0, 95:5, and 90:10 dichloromethane:EtOAc. The fractions containing the pure higher Rf product are combined and concentrated to a solid that is sonicated in tert-butyl methyl ether. The solids are collected by filtration to give pure 2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.07 g) as an off-white solid. Further chromatography of the combined mother liquor and impure fractions affords 120 mg of additional product. Total yield=2.19 g (20%). 1H NMR (DMSO): δ10.44 (1H, br s, exchanges with D2O), 7.11 (1H, d, J=2.2 Hz), 6.98 (1H, d, J=8.4 Hz), 6.61 (2H, br s, exchanges with D2O), 6.48 (1H, dd, J=8.4, 2.7 Hz), 4.20 (2H, q, J=7.0 Hz), 3.71 (3H, s), 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].[H-].[Na+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]Br)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:25][CH2:24][CH2:23][NH:22][C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])=[CH:6][C:5]=1[OH:11]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a 0° C. stirred solution of 2,4-dihydroxybenzoic acid methyl ester (5 g, 30 mmol) in dry DMF (100 mL) was added sodium hydride (1.2 g of a 60% suspension in mineral oil, 30 mmol). After 1 h, the solution was warmed to ambient temperature and stirred for 1 h. To the solution was added N-t-butyloxycarbonyl-3-bromopropylamine (10.6 g, 45 mmol). The reaction was stirred at ambient temperature for 24 and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL) and washed with water (2×200 mL) and brine (100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The product-containing fractions were pooled and the solvent was removed under reduced pressure. The resulting oil crystallized from ether to give 4-(3-(t-butyloxycarbonylamino)propyloxy)-2-hydroxybenzoic acid methyl ester (51% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(OCC)(=O)C>ClCCl>[C:25]([O:18][CH2:17][C:10]1[C@H:11]2[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]2[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[O:8][CH:9]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@H](C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@H](C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
(1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4-(hydroxymethyl)-7-methylcycopenta[c]pyran (10.0 g, 0.039 mol) obtained in Example 5 was dissolved in 200 mι of dichloromethane. After 9.52 mι (0.12 mol) of pyridine, 11.2 mι (0.12 mol) of acetic anhydride and 100 mg of N, N-dimethylaminopyridine were added, the reaction mixture was stirred at room temperature for 5 hours. After 600 mι of ethyl acetate was added to the reaction mixture solution, the organic layer was washed with water (300 mι×2), 2N hydrochloric acid solution, saturated sodium bicarbonate solution (300 mι×2) and saturated sodium chloride solution (300 mι), and was thereafter dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by chromatography using silica gel, and the fraction obtained from hexane:ether=1:1 eluent was concentrated. A colorless oily matter was thus obtained, i.e., (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran (9.27 g, yield=79.5%). This (1S, 4aS, 7S, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran had the following physicochemical properties: