Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: FC(F)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC(F)F)CC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432).
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=1)C1C=CC=CC=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH3:26][O:25][C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:11]1[N:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:27])=[O:8])=[O:24]
Reactant: COC(=O)c1cccc(Oc2ncccc2C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Yield: 76.2 %

Procedure:
To a solution 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid benzyl ester (1.1 g) in methanol (15 ml) and ethyl acetate (15 ml) was added 10% palladium on carbon (0.2 g). This was shaken under 30 psi hydrogen for 2 hours. The catalyst was removed by filtration, and the solution was concentrated to give a solid which was triturated in methylene chloride/hexane to give a white solid (0.630 g). MW 273.26; MS (m/e) 274 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[OH-].[Na+]>Cl.C(O)C.CO>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH2:34][CH2:35][CH3:36])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCO
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A solution of di(tert-butyl) 1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-C of Example 57, 0.507 g, 1.02 mmol) in 6 M HCl in ethanol (5 mL) was heated at 60° C. for 1.5 hours. The solution was allowed to cool to room temperature, and then was concentrated under reduced pressure to yield an oil. The oil was triturated with ether to obtain a solid that was isolated by filtration. The solid was dissolved in methanol and the solution was adjusted to approximately pH 14 with 50% aqueous sodium hydroxide. The solution was concentrated under reduced pressure and the crude product was purified by chromatography (silica gel, elution with 5% CMA in chloroform) followed by crystallization from hexanes/ethyl acetate to provide 0.084 g of 4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol as white needles, mp 135.0-136.0° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][NH:6][CH:5]([C:9]([NH:11][C@H:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH3:13])=[O:10])[CH2:4]2)[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CC#N>[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[CH2:4][CH:5]2[C:9]([NH:11][C@H:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[O:10])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: C[C@H](NC(=O)C1CC2(CCN1)CC2)c1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](NC(=O)C1CC2(CCN1Cc1ccc(C(F)(F)F)cc1)CC2)c1ccc(C(=O)OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 68 °C
Yield: 72.3 %

Procedure:
To a solution of 4-((1S)-1-(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (D128) (10 mg, 33.1 μmol) in dry MeCN, Na2CO3 (17.5 mg, 165.4 μmol) and 4-(trifluoromethyl)-benzylbromide (24 mg, 99.2 μmol) were added in sequence. The mixture was heated at 68° C. for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by Biotage SNAP-Si column (10 g) eluting with a mixture DCM/EtOAc from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compounds (D129) (14.8 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:71]([CH2:73][NH2:74])[OH:72]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:74][CH2:73][CH2:71][OH:72])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:33])[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCCO)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure G. To a solution of 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 30 mg, 0.065 mmol) in DMF (3 ml) was added BOP (35 mg, 0.090 mmol) and DIPEA (17 mg, 0.098 mmol), followed by ethanolamine (6 mg, 0.098 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:4]=1[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=O.[OH:27]O.O>C(O)(=O)C>[CH3:23][O:22][C:21]1[C:3](=[O:2])[C:4]([CH2:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:18]([CH3:26])[C:19](=[O:27])[C:20]=1[O:24][CH3:25]
Reactant: OO
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
9-(2',3',4'-Trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=Y=H3CO, X=H, n=8, in the free form) (0.09 part) was reduced with zinc amalgam (0.2 part) by a procedure similar to that described in Example 10 and oxidized with 30% hydrogen peroxide (10 volume parts) in acetic acid. Following the addition of water, the reaction mixture was extracted with diethyl ether (500 volume parts) and the extract was washed with water and dried. The ether was then removed by distillation. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][N:31](CC3C=CC=CC=3)[CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=[O:3])[CH3:2].Cl>CO>[C:1]([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][NH:31][CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:19](=[O:20])[C:6]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c2n(c(=O)n(C(C)C)c1=O)C(CCN(C)Cc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Agent: Cl
Solvent: CO
Product: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21

Procedure:
4-{2-[Benzyl(methyl)amino]ethyl}-2-(4-fluorobenzyl)-7-isopropyl-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate (456 mg, 0.85 mmol) was suspended in degassed MeOH (10 mL). Aqueous HCl (6 M) was added dropwise until all the solids dissolved. The resulting stirred solution was degassed and purged with nitrogen three times. Palladium on carbon (10%, 131 mg) was added and the mixture was again degassed and purged with nitrogen (×3) and was then placed under hydrogen atmosphere (balloon) and stirred overnight at room temperature. The mixture was filtered through Celite, washing the filter cake well with MeOH. The filtrate was concentrated in vacuo and the residual oil triturated with diethyl ether to afford the hydrochloride salt of the title compound as a bright yellow solid. ES MS (M+1)=447.5.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25]S[CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:56]([O-:60])([O-])(=[O:58])=S.[Na+].[Na+].C(OC)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][S:56](=[O:60])(=[O:58])[CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCSCC2)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCS(=O)(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[({2-[(2RS,3SR)-3-[(4-azepan-1-ylpyrimidin-2-yl)amino]-1-(tetrahydro-2H-thiopyran-4-yl)piperidin-2-yl]ethyl}amino)carbonyl]piperidine-1-carboxylate (73.5 mg) in dichloromethane (1.5 mL), trifluoroacetic acid (17 μL) and m-chloroperbenzoic acid (40 mg) were added and then stirred at room temperature for 3 hours. The reaction solution was added aqueous sodium thiosulfate solution and excessive tert-butylmethyl ether, extracted with aqueous 2N sodium hydroxide solution and saturated brine and obtained a crude product of the title compound (84 mg). The obtained crude product was purified by silica gel column chromatography (ethyl acetate:methanol:28% aqueous ammonia=1000:10:1→80:20:2) to obtain a more polar compound and a less polar compound of the title compound having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH2:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]([NH2:9])=[O:13])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
5-Bromo-2-cyano-3-nitropyridine (500 mg, 2.19 mmol) was dissolved in concentrated sulfuric acid (1 mL), and stirred at 100° C. for 2 hours. After cooled to 0° C., water was added thereto, and stirred at that temperature. The resulting pale gray solid was taken out through filtration and dried to obtain the intended compound (447 mg, 83%).
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[C:7]=2[C:6]([CH3:15])=[CH:5][C:4]=1[CH3:16].Br.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[C:8](=[O:14])[C:7]=2[C:6]([CH3:15])=[CH:5][C:4]=1[CH3:16]
Reactant: COc1c(C)cc(C)c2c1OC(C)(C)C2=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1O)OC(C)(C)C2=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
A mixture of 7-methoxy-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (1.10 g, 4.99 mmol) synthesized in Reference Example 68, 48% hydrobromic acid (20 mL) and acetic acid (4 mL) was stirred at 100° C. for 15 hours. The reaction solution was poured into cold saturated sodium bicarbonate water in ice bath and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5 to 80/20) to give 980 mg of the title compound (yield: 95%).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][NH:34]2)=[CH:30][CH:29]=1)[CH3:26].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CCOCC.O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][N:34]1[C:35]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH2:25][CH3:26])[CH:36]=2)[CH:32]=[CH:33]1
Reactant: CCOc1ccc2cc[nH]c2c1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc2ccn(CC(=O)OC)c2c1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Potassium tert-butoxide (0.77 g, 6.9 mmol) was stirred with dry ether (50 ml) containing 18-crown-6 (0.164 g, 0.62 mmol). 6-Ethoxyindole (1.0 g, 6.2 mmol) was added portionwise over 15 minutes at room temperature. This was stirred for 1/2 hour then cooled to 0° C. when methyl bromoacetate (0.65 ml, 6.9 mmol) in ether (5 ml) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature then poured into water (150 ml) and extracted with ether (2×100 ml). The extracts were washed with brine (2×75 ml), dried and concentrated to give crude methyl(6-ethoxyindol-1-yl)acetate (1.4 g, 96% yield) as a brown oil.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH:14]=1.C(O)C>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([NH2:24])[CH:18]=2)[CH:12]=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(C#Cc2cncc(Cl)c2)ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Yield: 78 %

Procedure:
Add tin chloride dihydrate (7.13 mg, 31.6 mmol) to a solution of 3-chloro -5-(4-fluoro-3-nitrophenylethynyl)-pyridine, (prepared as described in EXAMPLE 189) (0.97 g, 3.51 mmol) in 2:1 ethanol:tetrahydrofuran (150 mL). Heat the mixture at 70° C. for 2.5 h. Cool to room temperature and concentrate. Dilute with a 50% solution of aqueous potassium hydroxide (300 g) and extract with diethyl ether (5×150 mL). Wash the combined extracts with water (1×50 mL) and saturated aqueous sodium chloride (1×50 mL). Dry (sodium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a light yellow solid (670 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-fluoropyridin-2-yl)oxy]benzoic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 7.99 (1H, d, J=2.6 Hz), 7.97 (1H, d, J=3.1 Hz), 7.92 (2H, d, J=8.4 Hz), 7.50–7.39 (2H, m), 7.35–7.21 (3H, m), 6.99 (1H, d, J=8.6 Hz), 6.86 (1H, dd, J=8.9, 3.3 Hz), 5.31–5.17 (1H, m), 3.91 (3H, s), 1.42 (3H, d, J=6.9 Hz); MS (ESI) m/z 429 (M+H)+, 427 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]([OH:16])[C:6]=2[C:5]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[S:19](=[O:20])[C:4]=2[CH:3]=1.[OH:25]O>C(O)(=O)C>[Br:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]([OH:16])[C:6]=2[C:5]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[S:19](=[O:25])(=[O:20])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(O)c2c3c(cc(Br)c2n1)S(=O)c1ccccc1-3
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)c2c3c(cc(Br)c2n1)S(=O)(=O)c1ccccc1-3

Procedure:
To a solution of 0.6 g. of methyl 5-bromo-1-hydroxy[1]benzothieno[3,2-f]quinoline-3-carboxylate-7-oxide in glacial acetic acid is added excess 30 percent hydrogen peroxide. The mixture is heated to its reflux temperature and maintained at reflux for one hour, then allowed to cool. The precipitate is separated by filtration to give methyl 5-bromo-1-hydroxy[1]-benzothieno[3,2-f]quinoline-3-carboxylate-7,7-dioxide, crude m.p. 240°-260° C. Infrared spectral analysis is consistent with the assigned structure. This ester is hydrolyzed using the method of Example 32 (or 33) to provide 5-bromo-1-hydroxy[1]-benzothieno[3,2-f]quinoline-3-carboxylic acid-7,7-dioxide, m.p. 283°-285° C. (dec.). Analysis: Calculated for C16H8BrNO4S. 3/4 H2O: %C, 45.8; %H, 2.3; %N, 3.4; Found: %C, 46.1; %H, 2.2; %N, 3.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH2:19]([NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24])[CH2:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:19]([NH:22][C:23]([CH:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[CH:26]1[CH3:36])=[O:24])[CH2:20][CH3:21]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNC(=O)C1c2ccc(Oc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)cc2N(C)C1C

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2,-b]pyridine 4a with 6-hydroxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide 58b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.6 Hz), 7.96 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.7 Hz), 7.40 (1H, s), 7.06 (1H, d, J=10.7 Hz), 6.72 (1H, d, J=5.6 Hz), 4.61–4.53 (1H, m), 4.15–4.00 (2H, m), 3.91–3.73 (3H, m), 3.73 (3H, s), 3.53–3.40 (2H, m), 2.67 (3H, s), 2.28–2.07 (2H, m), 1.78–1.69 (2H, m), 1,18–1.04 (3H, m). LCMS (ESI+) [M+H]1z Calc'd 493. found 493.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]1(C=C)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1.CC[O:16][C:17](C)=[O:18]>O>[CH3:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:17]([OH:18])=[O:16])=[CH:8][CH:9]=1
Reactant: C=CC1(CC(C)(C)C)C=CC=CC1
Reactant: CCOC(C)=O
Solvent: O
Product: CC(C)(C)Cc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 1.74 g (7.76 mmol) of 4-(2,2-dimethylpropyl)-4-ethenylbenzene (from Step A) in 10 mL EtOAc and 10 mL H2O was added 8.30 g (38.8 mmol) of NaIO4 and 1 mg (0.0078 mmol) RuO2. The reaction mixture was heated to 40° C. for 30 min. The reaction mixture was cooled and stirred at rt for 16 hr. To the reaction mixture was added H2O and EtOAc, and layers were separated. The organic layer was dried and concentrated to dryness to provide 776 mg of the title compound: 1H NMR (500 Mhz) δ 0.91 (s, 9H), 2.53 (s, 2H), 7.12 (d, J=8.0, 2H), 7.84 (d, J=8.0, 2H); ESI-MS 193 (M+H); LC-1: 3.2 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[NH2:15])=O)C.Cl.Cl[C:18]([NH2:20])=[NH:19]>COCCOCCOC>[NH2:20][C:18]1[NH:15][C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[C:4](=[O:3])[N:19]=1
Reactant: CCOC(=O)c1sc2c(c1N)CCCC2
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(=O)c2sc3c(c2[nH]1)CCCC3
Temperature: 160 °C
Yield: 95.5 %

Procedure:
A 48 mL sealed tube was charged with 3-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.8 g, 12.3 mmol), chloroformamidine hydrochloride (2.0 g, 17.2 mmol), and diethylene glycol dimethyl ether (24.6 mL). The tube was sealed and heated to 160° C. for 12 h with vigorous stirring. Filtration afforded the desired compound as a beige solid (2.6 g). MS: No signal. 1H NMR (400 MHz, d6-DMSO) δ ppm 2.84-2.73 (m, 2H), 2.58-2.51 (m, 2H), 1.89-1.70 (m, 4H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+]>CO>[C:14]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydride in methanol=(reaction time: 5hours) followed by purification on a silica gel column using methylene chloride/methanol 20:1. This results in an approximately 50:50 diastereomer mixture of the base. This is recrystalised from a mixture of ether/ethyl acetate=65:10, and twice more from ethyl acetate. This results in diastereomer A in 98-99% purity.