Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[F:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:42]1[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(F)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg), sodium carbonate (45 mg), 4-fluorophenylboronic acid (35 mg), tetrakis(triphenylphosphine)palladium(0) (12 mg), toluene (2.0 ml), water (0.4 ml) and ethanol (0.4 ml) in a pear shape flask with dimroth was deaerated in a vacuum line, substituted with argon and stirred at 80° C. for 12 hrs. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (52 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[C:3](OCC)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[OH-].[Na+].Cl.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:25][C:2]([CH3:1])([C:3]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4])[CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)N1CCOCC1
Temperature: 165 °C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
A solution of ethyl 2,2-dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.1 g, 15 mmol) and morpholine (5 mL, 60 mmol) was heated at reflux overnight. An analysis by LC/MS indicated the reaction was incomplete. The solution was then heated overnight in a high-pressure vessel at 165° C. Again, an analysis by LC/MS indicated the reaction was incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (30 mL). Aqueous sodium hydroxide (1.35 mL of 50%, 20.0 mmol) was added, and the reaction was stirred for 1.5 hours. The solution was adjusted to pH 7 with the addition of concentrated hydrochloric acid (˜1 mL) and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL); a solution of oxalyl chloride (2.5 mL, 28 mmol) in dichloromethane (5 mL) was added dropwise over a period of two minutes. The reaction was stirred for 30 minutes, and additional oxalyl chloride (0.5 mL, 6 mmol) was added. The reaction was stirred for 30 minutes and diluted with dichloromethane (75 mL). A solution of morpholine (4.0 mL, 41 mmol) in dichloromethane (10 mL) was then added dropwise, and the reaction was stirred for two hours. The reaction was diluted with dichloromethane (45 mL), washed with saturated aqueous sodium bicarbonate (3×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The resulting dark oil was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 5.8 g of 1-(2,2-dimethyl-3-morpholin-4-yl-3-oxopropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a semi-solid.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([O:20][CH3:21])[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=3)[C:8]([CH3:22])=[CH:7]2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([O:20][CH3:21])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=3)[C:8]([CH3:22])=[CH:7]2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cc(OC)c2c(C)cn(C3CC3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
4.66 mL of 5 N NaOH aqueous was added to a solution of 3.19 g of ethyl 1-cyclopropyl-3-methyl-4-methoxy-1H-indole-6-carboxylate in 32 mL of MeOH and the mixture was stirred at 60° C. overnight. The mixture was cooled and 46.6 mL of 1N HCl was added thereto. The precipitate was filtered, collected and dried in vacuo to afford 2.70 g of 1-Cyclopropyl-3-methyl-4-methoxy-1H-indole-6-carboxylic acid as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1=[N:8][C:9]([F:12])=[CH:10][CH:11]=[C:6]1[C:5]2=O.C[Mg]Cl.II.[NH3:23]>C1COCC1.[Ag]OC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:14][O:13][C:7]([NH2:8])=[N:23]3)[C:6]3[C:7](=[N:8][C:9]([F:12])=[CH:10][CH:11]=3)[O:13][C:14]2=[CH:15][CH:16]=1
Reactant: N
Reactant: O=c1c2cc(Br)ccc2oc2nc(F)ccc12
Agent: N#CO[Ag]
Agent: C[Mg]Cl
Agent: II
Solvent: C1CCOC1
Product: NC1=NC2(CO1)c1cc(Br)ccc1Oc1nc(F)ccc12
Temperature: -25 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromo-2-fluoro-5H-chromeno[2,3-b]pyridin-5-one (150 mg, 0.510 mmol) in 5 mL of dry THF at −78° C. was added to methylmagnesium chloride, 3.0 M solution in THF (0.33 mL, 1.020 mmol) (0.33 mL) and the reaction was slowly warmed up to −30 C. At this temperature additional methylmagnesium chloride 3.0 M solution in THF (0.3 mL, 1.020 mmol) was added and stirring was continued for 1 hour. The reaction was quenched at −30° C. with saturated NH4Cl (150 mL) and extracted with EtOAc (3×150 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. The derived residue was treated with 1 mg of PPTS in CH2Cl2 at 25° C. for 0.5 h. This mixture was quenched with 0.1 g of NaHCO3 and the solvent was evaporated to dryness to give crude 7-bromo-2-fluoro-5-methylene-5H-chromeno[2,3-b]pyridine which was directly used in the next step. A solution of iodine (27.6 μL, 0.536 mmol) in THF at −25° C. was treated with silver cyanate (76 μL, 2.040 mmol). After 30 min, a solution of the above derived olefin (7-bromo-2-fluoro-5-methylene-5H-chromeno[2,3-b]pyridine) in 20 mL of THF was added dropwise. The slurry was maintained at −25° C. for 2 h at which point the slurry was filtered through celite, washing well with ether. The brown filtrate was concentrated to dryness, taken up in THF (10 mL), cooled to 0° C. and treated with ammonia (2 M solution in 2-propanol, 1.1 mL, 2.040 mmol). The reaction was allowed to slowly warm to rt and stirred overnight. Half of the solvent was evaporated in vacuo and the residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification by silica gel chromatography (CH2Cl2 to CH2Cl2/EA=3:1 to 2:1 to 1:1 to 1:2) afforded 7-bromo-2-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [OH-].[K+].[C:3]1([C@H:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C)=O>O>[C:3]1([CH:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(N)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Solid, powdered potassium hydroxide (4.6 mg, 8.2×10-5 mol) and (R)-1-phenylethylamine (98% ee) (1.00 g, 8.25×10-3 mol) are mixed with dimethyl sulfoxide (5 ml, 0.07 mol), and the mixture is heated to 80°C. and kept at this temperature for 16 h. The mixture is then cooled and diluted with water (5 ml), and the amine is extracted into ether (2×10 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to give 0.85 g (85%) of substantially racemic 1-phenylethylamine; purity >96% by 1HNMR, ratio (S):(R) recovered by HPLC with chiral column as 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:11]=[C:12]([CH:24]=[O:25])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH2:35]([Mg]Br)[CH3:36].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[CH:11]=[C:12]([CH:24]([OH:25])[CH2:35][CH3:36])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: COC(Cn1cc(C=O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(O)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: -78 °C

Procedure:
To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-formyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (168 mg) in tetrahydrofuran (6 ml) was added dropwise 0.89 M ethylmagnesium bromide (1.09 ml) with stirring at −78° C. After stirring at the same temperature for 10 min, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1–4:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (137 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:20]#[N:21])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: [C-]#N
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of benzyl bromide 4 (0.0758 g, 0.238 mmole) in 5 mL dimethylformamide was added pulverized potassium cyanide (0.0232 g, 0.3563 mmole) and 18-crown-6 ether (0.100 g, 0.378 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.046 g (82%) of benzyl nitrile 5 as a yellow solid: Mp=128-130° C.; 1H NMR (DMSO-d6) δ 7.85 (d, 2 H, 8.7 Hz), 7.19 (s, 1 H), 7.06 (d, 2 H, J=8.7 Hz), 7.00 (d, 1 H, J=2.5 Hz), 6.88 (d, 1 H, J=2.1 Hz), 3.82 (s, 3 Hz), 3.79 (s, 3 H); MS, 285 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH2:29][CH2:30][CH3:31])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1N
Yield: 81.3 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-propoxypiperidin-1-yl)benzoate obtained in Example (178a) (78 mg, 0.18 mmol) and a 10% palladium-carbon catalyst (100 mg), to obtain 42.8 mg of the title compound as a pale yellow oily substance (80%). The resulting compound was used for the next reaction without purification.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C1COCC1.[Zn].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
Zn dust (520 mg, 7.95 mmol) was vigorously stirred in THF (2 ml) under nitrogen and 1,2 dibromoethane (84 μl, 0.97 mmol) was added. The suspension was then heated at 80° C. for 8 min and next allowed to cool to room temperature. Trimethylsilyl chloride (115 μl, 0.92 mmol) in THF (1 ml) was then added and the mixture further stirred at room temperature for 45 min. A solution of 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (1.74 g, 6.14 mmol) in THF (2 ml) was then added dropwise to the solution over a period of 15 min and the reaction mixture stirred at room temperature for 2 h. Pd2(dba)3 (90 mg, 0.10 mmol) and P(2-furyl)3 (85 mg, 0.36 mmol) were then added to the mixture, followed by 2-bromo-5-nitropyridine (1.37 g, 6.74 mmol) in THF (4 ml). The mixture was then heated at 55° C. for 3 h, cooled to room temperature and quenched with saturated aqueous NaCl. Extraction with CH2Cl2, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (heptane:ethyl acetate, 3:1) to give the title compound (1.22 g, 71%) as a light yellow oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Br:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN([CH:25]=[O:26])C>C1COCC1>[Br:11][C:12]1[C:13]([CH:25]=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CN(C)C=O
Reactant: Brc1cnc2ccccc2c1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To isopropylmagnesium chloride lithium chloride complex solution (1.3M in THF; 50 mL, 65 mmol) was added 2,2,6,6-tetramethylpiperidine (11.5 mL, 68.3 mmol) dropwise, and the mixture was stirred overnight at room temperature. To 55 mL of the resulting solution at −25° C. under N2 was added 3-bromoquinoline (6.52 mL, 48 mmol) dropwise, and the reaction was stirred for 1 hour. DMF (3 mL) was added, and the reaction was slowly warmed to room temperature and monitored by analytical LCMS. The mixture was quenched with saturated aqueous NH4Cl and worked-up. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: CCN1CCc2sccc2C(O)C1
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: CCN1CCc2sccc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.C([Li])(CC)C.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[OH:25][C:19]1([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: Oc1ccc(Br)nc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2(O)CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a solution of 6-bromo-pyridin-3-ol (5.0 g, 28.7 mmol) in anhydrous THF (75 mL) and anhydrous toluene (40 mL) at −78° C. was added n-butyllithium (2.5 M in hexane, 28.73 mmol). The mixture was stirred for 20 min. A solution of sec-butyllithium (1.4 M in cyclohexane, 43.1 mmol) was added dropwise and the mixture stirred at −78° C. for 1 hour. To the mixture was added cyclohexanone (4.23 g, 43.1 mmol) in THF (25 mL) at −78° C. and the mixture stirred at −78° C. for 1 hour. Saturated NaH2PO4 solution (10 mL) was slowly added to the mixture and the mixture then warmed to room temperature. Water (300 mL) was added. The reaction mixture was neutralized with hydrochloric acid (2N), and the mixture extracted three times with EtOAc. The organic layer was washed with brine and dried (Na2SO4). Silica gel chromatography (EtOAc/heptane) provided 2.63 g of the title compound. C11H15NO2 (193.11), LCMS (ESI): 194.09 (M++H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:6]([C:10](Cl)=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].[CH3:13][OH:14].Cl>C(Cl)(Cl)Cl>[CH3:13][O:14][C:10]([C:6]1[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:9][S:8][CH:7]=1)=[O:11]
Reactant: CO
Reactant: O=C(Cl)c1cscc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1S(=O)(=O)Cl

Procedure:
44.1 G. (0.18 mol) of the obtained 4-chlorosulfonylthiophene-3-carboxylic acid chloride are dissolved in 450 ml. of absolute chloroform, 9.6 g. (0.3 mol) of absolute methanol are added and the solution is heated to reflux for 9 hours [until termination of the hydrogen chloride evolution]. The mixture is then evaporated to dryness in vacuo, the residue crystallizing out. There is obtained 4-chlorosulfonylthiophene-3-carboxylic acid methyl ester, which can be converted into the 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[3,4-e]-1,2-thiazine-3-carboxamide 1,1-dioxide in a manner analogous to that described in the last four paragraphs of Example 5.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.[I:21]I>C(OCC)(=O)C.C1COCC1>[I:21][C:20]1[C:15]([O:14][CH3:13])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: II
Reactant: COc1cnccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1nccnc1I
Reaction time: 0.33 h

Procedure:
To 20 ml of an anhydrous THF solution of 1.3 g of diisopropylamine was added 4.8 ml (2.5 M hexane solution) of n-butyllithium at −78° C., and the mixture was stirred at that temperature for 20 minutes. To the reaction mixture was added 10 ml of a THF solution of 1.1 of 2-methoxypyrazine, followed by stirring at −78° C. for 1 hour. To the reaction mixture was further added 10 ml of a THF solution of 4.0 g of iodine, followed by stirring for 4 hours while gradually elevating the temperature to room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform as a developing solution. The fraction containing the desired compound was concentrated to give 0.49 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:16])[C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21][C:5]=2[O:4][C:2]1=[O:3]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 2 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuranipyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 14.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[F:22])C1C=CC=CC=1>CCO.[Pt](=O)=O>[NH2:21][C:16]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:22])[CH:11]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1ncccc1-c1ccc(OCc2ccccc2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ncccc1-c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 3-(4-(benzyloxy)-3-fluorophenyl)pyridin-2-amine (8.5 g), and platinum(IV) oxide (400 mg) in EtOH (200 mL) was stirred at room temperature under hydrogen overweekend. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (3.20 g) as a pale yellow solid.