Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C[Si](C)(C)CCOC[O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]COCC[Si](C)(C)C)=[C:19]2[C:14]=1[CH2:15][O:16][C:17]2=[O:18]>CO>[OH:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][O:16][C:17]2=[O:18]
Reactant: C[Si](C)(C)CCOCOc1ccc(OCOCC[Si](C)(C)C)c2c1COC2=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C1OCc2c(O)ccc(O)c21
Temperature: 23 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of concentrated sulfuric acid (4.0 mL, 75 mmol, 15 equiv) in dry methanol (50 mL) at 23° C. was added to a solution of 4,7-bis[[2-(trimethylsilyl)ethoxyl]methoxy]phthalide (60, 2.148 g, 5.034 mmol, 1 equiv) in dry methanol (50 mL) at 23° C. The reaction mixture was stirred for 2.0 h at 23° C. The product solution was partitioned carefully between saturated aqueous sodium bicarbonate solution (200 mL), saturated aqueous sodium chloride solution (150 mL), and ethyl acetate (100 mL). The aqueous layer was separated and extracted further with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and were concentrated affording the 4,7-dihydroxyphthalide (57) as an off-white solid (821 mg, 98%), which was used without further purification. ##STR65##
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH3:22])=[O:2]
Reactant: CCO
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Reaction time: 10 h
Yield: 67.7 %

Procedure:
74.5 g (324.8 mmol) of N-carboxymethylene-4-chloroanthranilic acid are suspended in 1660 g of ethanol, 2.9 g (2.96 mmol) of concentrated sulfuric acid are added and the mixture is heated at the boiling point for 10 hours. After a reaction time of 5 hours, the same amount of sulfuric acid is again added. After 10 hours, the ethanol is distilled off and the product which precipitates out is filtered off in the cold and washed with cold ethanol. 55.5 g (0.22 mol, 73%) of N-carboethoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(C)([O-])C.[K+].CS(O[C@H:27]1[CH2:30][C@@H:29]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:28]1)(=O)=O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[CH3:14][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[O:15][C@H:27]1[CH2:28][C@H:29]([CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:30]1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](CN2CCOCC2)C1
Reactant: Cc1cc(O)cc(C)c1CN1CCCC1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cc1cc(O[C@H]2C[C@H](CN3CCOCC3)C2)cc(C)c1CN1CCCC1
Reaction time: 0.17 h

Procedure:
A solution intermediate 60, 3,5-dimethyl-4-(pyrrolidin-1-ylmethyl)phenol (0.62 g, 3.0 mmol) and potassium tert-butoxide (3 mL, 1M THF, 3.0 mmol) in DMSO (10 mL) was heated to 100° C. under vigorous stirring. The mixture was stirred at this temperature for 10 min. A solution of intermediate 41, cis-3-(Morpholin-4-ylmethyl)cyclobutyl methanesulfonate (0.3 g, 1.2 mmol) in DMSO (10 mL) and tetrabutylammonium bromide (0.16 g, 0.48 mmol) were added. The mixture was stirred at 100° C. overnight, cooled, and diluted with Et2O (50 mL). The solution was washed with water (50 mL), 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography using a 40 g ISCO column eluting with a gradient of 5%, 10% MeOH:CHCl3 with 0.2% NH4OH. The product containing fractions were collected and concentrate to give the title compound (282 mg, 66% yield) as an oil. LCMS-data: 359.2 (M+H)+ (calculated for C22H34N2O2 358.5). 1H NMR data (CDCl3) 6.43 (s, 2H), 4.71-4.68 (m, 1H), 3.71-3.69 (m, 4H), 3.54 (s, 2H), 2.62-218 (m, 21H), 1.63-1.80 (m, 4H); C13 NMR (CDCl3) d 156.1, 139.2, 114.6, 70.7, 67.2, 65.1, 54.2, 54.0, 52.9, 34.3, 26.4, 23.8, 20.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.O.[C:31]([OH:35])(=[O:34])[CH:32]=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]2[C:7]=1[CH:32]([C:31]([OH:35])=[O:34])[N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH2:9][CH2:8]2
Reactant: COc1ccc(Br)cc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c2c1CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)O
Reaction time: 12 h
Yield: 92.1 %

Procedure:
0.81 g (1.7 mmol) of N-[2-(5-bromo-2-methoxyphenyl)ethyl]-4-(4-fluorophenoxy)-benzenesulfonamide (crude product, 21A) is stirred with 0.32 g (3.4 mmol) of glyoxylic acid monohydrate in 10 ml of trifluoroacetic acid at room temperature. After 12 hours, the mixture is poured onto ice and extracted with dichloromethane. Drying with MgSO4 and concentration result in 0.84 g of the title compound which can be reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(O)(CC)(C)C>[Cl:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1
Reactant: CS(=O)(=O)c1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Reactant: C1COCCN1
Solvent: CCC(C)(C)O
Product: FC(F)(F)c1ccc(Nc2nc(N3CCOCC3)nc3sc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 130 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
To a mixture of [2-(2,6-dichloro-benzyl)-5-methanesulfonyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (49 mg, 0.1 mmol) in tert-amyl alcohol (2 mL) was added morpholine (24 mg, 0.3 mmol). The resulting mixture was heated to 130° C. in a sealed tube. After 12 h, the solution was cooled and purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (37 mg, 77%). MS (ESI): mass calcd. for C23H18Cl2F3N5OS, 539.0; m/z found, 540.0 [M+H]+. 1H NMR ((CD3)250): 10.14 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.49-7.42 (m, 1H), 4.69 (s, 2H), 3.66 (s, 8H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.NC[CH2:72][N:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:72][N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: NCCN1CCOCC1
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(NCCN3CCOCC3)nc2s1
Yield: 34 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 4-(2-aminoethyl)morpholine (1.531 mmol, 201 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-morpholinoethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96e (12 mg, 34%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.24 (s, 3H), 2.46 (br s, 4H), 2.56 (br s, 2H), 3.50 (br s, 2H), 3.60 (br s, 4H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.75 (m, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.18 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=584 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)/[CH:7]=[CH:8]/[C:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=2[S:11][CH:10]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1COCC1.C(OCC)(=O)C>[NH2:18][C:17]1[C:12]2[S:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]3[CH:19]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=4)[CH:3]=[CH:4][C:5]=3[CH3:20])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
(E)-7-(5-amino-2-methylstyryl)thieno[3,2-d]pyrimidine-4-amine (100 mg, 0.354 mmol) was dissolved in anhydrous THF, TEA (0.1 mL, 0.709 mmol) and 3-(trifluoromethyl)benzoyl chloride (81 mg, 0.390 mmol) were added thereto at room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (138 mg, 86% yield) (see Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:11]([CH3:13])[CH3:12])[C:6]=1[C:7]([O:9]C)=[O:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:11]([CH3:13])[CH3:12])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1c(Cl)cnn1C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1ncc(Cl)c1C(=O)O
Temperature: 105 °C
Yield: 99.2 %

Procedure:
A solution of methyl 4-chloro-1-(1-methylethyl)-1H-pyrazole-5-carboxylate (130 mg) in 1,4-dioxane (3 ml) was treated with 2M hydrochloric acid (3 ml) and the mixture heated at 105° C. for 90 h. The mixture was evaporated in vacuo to give the title compound as a white solid (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Br:48])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1-c1ccc(CO)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(OC)c1-c1ccc(CBr)c([N+](=O)[O-])c1

Procedure:
To a solution of 1.8 g (6.23 mmol) of 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl alcohol and 2.3 g (8.72 mmol) of Ph3P in CH2Cl2 (20 mL) at 0° C. was added 1.32 g (7.5 mmol) of NBS. The reaction mixture was stirred at 0° C. for 30 min at which time TLC analysis (eluted with 25% Et2O in hexanes) indicated that the starting material had been consumed. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel eluted with 50% Et2O in hexanes to give 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl bromide as a pale yellow solid. Trituration with hexanes gave the product as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:32][N:33]1CCOCC1.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:33][CH3:32])=[O:5]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 20 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.061 mL, 0.556 mmol), methanamine-HCl (4.70 mg, 0.070 mmol), and HATU (39.7 mg, 0.104 mmol). The reaction mixture was stirred overnight and then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.7 min) to give (R/S)-2-hydroxy-N-methyl-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (7 mg, 0.014 mmol, 20.3% yield): LCMS=445.1 [M+H]+); 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=7.92 Hz), 7.65-7.78(4 H, m), 7.49-7.66 (3 H, m), 5.12 (1 H, s), 2.79(3 H, s); HPLC Peak RT=8.3 min (Analytical Method A).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:26]([OH:28])[CH3:27])[C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[OH:28][C@@H:26]([CH3:27])[C@@H:13]([NH:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[O:15][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.4 %

Procedure:
To a solution of N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.69 g, 1.75 mmol) in THF (100 mL) were added PS-BEMP (2.39 g, 5.27 mmol, ˜2.2 mmol/g) and p-TsCl (353 mg, 1.85 mmol) at room temperature. The mixture was stirred at room temperature for 14 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (167 mg, 25%) as a foam and the dehydration product 4-(1-(5-phenyl-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (33 mg, 5%). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51˜7.57 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.22 (dd, J=4.7, 8.4 Hz, 1H), 4.80 (b, 1H), 4.65 (m, 1H), 1.42 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.05 (m, 2H), 7.95 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.55˜7.62 (m, 4H) 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:14][CH:15]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: COC(=O)CC(N)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COC(=O)CC(NS(=O)(=O)c1ccc(C)cc1)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1

Procedure:
Using a procedure similar to that described in Example 19, but starting from the product of Example 61, step (iii) and p-toluenesulphonyl chloride, the title compound was prepared; NMR(CDCl3): 1.34-1.55(m,2H), 1.95(d,2H), 2.0-2.2(m,1H), 2.38(s,3H), 2.62-3.05(m,4H), 3.55(s,3H), 3.78(d,2H), 3.96(d,2H), 4.65(m,1H), 5.65(brs,1H), 6.7(d,2H), 6.72(d,2H), 7.05(d,2H), 7.2(d,2H), 7.65(d,2H), 8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 524(M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=1[O:11][CH3:12])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(OC(=O)COCc2ccccc2)c(OC)c1OC
Reaction time: 2 h

Procedure:
6-Nitro-2,3,4-trimethoxyphenol (1.25 g) and triethylamine (1.12 mL) were dissolved in dichloromethane (20 mL), benzyloxyacetyl chloride (1.1 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours as it is. The reaction mixture was extracted with chloroform, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound. Yield: 1.38 g (66.5%).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:3]=[O:4].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13]/[CH:14]=[CH:15]/[CH3:16])[CH:3]=[O:4]
Reactant: CC(C=O)CSc1ccccc1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C/C=C/CC(C)(C=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 3-buten-2-ol (18.04 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) are added to 90 ml of xylenes. The reaction mixture is heated to reflux using a Dean-Stark trap to collect water. After 3 hours, the mixture is cooled to room temperature and quenched with 30 ml of saturated NaHCO3 solution. The two phases are separated and the aqueous phase is extracted with 30 ml of ethyl acetate. The combined organic extracts is washed with 20 ml of brine and dried with Na2SO4. After removing solvents, the crude product is purified by chromatography. The product is obtained in 74.3% as a colorless oil.
Reaction SMILES: S1C=CC2C=CCCC1=2.II.[I:12][CH:13]1[CH2:21][CH2:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]1[N:22]=[C:23]=[O:24].[NH3:25]>[Ag]N=C=O>[I:12][CH:13]1[CH2:21][CH2:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]1[NH:22][C:23]([NH2:25])=[O:24]
Reactant: O=C=NC1c2ccsc2CCC1I
Reactant: N
Agent: O=C=N[Ag]
Agent: C1=Cc2ccsc2CC1
Agent: II
Product: NC(=O)NC1c2ccsc2CCC1I

Procedure:
A sample of 6,7-dihydrobenzo[b]thiophene is stirred with silver isocyanate and iodine as described in Example 39 and the resulting product, 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is treated with concentrated ammonia solution to afford 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea. This latter product is then reduced in the manner described in Example 40 to afford 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 71.7 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (80 mg, 0.134 mmol), 4-methylsulfonyl phenylboronic acid (80 mg, 0.401 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9.4 mg, 0.013 mmol) in dioxane (1 mL) was added an aqueous sodium carbonate solution (2 M, 0.2 mL, 0.4 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous sodium bicarbonate solution (2×3 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (56 mg, 72%) as a light yellow solid: LC/MS m/e calcd for C29H30N2O5S3 [M+H]+ 583.76, observed 583.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:18]2[C:19]([F:21])=[CH:20][C:10]3[C:11]([CH:17]=2)=[N:12][C:13]2[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=2[CH:9]=3)[CH2:29]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN(C)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, 1.2 g of 3-(dimethylamino)azetidine dihydrochloride and 1.5 g of sodium carbonate in 30 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 5 hours. After cooling to approximately 20° C., the reaction mixture is treated with 60 cm3 of water. The insoluble matter is drained and washed with 3 times 20 cm3 of water. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine are obtained in the form of a yellow solid, melting point 224° C., which is used without further purification for the subsequent steps.