Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[O:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:2]3[CH:3]=[CH:4][C:5]4[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-morpholinophenyl borate (581.3 mg) and potassium carbonate (0.65 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphine palladium (0.14 g), and the mixture was refluxed for 20 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/dichloromethane=1:4) to give yellow crystals of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylate (664.4 mg).
Reaction SMILES: [OH:1][CH:2]([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1>O1CCOCC1.O=[Mn]=O>[CH3:21][N:20]1[C:16]([C:2]([CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:1])=[CH:17][N:18]=[CH:19]1
Reactant: Cn1cncc1C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A homogeneous solution of tert-butyl 4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylate (32.2 g, 109 mmol; Intermediate 58: step a) in dioxane (436 mL) was treated with MnO2 (47.6 g, 547 mmol) and stirred at 100° C. under air overnight (17 hours). Since the reaction was only ˜50% complete by NMR, the reaction was cooled to room temperature, additional MnO2 (48.0 g, 552 mmol) was added and the reaction stirred under air at 100° C. for 6.5 hours, then at room temperature for 18 days. The mixture was then filtered through a pad of Celite® and the black filter cake washed with EtOAc. The crude filtrate was treated with a third portion of MnO2 (28.5 g, 327 mmol) and stirred at room temperature overnight. The reaction was then filtered as above and concentrated to provide the crude title compound as a clear dark yellow oil. The crude material was flash chromatographed with an EtOAc to 50% acetone/EtOAc gradient to provide the title compound as a clear dark yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][C:12]#[CH:13].[OH:14]O>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][C:12]#[CH:13])=[O:14]
Reactant: OO
Reactant: C#CCSc1c(O)cc(C)oc1=O
Solvent: CC(=O)O
Product: C#CCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a suspension of 23.1 g. (0.124 mole) of 4-hydroxy-6-methyl-3-propargylthio-2-pyrone in 200 ml. of glacial acetic acid was added 14.1 g. (0.124 mole) of 30% hydrogen peroxide in 50 ml. of glacial acetic acid dropwise over a period of 20 minutes. The reaction mixture was stirred at room temperature for approximately 60 hours and then poured into 400 ml. of ice water. When no precipitate appeared, the solution was extracted with four 100 ml. portions of chloroform, and the extract was dried over anhydrous sodium sulfate. The chloroform was removed by evaporation in vacuo, leaving a solid residue and some acetic acid. The latter was removed by desiccation over sodium hydroxide at 0.2 mm. Hg. for four hours. The crude product was then recrystallized from ethanol, giving 17.7 g. (67 percent) of pale yellow crystals, m.p. 131°-134°C. A second recrystallization from ethanol gave the pure 4-hydroxy-6-methyl-3-propargylsulfinyl-2-pyrone as pale yellow needles, m.p. 133.5°-134.5°C.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:13])[C:4]([C@H:6]1[CH2:12][CH2:11][C@@H:10]2[C@@H:8]([O:9]2)[CH2:7]1)=[O:5]>>[NH2:1][C@H:8]1[C@H:10]([OH:9])[CH2:11][CH2:12][C@H:6]([C:4]([N:3]([CH3:13])[CH3:2])=[O:5])[CH2:7]1
Reactant: CN(C)C(=O)[C@H]1CC[C@H]2O[C@H]2C1
Reactant: N
Product: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](N)C1
Temperature: 40 °C

Procedure:
A 28% aqueous ammonia solution (5 ml) was added to (1S,3S,6R)—N,N-dimethyl-7-oxabicyclo[4.1.0]heptane-3-carboxamide (10) (1 g) at room temperature. The mixed solution was stirred at 40° C. for hours, and then, the solvent was concentrated under reduced pressure to obtain (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethylcyclohexanecarboxamide (1.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:39]OS(O)(=O)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:39])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 9.6 %

Procedure:
To a solution of 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 41) (1.9 mmol) in 25 mL of dry THF was added n-Bu4MgCl (3.8 mL of 2.0M THF solution, 7.5 mmol) slowly at 0° C. After stirring for additional 15 minutes, the solution was stirred at room temperature for 2 hours. The reaction mixture was re-cooled to 0° C. and triethylborane (9.5 mL of 1.0M THF solution, 9.5 mmol) was added. After stirring at for 2 hours, the mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with a solution of sodium acetate (2.3 g) in 10 mL of water. After stirring for 5 minutes, hydroxylamine-O-sulfonic acid (2.3 g) was added and the mixture was stirred for 20 hours. The reaction mixture was extracted with ether (2×100 mL). The ethereal layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (isopropanol/toluene, 5:95) to give 0.07 g of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl) -1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (8%): mp 242°-243° C. Anal. Calc'd. For C16H13F3N4O2S: C, 50.26, H, 3.43, N, 14.65, S, 8.39. Found: C, 50.02, H, 3.63, N, 14.26, S, 8.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C@H:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:32]>>[ClH:32].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C@H:13]([CH:21]([CH3:23])[CH3:22])[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 4 h

Procedure:
t-Butyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate (5.3 g, 12.2 mmol) is dissolved in methylene chloride (150 mL) and cooled to -10° C. Hydrochloric acid gas is bubbled into the solution for 10 minutes. The reaction mixture is then sealed, warmed to room temperature and stirred for 4 hours. The solvent is then evaporated to provide 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanoic acid hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Reactant: NCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 7 days. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H2O (3×15 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to give a yellow solid. The yellow solid was triturated with MeOH (1 mL) and the solid was collected by filtration to give intermediate (I-3a) as a white solid (48.5 mg).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([CH3:33])[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[CH3:36]B1OB(C)OB(C)O1>>[CH3:35][O:34][C:4]1[CH:3]=[C:2]([CH3:36])[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([CH3:33])[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:20][CH:21]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 71.7 %

Procedure:
Following General Procedure J, (S)-tert-butyl 2-(4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (150 mg, 0.269 mmol) was reacted with trimethyl boroxine (102 mg, 0.8 mmol) to afford the desired product (95 mg, 75%) as a brown solid: ESI MS m/z 493 [C28H32BrN2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[NH:24][C:23](=S)[C:22]=3[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=[CH:37][CH:36]=1>>[CH:15]1([C:20]2[S:29][C:28]3[NH:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[N:24]=[C:23]([N:13]4[CH2:12][CH2:11][NH:10][C@@H:9]([CH2:5][CH2:6][C:7]5[CH:37]=[CH:36][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=5)[CH2:14]4)[C:22]=3[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccncc1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Reactant: COc1cccc([C@H]2CNCCN2)c1
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C5CCCC5)nc43)CCN2)c1
Temperature: 85 °C

Procedure:
By using a method similar to the method of Example 491, using (S)-2-(3-methoxy-phenyl)-piperazine (1.10 g, 5.0 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.540 g, 1.79 mmol) in 6 ml of pyridine, and heat to 85° C. for 5 hour. After purification, give 310 mg of title compound as brown solid. Mass spectrum (electrospray) (m/e): C28H33N5OS, Cacl. Mass: 487.24; Found: 488.1 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 7.21–7.17 (m, 1H), 7.05–6.97 (m, 2H), 6.86 (dt, 1H, J=7.3 Hz, J=1.9 Hz), 6.79–6.72 (m, 3H), 6.61 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.78 (s, 3H), 3.02–2.89 (m, 4H), 2.69–2.63 (m, 3H), 2.07–2.04 (m, 2H1), 1.77–1.48 (m, 10M).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:36]([OH:44])[CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:36](=[O:44])[C:37]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)=[O:2])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(=O)c2ccncc2)cc1OC1CCCC1
Reaction time: 0.5 h

Procedure:
Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL) under nitrogen is treated with (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (2.0 g; that is prepared as described in Reference Example 67), in one portion. The resulting mixture is stirred for 1 hour and 30 minutes, and then filtered through a pad of diatomaceous earth, and the pad is washed with diethyl ether. The combined flitrate and ethereal washings are washed with saturated aqueous cupric sulfate solution (2×30 mL), followed by water (30 mL), and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the resulting oily residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione (0.4 g), in the form of a yellow solid, m.p. 117°-119° C. [Elemental analysis: C,70.1; H,6.0; N,4.1%; calculated: C,70.1; H,5.9; N,4.3%].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:25]1[CH2:28][C:27]([CH2:31][NH2:32])([CH2:29][NH2:30])[CH2:26]1>>[NH2:30][CH2:29][C:27]1([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:28][O:25][CH2:26]1
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2cc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.31 (d, 1 H), 7.85-7.74 (m, 4 H), 7.60-7.55 (m, 2 H), 6.22 (s, 1 H), 5.45 (d, 1 H), 5.11 (d, 1 H), 4.68 (brs, 1 H), 4.65-4.56 (m, 4 H), 4.47 (d, 1 H), 3.91 (m, 2 H), 3.55 (m, 2 H), 3.47 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[S:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e]-[1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaCHO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: N1N[CH:3]=[C:4]2C=COC=12.Cl[C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:21])[C:11]=1[CH:22]=O.C([CH:26]([OH:30])[C:27]([O-:29])=[O:28])C>>[CH3:21][C:12]1[C:11]2[CH:22]=[C:26]([C:27]([O:29][CH2:3][CH3:4])=[O:28])[O:30][C:10]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1
Reactant: c1cc2c[nH]nc2o1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: CCC(O)C(=O)[O-]
Product: CCOC(=O)c1cc2c(C)nn(-c3ccccc3)c2o1

Procedure:
Furo[2,3-c]pyrazole compounds were first synthesized by two of the present inventors, L. J. Haung and S. C. Kuo, and H. T. Li in an article published in J. Taiwan Pharm. Assoc. 31 (1), 47-55 (1979). Ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3) was synthesized in this article. As shown in the following Scheme 1, chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) and ethylglycolate (2) were condensed to form ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3); or 5-hydroxy-3-methyl-1-phenylpyrazole-4-carboxal-dehyde acetate (4) was reacted with ethylbromoacetate (5) to obtain the ethyl 3-methyl-1-phenylfuro[2,3-c]pyrazole-5-carboxylate (3). The product produced by these two methods are very low in yield and stability. Therefore, only one furo[2,3-c]pyrazole compound (3) was synthesized and no further investigation was conducted in the above-mentioned article. ##STR1##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:19])(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH:29]=[O:30].Cl>C1COCC1>[CH2:15]([CH:14]([CH:29]([OH:30])[CH2:28][CH:27]([O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:13]([OH:19])=[O:18])[CH:16]=[CH2:17]
Reactant: CCCCCCCCCCCC(CC=O)OC1CCCCO1
Reactant: C=CCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC(C(=O)O)C(O)CC(CCCCCCCCCCC)OC1CCCCO1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
C)a) 2 ml of diisopropylamine in 30 ml of dry THF were cooled to -20° C. and thereupon 9.68 ml of butyl lithium (1.6 M/hexane) were added dropwise in such a manner that the temperature did not exceed -20° C. The mixture was subsequently stirred for 15 minutes and then cooled to -50° C. Thereafter 0.720 ml of 4-pentenoic acid in 10 ml of THF was added dropwise and the mixture was stirred at 50° C. for a further 10 minutes. The mixture was stirred at room temperature for 1 hour and subsequently again cooled to -50° C. 2 g of rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal in 10 ml of THF were now added dropwise and the mixture was stirred at -50° C. for a further 30 minutes, then at room temperature for 72 hours. After hydrolysis with 2N hydrochloric acid the reaction mixture was evaporated. The residue was extracted with ether. The organic phase was dried over sodium sulfate, filtered and evaporated. The material obtained was filtered through a column of silica gel. There was obtained 2-allyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl) oxy]hexadecanoic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=1[F:16])(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:4]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[F:16])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=S(=O)(CCCCl)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(F)c1F)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5.9 mmol 1-(3-chloro-propane-1-sulfonyl)-2,3,4-trifluoro-benzene in 200 ml THF at −78° C. was added dropwise over 30 min 7.0 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT, and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HCl and extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 237.2 (M+H+, 100%)
Reaction SMILES: [CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>ClCCCl.CN(C1C=CN=CC=1)C>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CC3C(CN(C(=O)c4cccs4)c4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (60 mg, 0.15 mmol) in 3 mL of DCE was added DIEA (0.026 mL, 0.45 mmol), DMAP (cat.) and 4-tert-butylbenzene sulfonyl chloride (0.10 mL, 0.45 mmol). The resulting mixture was heated to 80° C. for 1.5 hours, cooled to room temperature and quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried and concentrated. The resulting crude material was purified via flash chromatography with 40% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 70 mg of a white foam. 400 MHz 1H NMR (CDCl3) δ 7.62-7.66 (m, 2H), 7.47-7.50 (m, 2H), 7.29-7.31 (m, 1H), 6.79-6.95 (m, 5H), 3.87-3.89 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.46 (d, J=9.13 Hz, 2H), 3.13-3.15 (m, 4H), 2.94-2.96 (m, 2H), 1.64 (s, 2H), 1.31 (s, 9H), 1.12-1.14 (m, 1H); MS (M+1) 598.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(Cl)cc(Cl)c(C(=O)O)c1N
Yield: 9.6 %

Procedure:
To a stirred solution of aniline 2-3 (11.5 g, 460 mmol) in methanol (250 mL) and H2O (70 mL) was added 2N NaOH (25 mL). The reaction mixture was heated under reflux for 1 h, more 2N NaOH (25 mL) was added and the mixture was heated under reflux for a further 1 h. The solution was cooled and methanol was removed in vacuo. The mixture was dissolved in H2O and extracted with ethyl acetate. The aqueous layer was acidified to pH 2 with conc. HCl. and then extracted into ethyl acetate (×3). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide the acid 2-4 as a beige solid (10.4 g, 95% yield). 1H NMR (MeOD, 400 MHz) δ 3.80 (s, 3H), 6.70 (s, 1H).