Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[S:2]([O-:5])([O-:4])=[O:3].[K+:6].[K+].S(S([O-])=O)([O-])(=O)=O.[K+].[K+].[C:17]([F:26])([O:21][C:22]([F:25])([F:24])[F:23])=[C:18]([F:20])[F:19]>O>[F:19][C:18]([F:20])([S:2]([O-:5])(=[O:4])=[O:3])[CH:17]([F:26])[O:21][C:22]([F:25])([F:24])[F:23].[K+:6]
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: O=S([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)OC(F)(F)F
Temperature: -35 °C

Procedure:
A 1-gallon Hastelloy C276 reaction vessel is charged with a solution of 114 g potassium sulfite hydrate (KHSO3.H2O, 95%, Aldrich, 0.72 mol), 440 g potassium metabisulfite (K2S2O5, 99%, Mallinckrodt, 1.98 mol) and 2000 mL of deionized water. The pH of this solution is 5.8. The vessel is cooled to −35° C., evacuated to −3 psig (81 kPa), and purged with nitrogen. This evacuate/purge cycle is repeated two more times. 600 g perfluoro(methyl vinyl ether) (PMVE, 3.61 mol) is added to the vessel, which is heated to 125° C. at which time the internal pressure is 462 psig (3290 kPa). The reaction temperature is maintained at 125° C. for 6 hr. The pressure drops to 25 psig (275 kPa) at which point the vessel is vented and cooled to 25° C. Once cooled, a white crystalline precipitate of the forms, leaving clear colorless liquid above it (pH=7). 19F NMR of the white solid shows it to be the desired product in high purity (>98%). 19F NMR of the liquid shows a small but detectable amount of the hydration product of Equation (3), above.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].Cl.Cl.[NH2:17][CH:18]([CH2:24][NH:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:17][CH:18]([CH2:24][NH:25][C:26]([CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(N)CNC(=O)C1CCN(c2ccncc2)CC1
Agent: Cl
Product: CCOC(=O)C(CNC(=O)C1CCN(c2ccncc2)CC1)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with ethyl 2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate dihydrochloride salt to give ethyl 2-(2-naphthalenesulphonamido)-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate as a foam in 37% yield;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].C([O-])(O)=O.[Na+]>CCOCC>[CH2:30]([O:29][C:27]([CH:26]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1=[O:14])=[O:28])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a 0° C. solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (11.3 g, 56.7 mmol) in Et2O (170 mL) was added BF3.Et2O (7.2 mL, 56.7 mmol) and ethyl diazoacetate (7.2 mL, 68.0 mmol) dropwise over 30 min. After an additional 1 h, satd. aq. NaHCO3 was added and the solution was stirred for 1 h, then was extracted with Et2O (2×). The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified via SiO2 chromatography (10-30% EtOAc/hexanes) to give 5.48 g (34%) of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. In addition, 5.25 g (32%) of the more polar 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:19][C:20]1[NH:24][C:23]2[CH:25]=[C:26]([O:34][CH2:35][CH:36]([F:38])[F:37])[C:27]([C:29]([O:31]CC)=O)=[CH:28][C:22]=2[N:21]=1.[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C[Al](C)C.C1(C)C=CC=CC=1>O1CCOCC1>[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:29]([C:27]2[C:26]([O:34][CH2:35][CH:36]([F:37])[F:38])=[CH:25][C:23]3[NH:24][C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]5([C:15]([F:18])([F:17])[F:16])[CH2:13][CH2:14]5)=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:21][C:22]=3[CH:28]=2)=[O:31])=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F
Reactant: Nc1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cc1)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F

Procedure:
The title compound was prepared in accordance with Example 59 (i) using ethyl 2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylate (0.200 g; 0.36 mmol), 4-bromoaniline (0.184 g; 1.07 mmol), Me3Al in toluene (0.900 mL; 2 M; 1.80 mmol) and 1,4-dioxane (10 mL). Yield: 0.115 g (47%). 400 MHz 1H-NMR (DMSO-d6, ppm) 11.3-11.1 (1H, br s) 10.17 (1H, s) 9.1-8.8 (1H, br s) 8.65-8.57 (1H, m) 8.53 (1H, t, J=5.8 Hz) 7.95-7.90 (1H, m) 7.80-7.73 (2H, m) 7.63-7.57 (2H, m) 7.49 (1H, d, J=8.4 Hz) 7.31-7.26 (1H, m) 6.94 (1H, dd, J=8.2, 1.6 Hz) 6.59 (1H, tt, J=54.3, 3.1 Hz) 4.57 (2H, td, J=14.9, 3.0 Hz) 4.38 (2H, d, J=5.8 Hz) 1.54-1.47 (2H, m) 1.38-1.31 (2H, m). MS m/z: 686, 688, 690 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21].[CH3:22][O:23][C:24](OC)([O:29]C)[CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][CH2:27][CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:29]
Reactant: COC(CCCBr)(OC)OC
Reactant: Cc1cc(Cl)ccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (841 ul, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5 N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to −78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at −78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at −78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1 N HCl. The organic phase was washed twice with 1 N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatogaphy (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, —COOCH3), 2.69 (t, J=7.8 Hz, Ar—CH2—), 2.35 (t, J=7.0 Hz, —CH2—COO—), 1.70-1.55 (m, —CH2—CH2—CH2—CH2—).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[BH4-].[Na+]>CO.CCOC(C)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([NH2:9])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a stirred solution of 1-ethyl-piperazine (1.37 g, 12 mmol) in MeOH (30 mL) was added Ti(OiPr)4 (1.73 g, 6 mmol). Then the solution was stirred at room temperature for 15 min. Then 4-amino-3-nitro-benzaldehyde (Procedure 2F, steps a-b, 1.5 g, 9 mmol) in MeOH (10 mL) was added and the solution was stirred at room temperature overnight. Then NaBH4 (380 mg, 10 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4. Concentration gave product, which was purified by flash chromatography on silica to obtain the title compound (800 mg, yield: 34%). MS (ESI): 265 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([F:25])=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(CBr)cc1F
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,4-difluorobenzyl bromide
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([O:14][CH2:15][O:16][CH3:17])[C:5]=1[C:18](=O)[CH3:19].C1O[CH2:37][CH2:36]OCCOCCOCCOCCOC1.C(=S)=[S:40].CI>C1COCC1.O>[CH3:17][O:16][CH2:15][O:14][C:6]1[CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=[C:4]2[C:5]=1[C:18](=[S:40])[CH:19]=[C:36]([CH3:37])[O:3]2
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Reactant: S=C=S
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COCOc1cc(OCOC)c2c(=S)cc(C)oc2c1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Under cooling on ice, potassium hydride (0.5 ml of 35% mineral oil) was suspended in 2 ml THF. 2 ml of 126 mg of 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone (0.492 mmol) and 130 mg of 18-crown-6 (0.492 mmol) in THF was added dropwise to the above suspension, and the mixture was stirred for 1 hour. After addition of 0.89 ml of carbon disulfide (14.76 mmol), the solution was stirred for 20 hours at room temperature. Then, 0.5 ml of methyl iodide was added thereto, and the solution was stirred for 30 min. After water was slowly added thereto, the reaction solution was extracted twice with ether, and the organic layer was washed with saturated NaCl water and then dried over sodium sulfate anhydride. The solvent was distilled off and the resulting crude product was washed with hexane, to give 133.5 mg of 5,7-bis(methoxymethoxy)-2-methylthiochromone (87% yield).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>>[S:9]1[CH:13]=[CH:12][C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:10]1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1ccsc1
Product: O=C1C=C(c2ccsc2)CCC1
Yield: 72 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3-thiophene boronic acid according to the general procedure described for the Suzuki coupling. The product was purified by automated flash chromatography using gradient elution (0 to 50% ethyl acetate/hexanes). A yellow solid was isolated after collection of fractions and recrystallized from hexanes and ethyl acetate to give 0.086 g of colorless needles (72%). 1H NMR (CDCl3, 300 MHz): δ 2.13 (quintet, J=6.3 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 2.76 (dd, J=6.3, 1.2 Hz, 2H), 6.39 (t, J=1.2 Hz, 1H), 7.31-7.36 (m, 2H), 7.55 (dd, J=2.7, 1.5 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.6, 27.8, 37.4, 123.8, 124.9, 125.0, 126.6, 140.5, 153.3, 199.9. LCMS (ESI): mass calcd for (C10H10OS) m/z 178.05; measured [M+H]+: m/z 179.04.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][C@@H:63]([C@H:83]([OH:85])[CH3:84])[C:64]([NH:66][C:67]1([C:70]2[N:75]=[CH:74][C:73]([C:76]3[C:77]([CH3:82])=[N:78][N:79]([CH3:81])[CH:80]=3)=[CH:72][N:71]=2)[CH2:69][CH2:68]1)=[O:65]>C1COCC1>[CH3:81][N:79]1[CH:80]=[C:76]([C:73]2[CH:74]=[N:75][C:70]([C:67]3([NH:66][C:64]([C@@H:63]([NH:62][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=6)([CH3:29])[C:9](=[O:28])[N:10]([C:19]6[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=6)[C:11]5=[N:15][CH:14]=4)=[O:18])[C@H:83]([OH:85])[CH3:84])=[O:65])[CH2:68][CH2:69]3)=[N:71][CH:72]=2)[C:77]([CH3:82])=[N:78]1
Reactant: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](N)[C@@H](C)O)CC2)nc1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)c(F)c(Cl)c3)[C@@H](C)O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask was added (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.80 g, 2.18 mmol), TBTU (0.73 g, 2.28 mmol) and Et3N (0.91 mL, 6.54 mmol) and THF (10 mL). The mixture was allowed to stir at RT for 30 min. The mixture was transferred to a separate flask containing (2S,3R)-2-amino-N-{1-[5-(1,3-dimethyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-cyclopropyl}-3-hydroxy-butyramide hydrochloride (1.0 g, 2.18 mmol) in THF (30 mL). The mixture was stirred at RT for 24 h. The mixture was concentrated and purified by silica gel chromatography to provide 1.45 g of the title compound as a white solid following removal of the solvent, m/z=771.8 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27]C(=O)OC(C)(C)C)([CH3:25])[C:21]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:27][CH2:26][C@@:22]1([CH3:25])[CH2:23][CH2:24][C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[C:21]1([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of tert-butyl (((1S,3S)-3-((3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (236 mg, 0.480 mmol) in dichloromethane (3910 μl) at 0° C. was added trifluoroacetic acid (452 μl, 5.87 mmol. The reaction mixture was allowed to warm to room temperature and stirring was continued for 1 hr. The reaction mixture was concentrated under reduced pressure, yielding a yellow oil. The oil was diluted with ethyl acetate (50 ml) and washed successively with saturated sodium bicarbonate, water, and saturated sodium chloride. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduce pressure, yielding 4-(((1S,3S)-3-(aminomethyl)-2,2,3-trimethylcyclopentyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (182 mg, 0.465 mmol, 97% yield) as a tan solid. ESI-MS m/z 392.3 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:25]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:32]=[C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:34]=[CH:35][C:9]=2[OH:8])[CH:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(furan-2-yl)benzoate (0.14 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.029 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 85-75% hexane/ethyl acetate] to obtain 0.085 g of tert-butyl 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholin-4-yl)benzamido)benzoate as a yellow solid.
Reaction SMILES: O[CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[C:17]1([C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:17]1([C:23]2[CH2:28][CH2:27][N:26]([CH2:4][CH:3]=[CH:2][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[CH2:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc(C(O)CCCl)ccc2N1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(C=CCN3CC=C(c4ccccc4)CC3)ccc2N1

Procedure:
2.5 Grams of 6-[1-hydroxy-3-chloropropyl]-3,4-dihydrocarbostyril and 3.0 g of 4-phenyl-1,2,5,6-tetrahydropyridine were mixed in 50 ml of toluene and the mixture was refluxed by heating for 5 hours, then toluene was removed by distillation. To the residue thus obtained was added 50 ml of 5%-sodium hydrogencarbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water and dried, then chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 2.1 of 6-[3-(4-phenyl-1,2,5,6-tetrahydropyridyl)-1-propenyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Melting point: 182°-183° C. (decomposed).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][O:22][CH2:23][CH2:24][CH2:25][Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClCCCOCC1C=CC=CC=1.[Cl-].[NH4+]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]([OH:11])[CH2:25][CH2:24][CH2:23][O:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cl[Mg]CCCOCc1ccccc1
Agent: ClCCCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
A THF solution (20 ml) of N-(tert-butoxycarbonyl)-L-prolinal (4.50 g) was dropwise added to a THF solution (30 ml) of 3-(phenylmethyloxy)propyl magnesium chloride prepared from 1-chloro- 3-(phenylmethyloxy)propane (5.00 g), at -78° C. After stirring for 15 minutes, saturated ammonium chloride (10 ml) was added, and the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give two stereoisomers (1.89 g of low polar isomer and 3.05 g of high polar isomer).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:12]I>O1CCCC1>[CH3:12][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: c1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2ccccc21
Temperature: 0 °C
Yield: 60.8 %

Procedure:
NaH (15 g, 375.00 mmol) was added in several batches to a chilled (0° C.) solution of indoline (30 g, 252.10 mmol) in tetrahydrofuran (400 mL). Methyl iodide (53 g, 373.24 mmol) was then added dropwise with stirring, while maintaining the temperature of 0° C. The resulting solution was stirred at room temperature for 15 hours, then quenched by the addition of ethanol (200 mL). The mixture was concentrated, water (400 mL) was added, and the product was extracted with methylene chloride (3×200 mL). The organics were combined, dried (Na2SO4), filtered and concentrated to provide 20.4 g (60%) of 1-methylindoline as a brown liquid.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:9]([C:20](O)=[O:21])=[CH:8]2.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:36][CH:34]1[CH2:35][N:32]([C:29]2[N:28]=[CH:27][C:26]([NH:25][C:20]([C:9]3[N:10]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[C:11]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[Si:2]([CH3:1])([CH3:23])[CH3:24])=[O:21])=[CH:31][CH:30]=2)[CH2:33]1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Reactant: C[Si](C)(C)c1cccc2cc(C(=O)O)n(Cc3cccc(F)c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1cccc2cc(C(=O)Nc3ccc(N4CC(O)C4)nc3)n(Cc3cccc(F)c3)c12
Yield: 12.6 %

Procedure:
Compound No. 6 was prepared according to a process similar to that described in stage 5.4, by reacting 0.15 g (0.44 mmol) of 7-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 5.3, with 109 mg (0.66 mmol) of 3-amino-6-(3-hydroxyazetidin-1-yl)pyridine, prepared according to the protocol described in stage 2.2, in the presence of 87 mg (0.44 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 61 mg (0.44 mmol) of 1-hydroxybenzotriazole (HOBT) in 5 ml of dimethylformamide. 27 mg of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23]C(C)(C)C)=[O:22])[S:17][CH:18]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]3[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([OH:23])=[O:22])[S:17][CH:18]=3)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-4′-fluoro-biphenyl-3-carboxylic acid methyl ester (250 mg) obtained in Example 92-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (175 mg) as a colorless oil.