Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1SC2C(C(=O)N2C(=C(O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:124][CH2:123][O:122][CH2:121][CH2:120]2)[CH3:118])[C:101]([O:103][CH:104]([C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Br:126]Br>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:120][CH2:121][O:122][CH2:123][CH2:124]2)[CH2:118][Br:126])[C:101]([O:103][CH:104]([C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
Reactant: BrBr
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Agent: CC(O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: C1COCCN1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (4.84 g) in tetrahydroufran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3 hours at room temperature, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70% IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4 Hz)1H, 5.66 dd(9:4)1H, 6.77d(9 Hz)1H, 6.90s1H, 7.35 ml 5H.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[I:19][CH3:20]>CO>[I-:19].[CH3:20][N:3]1[CH:4]=[CH:5][NH+:1]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:2]1
Reactant: CS(=O)(=O)Nc1ccc(CCn2ccnc2)cc1
Reactant: CI
Solvent: CO
Product: CN1C=C[NH+](CCc2ccc(NS(C)(=O)=O)cc2)C1
Product: [I-]
Temperature: 25 °C

Procedure:
Heat a mixture of 5 g (0.019 mole) of N-[4-[2-(1H-imidazol-1-yl)ethyl]phenyl]methanesulfonamide, 5 mL of iodomethane and 25 mL of methanol in a pressure tube at 75° C. for about 24 hours. Cool the mixture to room temperature and remove the solvents in vacuo. Slurry the residue in acetone (50 mL) and filter and wash with acetone (100 mL). Drying provides the title compound, which may be recrystallized from methanol.
Reaction SMILES: [F:1][C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2](=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl 4-(fluoro(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (600 mg, 1.32 mmol) in CH2Cl2 (10 mL) was added TFA (0.98 mL, 13.26 mmol) dropwise maintaining ice-cooled conditions. The mixture was stirred for 1 h. The TFA was evaporated and the reaction mixture was partitioned between saturated NaHCO3 solution and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (340 mg). 1H NMR (500 MHz, CDCl3): δ 2.3 (m, 2H), 2.6 (m, 2H), 2.8 (m, 2H), 2.9 (m, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.4 (m, 4H), 7.9 (d, 1H, J=2 Hz), 8.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N,N-dimethylformamide (5 drops) in 1,2-dichloroethane is treated dropwise with oxalyl chloride (30.8 mL, 0.353 mol), refluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19]O)[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:28].[C:29]1([P:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[Br-:28].[CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][P+:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CO
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.525 g, 1.43 mmol) in acetonitrile (50 mL) was added triphenylphosphine hydrobromide (0.49 g, 1.43 mmol; commercially available from Sigma Aldrich). The reaction was heated to 80° C. for 24 hr after which time all starting material was consumed as determined by TLC. The reaction solvent was removed under reduced pressure and the resulting white solid was dried under high vacuum for 12 hr to provide [5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-triphenyl-phosphonium bromide (0.977 g, 98%) in sufficient purity for use in the next step.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO.O1CCCC1>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 5 h
Yield: 47.5 %

Procedure:
Magnesium chloride (27.7 g, 0.29 mol) was added to 2-methoxyethanol (400 mL) and the mixture heated to reflux. A solution of 3-(3,4-Dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (0.29 mol) in 2-methoxyethanol (100 mL) and tetrahydrofuran (40 mL) was slowly added to the MgCl2 mixture over 1 hour. Upon completion of addition, the mixture was stirred for 5 hours at reflux, and then concentrated in vacuo. The concentrated crude mixture was treated with 2N hydrochloric acid (500 mL) and extracted with dichloromethane (3×400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with 20% ethyl acetate/hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 31.6 g (48%) of the desired compound as an orange solid.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[C:22]([O:24]C)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:26]>C(#N)C.O.C(#N)C.O>[OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1cc(CCCCC#CCCCC#CCO)c(O)c2ccccc12
Solvent: O
Solvent: CC#N
Product: O=C1C=C(CCCCC#CCCCC#CCO)C(=O)c2ccccc21
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2-(12-Hydroxydodeca-5,10-diynyl)-1-hydroxy-4-methoxynaphthalene (80 mg) is dissolved in 1 ml of acetonitrile and 0.75 ml of water. This mixture is cooled in an ice bath and the addition of ceric ammonium nitrate (0.377 g) in 2 ml of 50% acetonitrile/water is carried out over 10 minutes. Stirring is continued an additional 30 minutes (after only 5 minutes a yellow precipitate forms). The above contents are poured into a separatory funnel and additional water is added. The mixture is extracted three times with methylene chloride and the combined organic extracts are washed with water, saturated sodium bicarbonate, and brine, dried with magnesium sulfate, filtered, and concentrated to provide 74.9 mg of the title compound as a yellow solid, mp 88°-89.5° C. By TLC (in 2% acetone/methylene chloride) the material is fairly clean, with a small amount of impurities at lower Rf. Drying the sample under low vacuum (0.2 mm) overnight changes the melting point slightly, mp 89°-90.5° C.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[CH2:21]([NH2:23])[CH3:22]>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[C:8]([S:16](=[O:17])(=[O:18])[NH:23][CH2:21][CH3:22])[C:7]=1[OH:20]
Reactant: CCN
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Product: CCNS(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Product: Cl

Procedure:
This compound is prepared analogously to Examples 11c and 11d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and ethylamine.
Reaction SMILES: [N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45]CC)=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].O>C1COCC1>[N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
ethyl 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetate (268 mg, 0.392 mmol) was dissolved in THF (Ratio: 1.000, Volume: 2 mL) then LiOH (46.9 mg, 1.960 mmol) and Water (Ratio: 1.000, Volume: 2 mL) were added and the reaction was heated to 65° C. for 2 h. The solvent was removed under vacuum and water was added back to the flask and the pH adjusted to ˜7 with 1N HCl. A solid precipitated out of solution and this was collected, washed with water, and dried to give 2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid (130 mg). 1H NMR (400 MHz, MeOD) δ ppm 0.62-0.70 (m, 2H), 0.94-1.02 (m, 2H), 1.15-1.34 (m, 4H), 2.10 (br. s., 4H), 3.08 (br. s., 2H), 3.30-3.33 (m, 4H), 3.49 (s, 2H), 4.51 (s, 2H), 4.86-4.93 (m, 2H), 6.85-6.94 (m, 2H), 7.08-7.16 (m, 2H), 7.16-7.25 (m, 2H), 7.42-7.54 (m, 2H); LC-MS (Condition A), MS m/z (M++H) 656.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][C:13]([CH:15]=[CH2:16])=O>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:12][CH:13]=[C:15]2[CH3:16]
Reactant: C=CC(C)=O
Reactant: COc1ccc(N)cc1OC
Agent: Cl[Fe](Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nccc(C)c2cc1OC
Temperature: 60 °C
Yield: 38 %

Procedure:
The Reference Compound No. 1-1 was prepared following the method described in J. Org. Chem., 62, 568-577 (1997). Namely, iron (III) chloride hexahydrate (5.7 g, 21 mmol) and 3,4-dimethoxyaniline (3.1 g, 20 mmol) were added to acetic acid (60 mL), and then the mixture was stirred at 60° C. After all the solids were dissolved, methylvinylketone (1.8 mL, 22 mmol) was added dropwise for 5 minutes. Then the mixture was stirred at 140° C. for 1 hour, and allowed to cool down to room temperature, and the resulting solid was filtered off. Ethyl acetate (200 mL) was added to the solid, and the resulting organic solution was washed with 0.1N sodium hydroxide aqueous solution (200 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with diethyl ether to give 1.6 g of the title reference compound as a light brown solid (Yield: 38%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].C(N)CN>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[N:25])=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of the 4-benzyloxy-3-(phenethyl)phenylbromide, (5.5 g, 15 mmol) in DMF (200 ml, dried) was added CuCN (3.32 g, 37 mmol). The reaction was heated to reflux and held at reflux for 20 hours, under argon. The reaction mixture was allowed to cool to ambient temperature, poured into ice water, treated with ethylene diamine (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (2×60 ml), dried (MgSO4) and evaporated. The crude material was purified by chromatography to give 4-benzyloxy-3-phenethylbenzonitrile as a white solid (2.0 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29](O)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:30]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)(C(=O)O)S(C)(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(OC(=O)C(C)(C)S(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol), 2-methyl-2-(methylsulfonyl)propanoic acid (65.6 mg, 0.395 mmol) and triphenylphosphine (104 mg, 0.397 mmol) in tetrahydrofuran (5.0 mL) was added a solution of diethylazodicarboxylate in toluene (2.2 M, 0.18 mL, 0.396 mmol) at 0° C. After stirring at room temperature for 20 hr, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture to give the title compound (83.0 mg, 0.149 mmol, 61%) as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH2:20][OH:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[Na+]>ClCCCl.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH:20]=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)n1c(CO)cc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 0.93 g of {1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl}methanol and 1.1 mL of triethylamine in 10 mL of 1,2-dichloroethane, a solution of 1.21 g of sulfur trioxide-pyridine complex in 5 mL of DMSO was added under ice cooling, and the resulting mixture was stirred under ice cooling for 1 hour. The solution was poured into a mixed solution of 25 ml of ice water and 25 mL of saturated aqueous sodium chloride solution, the resulting mixture was extracted with 100 mL of ethyl acetate, the extract was washed with 5% aqueous potassium hydrogen sulfate solution, water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain 0.91 g of 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carbaldehyde as a beige solid. FAB+: 364, 366
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]1COCC1.[H-].[Na+].CI>O>[CH3:9][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1cccnc1
Reaction time: 0.25 h

Procedure:
To a mixture of 10.0 g of 3-hydroxymethylpyridine and 200 ml of THF, 3.7 g of 60% sodium hydride (in oil) was added in small portions at room temperature and then stirred for 15 minutes. To the reaction mixture, 13.0 g of methyl iodide was added dropwise, and the reaction mixture was stirred at room temperature for three hours. To the reaction mixture, 25 ml of water was added. Then, the reaction mixture was concentrated under reduced pressure. To the residue, 25 ml of water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8.17 g of 3-methoxymethylpyridine.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:30]2[C:31]3[C:26](=[C:25]([Cl:24])[CH:34]=[CH:33][CH:32]=3)[CH:27]=[CH:28][CH:29]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 5-chloronaphthalenecarboxylic acid (186 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (136 mg, 29%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=O)[C:25]=3[F:33])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([OH:40])[CH2:37][CH2:38][CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:33][C:25]1[C:26]([C:30](=[O:32])[NH:34][CH2:35][C:36]([OH:40])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH3:39])=[N:27][CH:28]=[CH:29][C:24]=1[S:23][C:20]1[S:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:12][CH:13]=2)=[N:22][CH:21]=1
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(CN(C)C(=O)OC(C)(C)C)cn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 4-(2-(5-((tert-butoxycarbonyl(methyl)amino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (120 mg, 0.244 mmol) and 1-amino-2-phenylpentan-2-ol (1.3 eq, 0.317 mmol, 57 mg) in NMP (4 mL) was added HOBT (1.3 eq, 0.317 mmol, 43 mg), EDAC (2 eq, 0.488 mmol, 94 mg) and diisopropylethylamine (5 eq, 1.22 mmol, 157 mg, 213 uL). The reaction was stirred at 23° C. overnight. The product was precipitated by addition of water to the reaction mixture. The solid was isolated by filtration to give the crude title material (97 mg, 61%) as a solid which was used as such in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.90 (1H, m), 1.18-1.32 (1H, m), 1.41 (9H, s), 1.65-1.84 (2H, m), 2.75 (3H, s), 3.62 (2H, d, J=5.81 Hz), 4.32 (2H, s) 7.04 (1H, t, J=5.18 Hz), 7.11 (1H, d, J=8.59 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.44 (2H, d, J=7.33 Hz), 7.66 (1H, s), 7.82 (1H, s), 8.13-8.32 (3H, m), 11.93 (1H, s). LC/MS (M+H)+: 653. Ret. time: 2.257 (Condition A).