Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1C(Cl)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:19]1CCC[CH2:20]1.[OH:24][C:25]1[CH:37]=[CH:36][C:35]2[C:34]3[C:29](=[CH:30][C:31]([OH:38])=[CH:32][CH:33]=3)[CH:28]([CH3:39])[C:27]=2[CH:26]=1.Cl>N1C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:15][C:16]([C:20]([O:24][C:25]2[CH:37]=[CH:36][C:35]3[C:34]4[C:29](=[CH:30][C:31]([OH:38])=[CH:32][CH:33]=4)[CH:28]([CH3:39])[C:27]=3[CH:26]=2)=[O:19])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccccc1C(=O)Cl
Reactant: C1CCOC1
Reactant: CC1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(O)ccc2-3)cc1

Procedure:
Octyloxybenzoic acid chloride 12.5 g was added dividing into several times to a tetrahydrofuran (100 ml) solution of 2,7-dihydroxy-9-methylfluorene 10 g and pyridine 8 g, and the solution was refluxed for 5 hours. 5% hydrochloric acid 50 ml was added to the reaction mixture, and the solution was extracted with methylene chloride. The extract was washed with 5% hydrochloric acid until pH became acidic, and then it was washed with a saturated sodium hydrogencarbonate aqueous solution and dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was refined by silica gel column chromatography (eluent solvent: methylene chloride) to obtain 10 g of 2-(4-octyloxybenzoyloxy)-7-hydroxy-9-methylfluorene (J1). Melting point: 140 to 143° C.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH2:25][CH2:24][C:10]2[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8]1.[OH-].[Na+].[ClH:28]>C(OCC)C.C(O)C>[ClH:28].[CH3:6][N:7]1[CH2:25][CH2:24][C@H:10]2[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C@@H:9]2[CH2:8]1
Reactant: CN1CCc2c(c3ccccc3n2-c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 180 ml 1 molar BH3 in THF (0.18 mole BH3) which was cooled in an ice bath, was added a solution of 7.9 grams 2,3,4,5-tetrahydro-2-methyl-5-phenyl-1H-pyrido[4,3-b]indole (0.03 mole) in 200 ml freshly chromatographed THF, dropwise with stirring over 30 minutes in a nitrogen atmosphere. The ice bath was then replaced with a heating mantle and the mixture was refluxed for 19 hours in the nitrogen atmosphere. The mixture was cooled and evaporated under vacuum to a clear gel. The gel was then refluxed in 75 ml of a 1:1 mixture of glacial acetic acid and 5 N HCl. A clear light brown solution was obtained after about 1/2 hour and refluxing was continued for a total of 1 hour. The resulting solution was cooled to about 50° C. and treated with 50% aqueous NaOH until basic, during which time the temperature rose to 80° C. The mixture was cooled again and a light purple oil was extracted into CHCl3. The mixture was again extracted with CHCl3, the extracts were combined and washed with saturated NaCl solution, then dried over Na2SO4. The CHCl3 was then evaporated under vacuum, leaving a purple oily residue which was taken up in about 50 ml diethyl ether and some ethanol. Ethereal HCl was added and 8.1 grams of pale greenish-white powder were obtained by filtration and drying. Recrystallization from methanol provided 6.2 grams of the title compound, m.p. 256°-258° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)c(Cl)c4)cc3CC[C@@H]12
Yield: 73.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-chloro-4-fluorophenylboronic acid (136 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 170 mg (73%) of the title compound as a white solid. mp 114°-116°. FDMS: m/e=357. α[D]589 =+86.00 (c=1.00, methanol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:42])([CH2:27][C:28](=O)[CH2:29][S:30][C:31]1[S:32][C:33]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:34]=2[N:35]=1)[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][C:31]3[S:32][C:33]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:34]=4[N:35]=3)=[C:28]2[CH2:27][C:22]([CH3:42])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSc1nc2cc(Cl)ccc2s1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC(C)c1ccc2c(c1)c(Sc1nc3cc(Cl)ccc3s1)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 104, but 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(5-chlorobenzothiazol-2-ylthio)pentanoate as starting materials followed by hydrolysis at reflux gave the title compound, m.p 154°-156°.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CO>[Br:20][CH2:2][C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 40 °C

Procedure:
4-acetyl-N-(4-fluorophenyl)benzamide (1.5 g, 0.00583 mol) is dissolved in 100 ml of methanol. Pyridinium tribromide resin is added (4 g of resin to 2 mmol of Br3 per gram, 0.0081 mol) followed by heating for 4 hours at 40° C. The reaction medium is filtered on frit, rinsed with methanol and evaporated to dryness. A pale yellow-coloured powder is obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=3[CH3:47])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(OCC)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=3[CH3:47])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(-c2ccc3[nH]ccc3c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc3[nH]ccc3c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogen carbonate (0.75 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[5-(1H-indol-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL). N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.09 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@@H:20]([N:23]=[N+]=[N-])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H][H]>CCO.[Pt](=O)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C@@H:20]([NH2:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [H][H]
Reactant: Cc1c(N2C(=O)N3CC[C@H](N=[N+]=[N-])[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1c(N2C(=O)N3CC[C@H](N)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To 69B (15.0 mg, 0.0391 mmol) in EtOH (1 mL) was added platinum (IV) oxide (5 mg) and hydrogen was bubbled through the system for 10 min. The hydrogen outlet was removed and the system was stirred under a hydrogen atmosphere. After 2 h, the reaction was filtered through celite and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 21×100 mm, eluting with 50-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 10 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (6.00 mg) as a clear film. MS: m/z 419 [M+HCO3]−
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=[O:17].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)(Br)CC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A suspension of 1-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 5 (7.78 g, 19.6 mmol) in THF (50 mL) was treated with DBU (8.79 mL, 58.8 mmol, 3.0 eq) dropwise at about 20° C. A dark green suspension was obtained while heat was generated upon addition of DBU. It was stirred at about 20° C. for about 18 hours. The reaction mixture was concentrated and the residue was treated with saturated NH4Cl (aq) solution to neutral. A light brown colored precipitate was obtained. It was filtered off and washed with H2O (2×50 mL), small amount of MeOH and CH2Cl2, and finally dried under vacuum to give 4.83 g (78%) of the desired compound 6. 1H NMR (DMSO) δ 10.68 (br s, 1H, NH), 7.43 (d, 1H, J=8.5 Hz, ArH), 7.08 (d, 1H, J=8.5 Hz, ArH), 6.70 (br s, 1H, NH), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3). LC/MS 316 (MH+); RP-HPLC RT 2.80 minutes.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 3.1 g (15.6 mmol) of ethyl 2-isopropylthiazole-4-carboxylate in 50 ml of dichloromethane was cooled under N2 atmosphere to -78° C. and treated dropwise with 15.6 ml (23.4 mmol) of a 1.5M solution of diisobutylaluminum hydride in toluene over a period of 1.5 h. After being stirred for an additional 0.5 h, the solution was quenched with 5 ml of methanol followed by 15 ml of aqueous Rochelle's salt. The resulting mixture was partitioned between chloroform and aqueous Rochelle's salt, dried over Na2SO4, and concentrated to provide 1.37 g (56%) of the crude desired compound, Rf 0.47 (20% ethyl acetate in hexane). 1H NMR (CDCl3) δ 1.45 (d, J=7 Hz, 6H), 3.39 (heptet, J=7 Hz, 1H), 8.07 (s, 1H), 10.00 (s, 1H). Mass spectrum: (M+H)+ =156.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)[CH:7]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:3]1[C:2]([NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:7][C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)=[C:5]([F:19])[CH:4]=1
Reactant: Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.3 %

Procedure:
A mixture of 0.45 g (0.0014 mole) of 9-(5-amino-4-chloro-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, 0.18 g (0.0014 mole) of ethanesulfonyl chloride, and 0.22 g (0.027 mole) of pyridine in approximately 30 mL of methylene chloride was stirred at room temperature for two days. The reaction mixture was heated at 26° C. for approximately 24 hours, then at reflux for 36 hours. The solvent was evaporated from the mixture leaving an oily residue. The residue was washed with an aqueous, 10% hydrochloric acid solution. The washed residue crystallized upon standing and was recrystallized from ethyl acetate and n-heptane to give 0.12 g of 9-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 146°-148° C., Compound 11 of Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][NH2:29])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 72.1 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (450 mg, 1.43 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (257 mg, 1.43 mmol) and anhydrous NaOAc (125 mg, 1.52 mmol) in EtOH (23 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2iPE, 1:5) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)propyl]phenyl}trifluoromethanesulfonamide 128 (455 mg, 72%), as a yellow solid. M.p. 87-88° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.18, br s, 1H; 7.71, d, J=8.8 Hz, 1H; 7.58, d, J=2.6 Hz, 1H; 7.41, dd, J=2.6 and 8.8 Hz, 1H; 7.35, d, J=8.8 Hz, 2H; 7.11, d, J=8.8 Hz, 2H; 3.02, q, J=7.6 Hz, 2H; 1.30, t, J=7.6 Hz, 3H.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][CH2:36][NH:37][C:38]1[NH:39][CH:40]=[CH:41][N:42]=1)[N:29]=[CH:28]2)=[O:24])[C:18]([OH:20])=[O:19])=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][CH2:36][NH:37][C:38]1[NH:39][CH:40]=[CH:41][N:42]=1)[N:29]=[CH:28]2)=[O:24])[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 2 h
Yield: 112 %

Procedure:
2-(6-((Tert-butoxy)carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.0322 g, 0.0551 mmol) was dissolved in methylene chloride (1 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 2 h. The reaction was concentrated to an oil under high vacuum. The oil was triturated with ether. The product was filtered, washed with ether, dissolved in 50/50 acetonitrile/water, and lyophilized to give 29.9 mgs (91%) of product. ESMS: Calcd. for C23H32N8O4, 464.25. Found, 485.2 [M+H]+1 Analytical HPLC, Method B, Rt=111.02 min, Purity=97%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[Br:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][N:35]=[C:17]([C:13]2[C:12]([OH:20])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[N:15]([CH3:16])[N:14]=2)[CH3:18])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Br
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br
Temperature: 0 °C
Yield: 86.3 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.554 mmol, 150.9 mg) synthesized in Synthetic Example 3, methyl 2-bromo-4-hydrazinocarbonylbenzoate (0.554 mmol, 150.8 mg) synthesized in Reference Synthetic Example 42 and p-tosylic acid monohydride (30 mol %, 28.6 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (252.3 mg, yield 86%).
Reaction SMILES: [Li]C(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CN([CH:23]=[O:24])C.O>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[C:11]([Cl:13])[C:12]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc(Cl)cc(N2CCOCC2)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Add sec-BuLi (1.4M in cyclohexane, 5.44 mL) in a dropwise manner to a solution of 4-(3,5-Dichloro-phenyl)-morpholine (Tetrahedron (2001), 57(36), 7657-7664, 1.60 g, 6.93 mmol) in dry THF (20 mL) under N2 at −78° C. Allow to stir for 30 min. Slowly add DMF (2.68 mL, 34.7 mmol) to the cold solution. Upon disappearance of the starting material by TLC, warm the reaction to 0° C. Quench the reaction by addition of H2O (15 mL) and extract the mixture with EtOAc (150 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Triturate the resulting solid with Et2O to yield the title compound. Evaporate the filtrate to yield another crop of the title compound as a yellow solid: 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 3.46-3.54 (m, 4 H) 3.85-3.93 (m, 4 H) 7.06 (s, 2 H) 10.44(s, 1 H); MS (m/z) 260.0 (M+1).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[CH:9][CH:8]=1)([O-])=O>C(O)(=O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc([N+](=O)[O-])cc3)c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3)c2c1
Yield: 100.9 %

Procedure:
Six milliliters of ethanol and 0.8 ml of acetic acid were added to 0.50 g of 1-(4-nitrobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 0.47 g of reduced iron, and the mixture was refluxed for 4.5 hours. The reaction mixture was extracted with water and with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under reduced pressure to give 0.46 g of 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (363).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[I-].[CH3:19][S+](C)(C)=O.[H-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10]2([C:11]([F:13])([F:14])[F:12])[CH2:19][O:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one (68 mg, 2.2 mmol) in 2.9 mL of anhydrous DMSO was added over 5 minutes a solution the ylide of trimethylsulfoxonium iodide (3.3 mL of a 0.8M DMSO solution prepared from 2.66 g (12.1 mmol) of trimethylsulfoxonium iodide in 15 mL of anhydrous DMSO and 483 mg of 60% NaH in mineral oil (12.1 mmol) added in portions and aged for 30 minutes). The mixture stirred 2 hours and quenched with water and ethyl acetate. The organic phase was washed with water and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded the yellow oil 2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane which was used without further purification.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[N:8]2)=[CH:4][CH:3]=1.O.ON1C2C=CC=C[C:20]=2N=N1.Cl.Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1([C:46]2[CH:47]=[C:48]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:45]2[CH:41]1[CH2:42][NH:43][CH2:44]2.C(N(CC)CC)C>CN(C)C=O>[NH3:8].[CH3:39][C:40]1([C:46]2[CH:47]=[C:48]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:45]2[CH:41]1[CH2:42][N:43]([C:12](=[O:14])[CH2:11][C:6]1[C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[N:8]([CH3:20])[CH:7]=1)[CH2:44]2
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc2c(c1)N=CC2CC(=O)O
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc(CC(=O)N2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)c2ccccc21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
To a solution of 2-(6-methyl-3H-indol-3-yl)acetic acid (117 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (58 mg, 20%).