Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1>[Cl-:20].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:23][CH:22]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Reaction time: 8 h
Yield: 126.3 %

Procedure:
A stirred solution of 158 g, (0.6 mole) of triphenylphosphine in 800 ml of xylene is treated with 97 g of 4-chlorobenzyl chloride. The resulting solution is heated (product begins to crystallize at this point) and refluxed for six hours. After standing overnight at room temperature, the solid is filtered, washed with xylene and then with ethyl acetate, and dried in a desiccator to yield 161 g of colorless solid [(4-chlorophenyl)methyl]triphenylphosphonium chloride; m.p. 283°-285°.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].O=S(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)[Cl:26])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: OC(c1ccc(Br)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)Oc1ccc(C(Cl)c2ccc(Br)nc2)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution [3,4-Bis(difluoromethoxy)phenyl]-(6-bromo-3-pyridyl)methanol (15.8 g,40.0 mmol) in 400 mL of CH2Cl2, was added 3.8 mL (52.0 nimol) of SOCl2. The solution was stirred 45 minutes at room temperature and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dry over MgSO4 and concentrated under reduced pressure. The crude chloride was used directly for the next step without any purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=2)=[CH:4][C:5]([CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@@H:11]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@@H](N5CCCCC5)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2-fluoro-5-methyl-4-(cis-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.41 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H+).
Reaction SMILES: [CH:1]([O:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)ONC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)ON(C)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
An ACE® pressure tube was charged with benzyl isopropoxycarbamate (4.98 g, 23.80 mmol), anhydrous K2CO3 (4.94 g, 35.70 mmol), methyl iodide (6.7 mL, 107.10), and anhydrous acetone (30 mL). The reaction mixture was heated at 70° C. for 24 h. The reaction mixture was filtered, and the acetone was evaporated. The resulting slurry was dissolved in EtOAc, washed with water (3×50 mL), dried (Na2SO4), and filtered. The solvent was removed to yield benzyl isopropoxy(methyl)carbamate (4.96 g, 93%). 400 MHz 1H-NMR (DMSO-d6, ppm) 7.41-7.30 (5H, m), 5.12 (2H, s), 4.08 (1H, septet, J=6.2 Hz), 3.08 (3H, s), 1.12 (6H, d, J=6.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:46](Cl)(=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:17][CH:16]=2)[C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH:3]=2)[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nn(-c2cccc(N)c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCC(=O)Nc1cccc(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2=O)c1
Yield: 67 %

Procedure:
This material was prepared from 2-(3-aminophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 66, Step E), sodium hydride, and valeryl chloride according to the procedure of Example 62. The crude product was flash chromatographed over silica gel to afford the title compound in 67% yield as a cream-colored solid, mp 102°-105° C., homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 700 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[Li]CCCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][O:11][CH3:12])=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCOc1ccc(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Reaction time: 0.75 h
Yield: 112.8 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. Step 2: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. Step 3: A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([OH:18])[CH2:15][CH:16]=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:29].[Na+]>CO.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH:14]([OH:18])[CH2:15][CH:16]=[O:29])=[C:12]([CH:19]([CH3:20])[CH3:21])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C(O)CC=O
Yield: 3 %

Procedure:
To a solution of N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (2 g, 5.08 mmol) in a mixture of 30 mL methanol and 4 mL buffer solution (pH=7), sodium periodate (3.2 g, 15.2 mmol) and osmium tetroxide (0.3 mL, 4% wt. in water, 13 mg) are added at room temperature. The reaction mass is stirred and the progress of the reaction is monitored by TLC. Upon completion of the reaction, the reaction mixture is filtered through celite bed (1 g) and washed with ethyl acetate (2×10 mL). The filtrate is distilled under reduced pressure until solvents are removed. To the residue, ethyl acetate (200 mL) is added and washed with DM water (50 mL) and brine (50 mL), subsequently. The solvent is distilled off under reduced pressure to afford 2.1 g crude product. Part of the residue (200 mg) is purified through silica gel column chromatography eluting with (20%-30%) ethylacetate:cyclohexane to obtain 60 mg pure N-(4-(4-fluorophenyl)-5-(1-hydroxy-3-oxopropyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38](Br)[C:37]=1[OH:43])=[O:35])[CH3:32].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38]([N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[Cl:20])[C:37]=1[OH:43])=[O:35])[CH3:32]
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Reactant: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(N(CCOCc2ccccc2)c2cc(OC)ccc2Cl)CCC1
Temperature: 25 °C
Yield: 104.9 %

Procedure:
(2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) (10.0 g, 34.2 mmol) was stirred in dry THF (100 mL) at −40° C. under nitrogen and potassium bis(trimethylsilyl) amide (143.0 mL of a 0.5 M solution in toluene, 72.0 mmol) was added over 30 min. 3-bromo-2-hydroxycyclohex-1-enecarboxylic acid ethyl ester (4) (8.5 g, 34.2 mmol) in dry THF (10 mL) was then added and allowed to warm to RT over a period of 1.5 h. Acetic acid (10.0 g, 166 mmol, 10.0 mL) was added and concentrated in vacuo to remove the THF. Ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL) was added and the mixture vigorously shaken. The ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 16.5 g (quantitative) of 3[(2-Benzyloxy-ethyl)-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclohex-1-ene carboxylic acid ethyl ester (5) as a gum which was used crude in the next step. HPLC (Gemini 150×4.6 mm, 50-95% methanol/water over 20 min) of crude reaction mixture, 18.9 min (38%), 19.2 min (25%), 23.1 min (28%). One component of the reaction was isolated 13C NMR (75 MHz, CDCl3) δC 14.3, 20.6, 21.8, 26.4, 38.6, 43.0, 55.8, 60.5, 68.7, 73.3, 93.4, 106.3, 108.2, 119.3, 121.5, 127.5, 127.6, 128.3, 135.7, 137.0, 137.9, 155.7, and 175.0.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CCOCC>[C:19]([O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (11.4 g, 0.04 mol), acetyl chloride (3.15 g, 0.041 mol) and pyridine (3.2 g, 0.041 mol) were mixed in 100 ml ether and stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure, and water and CH2Cl2 were added. The organic layer was then washed three times each with 1N HCl and then 5% Na2CO3, dried with MgSO4 and the solvent evaporated under reduced pressure to yield the product, 8.4 g, 64%. The structure was confirmed as such by nuclear magnetic, infrared and mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH:16]([NH2:18])=[O:17]>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:18][CH:16]=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: NC=O
Solvent: O
Product: O=CNC(c1ccccc1)c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4525.6 %

Procedure:
3-Hydroxybenzophenone (25 g, 126.1 mmol) in formamide (130 mL, 3.3 mmol) was heated to 180° C. for 18 hours. The reaction was allowed to cool slightly then poured into ice-cooled water and stirred for 30 minutes, filtered, and washed with water. The solid was stirred in water (60 mL) and ethanol (60 mL) and heated to 50° C. for 1 hour, then allowed to cool. The solid was filtered and washed with water to give the title compound (33.94 g, 118%).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH2:18](O)[CH2:19][OH:20]>C1(C)C(S(O)(=O)=O)=CC=CC=1.O>[O:1]([CH2:8][C:9]([O:11][CH2:18][CH2:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(COc1ccccc1)OCCO
Reaction time: 8 h

Procedure:
Into a 5000 ml. 3-necked flask, equipped with thermometer, stirrer, condenser and Dean-Stark trap were weighed 924 gms. of phenoxyacetic acid. There were added 2 gms. toluene sulfonic acid as catalyst and 100 mls. of benzene. Heating was started with stirring and there were added 2270 gms. of ethylene glycol. At reflux temperature water was collected and taken off. After 11 and 1/2 hours of refluxing the reaction mixture was transferred to a 6 liter separatory funnel where excess ethylene glycol was separated and recovered. The benzene layer was extracted with hot water and sodium bicarbonate and the benzene layer was filtered warm through a molecular sieve to remove residual water. The benzene extract was allowed to stand overnight and the crystals which formed were removed by filtration and dried in a vacuum oven. A total of 370.2 gms. product was recovered, m.p. 61°-63° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH2:19]([C@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:19]([C@H:21]1[CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][N:22]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:20]
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 60.3 %

Procedure:
Heat a mixture of 1-chloro-4-(4-fluorophenyl)phthalazine (5.02 g, 19.4 mmol), (S)-tert-butyl 2-ethylpiperazine-1-carboxylate (5.00 g, 23.3 mmol) and K2CO3 (5.38 g, 38.9 mmol) in DMSO (75 mL) at 120° C. for 1 d. Pour the reaction mixture into water, rinsing with EtOAc. Extract with EtOAc. Wash the organic layer with water (2×), then brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 20 to 80% EtOAc in hexanes) to provide the title compound (5.11 g, 60%). ES/MS m/z 437.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH:14](O)[C:6]1=[C:5]2[CH3:18].CS([Cl:23])(=O)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[ClH:23].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH:14]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:6]1=[C:5]2[CH3:18]
Reactant: Cc1c2n(c3ccc(Br)cc13)CCC(C)(C)C2O
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c2n(c3ccc(Br)cc13)CCC(C)(C)C2N1CCCC1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of 2-bromo-6,7,8,9-tetrahydro-8,8,10-trimethylpyrido[1,2-a]indol-9-ol (616 mg, 2 mmol) in anhydrous pyridine (10 mL) was added methanesulfonyl chloride (458 mg, 4 mmol) at room temperature. The reaction mixture was stirred for 60 minutes, cooled to 0° C., and distilled pyrrolidine (852 mg, 12 mmol) was added. Stirring was continued at room temperature for 2 hours, and then at 40° C. for 30 minutes. After adding a second portion of pyrrolidine (852 mg), the mixture was stirred at ambient temperature overnight, and then evaporated. The residue was partitioned between 5% aqueous NaHCO3 and ether. The organic layer was washed with 1.5% hydrochloric acid, and the separated aqueous part was basified (pH 8) with a saturated solution of NaHCO3. The product was extracted with ether, the combined extracts were dried (MgSO4), filtered, and evaporated. The residual oil was chromatographed on neutral alumina (activity III). Elution with chloroform-hexane 1:1 afforded 355 mg (63%) of the title base. The corresponding hydrochloride salt was crystallized from ethanol-ether, m.p. 183.5°-184.5° C.
Reaction SMILES: CS(O)(=O)=O.[C:6]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:26]O>>[C:6]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][OH:26])=[O:24])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OO
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)O
Agent: CS(=O)(=O)O
Product: CCCCCCCCCC(=O)NCCCCCC(=O)OO
Temperature: -15 °C
Yield: 97.8 %

Procedure:
A 400 mL beaker was charged with 100 mL of 98% methanesulfonic acid and 500 g (0.175 mol) of N-decanoyl-6-aminocaproic acid. The resulting solution was cooled in an ice bath and, with stirring, 33.1 g of 90% hydrogen peroxide (29.8 g, 0.877 mol of hydrogen peroxide) was added dropwise at a rate such that the temperature of the reaction mixture did not rise above 20° C. The addition required a total of 10 min. The resulting mixture was stirred at room temperature for 3 hrs., cooled to -15° C., and poured into 500 mL of ice water. The precipitated solid was extracted into 200 mL methylene chloride. The methylene chloride solution was separated, washed with 100 mL portions of water until the wash water was neutral (6 washings required), dried over sodium sulfate, and evaporated on a rotary evaporator to yield 51.6 g of white solid having a peroxyacid AvO of 4.93% (theoretical yield=52.7 g of AvO 5.32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([C@@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@H:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([O:43][CH3:42])[CH:45]=2)[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cccc([C@H](C)N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc([C@H](C)NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 127.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(3-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (67 mg, yield 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76](=[O:94])[C@@H:77]([NH2:93])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]2[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=2)=[CH:81][CH:80]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:23])[NH:93][C@H:77]([C:76]([O:75][CH3:74])=[O:94])[CH2:78][C:79]2[CH:80]=[CH:81][C:82]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=3)=[CH:83][CH:84]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Yield: 79.9 %

Procedure:
To a stirring solution of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (146 mg), HBTU (95 mg) and DIEA (0.088 mL) in DMF (5 mL), was added (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (79 mg). After 4 hours a sufficient amount of water was added and the mixture extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the crude amide. The residue was purified by column chromatography on silica gel (with an eluent of hexanes/ethyl acetate from 80:20 to 60:40) to give the product (169 mg).