Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:41]([CH3:43])[CH3:42])[C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])=[O:27].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:41]([CH3:43])[CH3:42])[C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([O:40][CH2:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:39])=[O:31])=[O:27]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (750 mg, 2.02 mmol) in MeCN (20 mL) was added (2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid (600 mg, 2.09 mmol) and DIPEA (0.35 mL, 2.02 mmol) and the solution was heated to 60° C. After stirring for 4 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 80% EtOAc/hexanes) to afford (2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (1.16 g, quant.).
Reaction SMILES: C(O[C:4](=[O:30])[CH:5]([F:29])[C:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)=O)C.C(O)(=O)C.[CH:35]([NH2:37])=[NH:36].CO.C[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[F:29][C:5]1[C:4](=[O:30])[NH:37][CH:35]=[N:36][C:6]=1[C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1
Reactant: CCOC(=O)C(F)C(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1nc[nH]c(=O)c1F)n2Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-oxopropionic acid ethyl ester obtained in Example 36 (3) (88 mg), formamidine acetate (42 mg) and methanol (1.2 ml), sodium methoxide (0.6 ml, 1 mol/l solution in methanol) was added at 15 to 30° C. and the mixture was stirred at the same temperature for 18 hours. The mixture was neutralized with acetic acid and diluted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=5:95) to obtain the desired product (23 mg) in a white amorphous form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([C:4]2[C:5]3[O:12][C:9]4([CH2:11][CH2:10]4)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=2)[CH2:17][CH2:18]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 42, 0.74 g, 2.4 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (8 mL), anhydrous tetrahydrofuiran, copper(I)iodide (0.050 g, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.22 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.62 g, 80%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:28]CCC.CI>C1COCC1>[CH3:28][C:13]1[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:17][CH:16]=2
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.6 g, 4.4 mmol, synthesized as described in Example 22A) in THF (10 mL), under N2, at −78° C., was added n-BuLi (2.5 M solution in hexanes, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, methyl iodide (0.94 g, 6.6 mmol) was added. After 30 min, the −78° C. bath was removed. The solution was warmed to rt. 5% HCl (10 mL) was then added and the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% EtOAc-hexanes gradient) to afford the title compound (0.8 g, 77% yield): MS (ES) m/z 478 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][C:21]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:20][C:19]=4[N:18]=[C:17]([NH2:32])[C:16]=3[N:15]=[C:14]2[CH2:33][O:34][CH2:35][CH3:36])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:32][C:17]1[C:16]2[N:15]=[C:14]([CH2:33][O:34][CH2:35][CH3:36])[N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][CH:37]=3)[C:25]=2[C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CN)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNS(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added dropwise to a mixture of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.520 g, 1.2 mmol) in dichloromethane (10 mL). The reaction was stirred for 16 hours and then saturated aqueous sodium carbonate was added. The layers were separated and the aqueous fraction was extracted with 95:5 chloroform/methanol. The organic fractions were combined and washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography with a gradient of CMA (2%-10%) in chloroform as the eluent. A final recrystallization from 2-propanol provided 0.240 g of N-{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}methanesulfonamide as white granular crystals, mp 228.0-229.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[OH:23].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[O:23][CH:25]([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.23 g of potassium carbonate, 14.6 g of caesium carbonate, 22 ml of dimethylformamide and 1.0 g of 2-bromo-6-nitrophenol are successively introduced into a three-necked round-bottomed flask under argon. The resulting suspension is stirred at ambient temperature for 10 min, and then 0.91 ml of 2-iodopropane is added in one go. The round-bottomed flask is rinsed with 10 ml of dimethylformamide and then the reaction mixture is heated at 40° C. for 48 h. After cooling to ambient temperature, the mixture is treated with 50 ml of water and extracted four times with 30 ml of ethyl acetate. The organic extracts are combined and washed with 30 ml of saturated brine and then 30 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g silica cartridge, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 30 ml/min, so as to obtain 1.04 g of 1-bromo-2-isopropoxy-3-nitrobenzene in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F-:15].[K+].[Cl:17][C:18]1[C:23]([OH:24])=[C:22]([Cl:25])[C:21]([Cl:26])=[C:20]([OH:27])[C:19]=1[Cl:28]>C(#N)C>[C:8]([C:7]1[C:2]([F:1])=[C:3]([C:4]([F:13])=[C:5]([F:12])[C:6]=1[C:10]#[N:11])[O:24][C:23]1[C:18]([Cl:17])=[C:19]([Cl:28])[C:20]([O:27][C:3]2[C:4]([F:15])=[C:5]([F:12])[C:6]([C:10]#[N:11])=[C:7]([C:8]#[N:9])[C:2]=2[F:1])=[C:21]([Cl:26])[C:22]=1[Cl:25])#[N:9]
Reactant: Oc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Reactant: [F-]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c(Oc2c(Cl)c(Cl)c(Oc3c(F)c(F)c(C#N)c(C#N)c3F)c(Cl)c2Cl)c(F)c1C#N
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
In a 500 ml 4-necked flask, were poured 71.15 g (355 mmol) of tetrafluorophthalonitrile, 2.16 g (37.1 mmol) of potassium fluoride and 210 g of acetonitrile, and resulting was heated to 80° C. This mixture was kept at 80° C. with stirring, and to this mixture were dropped 4.40 g (17.7 mmol) of tetrachlorohydroquinone in 200 ml of acetonitrile over 1 hour. After dropping, reaction was performed at 80° C. for 6 hours. The reaction solution was cooled, filtrated, and the resulting residue washed with 30 ml and 15 ml of acetonitrile. After the filtrate had been concentrated on an evaporator to remove the solvent, 62.34 g of tetrafluorophthalonitrile was removed under in vacuo. To this was poured 27 ml of toluene and reflux performed for 1 hour. After cooling, the residue was washed with 5 ml, 25 ml and 5 ml of toluene, respectively, and further 12 ml of deionized water for three times. Finally, by drying the residue at 70° C. in vacuo, 9.08 g of 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrachlorobenzene were obtained (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6](SC)[CH2:5]2.[S:14]([O:18]OS([O-])(=O)=O)(O)(=O)=[O:15].[K+].OOS([O-])=O.[K+].[CH2:31](O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:14]([CH3:31])(=[O:18])=[O:15])[CH2:5]2
Reactant: O=S(=O)([O-])OOS(=O)(=O)O
Reactant: CSC1Cc2cc(Cl)ccc2C1=O
Reactant: CCO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 g of 5-chloro-2-methylsulfanylindan-1-one was dissolved in 10 ml of dry ethanol. At 0° C., a solution of 4.33 g of potassium hydrogenpersulfate (2KHSO5xKHSO4xK2SO4; “Oxone”) in 10 ml of water was added dropwise and the reaction mixture was then stirred at room temperature for 5 h. The alcohol was distilled off under reduced pressure at room temperature. 20 ml of dichloromethane and 10 ml of water was added to the residue, and the mixture was stirred for 10 min. The organic phase was separated off, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was dried. This gave 5-chloro-2-methylsulfonylindan-1-one of melting point 196° C.
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:22])[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Pd]>[NH:1]([C:8]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:22])[C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c([nH]c3ccc(Nc4ccccc4)cc13)CCCC2
Agent: [Pd]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2ccc(Nc3ccccc3)cc12
Yield: 88.9 %

Procedure:
A mixture of 70 g of 5,6,7,8-tetrahydro-2-anilinoacridone and 700 ml of Dowtherm® A was brought to reflux in a 2-liter resin kettle, in a nitrogen atmosphere. A stainless steel mesh basket containing 14.5 g of 0.5% palladium on 1/8 inch alumina pellets was lowered into the reaction mixture. The mixture was refluxed for 18 hours. The basket was removed from the reaction mixture, which was then allowed to cool. The precipitated product was collected on a filter and washed with four 350 ml aliquots of methanol. Vacuum oven drying at 100° C. overnight gave 61.4 g (89%) of the product that was analyzed by microanalysis.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:22])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 2-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1) to yield the desired product.
Reaction SMILES: Cl.[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OC1C2N=NNC=2C=CC=1.[C:34]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH:22][C:49](=[O:50])[C@@H:45]([NH:44][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH:46]([CH3:48])[CH3:47])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (2.10 mmol) was dissolved in DMF (30 mL) under nitrogen and stirred at 0° C. To this was added sequentially hydroxybenzotriazole (0.91 g, 6.72 mmol), N-Cbz-L-valine (0.63 g, 2.52 mmol), triethylamine (0.58 mL, 4.2 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.48 g, 2.52 mmol). The stirred reaction mixture was allowed to warm to room temperature and continued to stir overnight. The reaction was diluted with ethyl acetate (300 mL) and was washed with brine (100 mL). The brine layer was back extracted with ethyl acetate (2×100 mL) and the organic fractions were combined and were washed with 10% citric acid (2×100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by flash chromatography (as in Method A) to give (0.72 g, 1.29 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[O:9]C)(=[O:3])[CH3:2].CC(O)CC(O)C.CN1CCCC1=O>O.CCOC(C)=O>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:3])[CH3:2].[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[OH:9])(=[O:3])[CH3:2]
Reactant: COC1CCCN1C(C)=O
Agent: CC(O)CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)N1C=CCC1
Product: CC(=O)N1CCCC1O

Procedure:
One g of N-acetyl-2-methoxypyrrolidine (largely E plus lesser an amounts of B, C and D), 0.9 g of 2,4-pentandiol and 240 mg of N-methyl-2-pyrrolidone internal standard were heated at 50°-55° C. in 1 mL of H2O. A separate sample was heated in 1 mL of EtOAc. Results in both samples were similar: rapid initial formation of a small peak at 8.02 min (cyclic hemiamidal of the diol?), followed by growth of major product peaks at 8.35 and 8.73 min, the epimeric cyclic acetals. Small quantities of dehydrated product G (r.t.=4.75 min), and, in the aqueous sample, N-acetyl-2-hydroxypyrrolidine, F (before A at ~5.6 min) were also produced. One of the diols appeared to react faster and to a greater extent than the other. Measurements at 3-4 hr were close to the overnight values: ~87% conversion of A, 60-70% of B and essentially quantitative conversion of C and D.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=C(\C)/CCC(OC)=O)=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:32]OS([O-])=O.[K+]>C(Cl)Cl.CO.N1C=CC=CC=1>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:32])=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (10.6 g) in methylene chloride (150 ml), methanol (150 ml) and pyridine (5 ml) was treated with an excess of Oxone® at -70° C. The reaction was quenched with dimethylsulfide (20 ml) and stirred for 5 hours at 25° C. The reaction mixture was poured into 1N aqueous sodium hydrogen sulfate. Extraction with 1:1 ethyl acetate:hexane gave an oil which on purification by silica gel chromatography gave 2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 90.9°-91.6° C.
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)NCCc1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Add dropwise via an addition funnel a solution of [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid methyl ester (13.0 g, 62.2 mmol) in tetrahydrofuran (100 mL) to a stirred solution at 0° C. of 11.0M lithium aluminum hydride in tetrahydrofuran (156 mL) and tetrahydrofuran (250 mL). Reflux for 18 hours, cool to 0° C., quench with saturated aqueous ammonium chloride then stir at room temperature for 3 hours. Filter off the aluminum salts, concentrate on a rotary evaporator, and dry under vacuum to yield 6.6 g of 4-(2-methylamino-ethyl)-phenol: 1H NMR (DMSO-d6, 300.00 MHz): 6.97 (d, 2H); 6.65 (d, 2H); 2.65-2.55 (m, 4H); 2.28 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.CI.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:31][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), methyl iodide (0.1 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution 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 a colorless solid (0.52 g, 100%).