Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.B1C2CCCC1CCC2.[O:22]1CCCC1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:22])=[CH:6][CH:5]=1
Reactant: C=Cc1ccc(C(=O)OC)cc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Methyl-4-vinylbenzoate 70 (2.270 g, 14.00 mmol) was dissolved in 50 ml of tetrahydrofuran and cooled to 0° C. 9-BBN (0.5M in THF)(28.00 ml, 14.00 mmol) was added and the mixture was stirred for 2 hours. The solution was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was cooled to 0° C. and quenched with alkaline hydrogen peroxide. The mixture was then extracted with diethyl ether. The extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.632g (64.7%) of 4-(2-hydroxyethyl)benzoic acid methyl ester 71 as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2=[N:12][C:13]([C:15](OCC)=[O:16])=[N:14][N:4]2[C:3]1=[O:20].[NH3:21]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2=[N:12][C:13]([C:15]([NH2:21])=[O:16])=[N:14][N:4]2[C:3]1=[O:20]
Reactant: CCOC(=O)c1nc2c3ccccc3n(C)c(=O)n2n1
Reactant: N
Solvent: CN(C)C=O
Product: Cn1c(=O)n2nc(C(N)=O)nc2c2ccccc21
Reaction time: 48 h

Procedure:
12.0 g of ethyl 6-methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate were suspended in 600 ml of absolute dimethylformamide, and 200 ml of a 7% strength methanolic NH3 solution were added. The mixture was stirred for 48 hours, after which the precipitate was filtered off under suction, washed with dimethylformamide and water, and dried. Yield: 4.8 g (42%), mp. 286°-287° C.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58])=[CH:48][CH:47]=1>>[OH:58][CH2:57][CH2:56][CH2:55][CH2:54][C:53]#[C:52][C:49]1[CH:48]=[CH:47][C:46]([NH:45][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:51][CH:50]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: Nc1ccc(C#CCCCCO)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 48 in place of 8-aminooctanol. ES/MS calcd. for C37H35N4O6S+ 663.2. Found m/z=663.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([NH:10][C:11]1[S:12][CH:13]=[N:14][N:15]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>O1CCCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:2][CH:3]([C:8]([NH:10][C:11]1[S:12][CH:13]=[N:14][N:15]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:28]
Reactant: CC(C)CC(N)C(=O)Nc1nncs1
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)NCCCl)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
7.5 g of 2-DL-leucylamino-1,3,4-thiadiazole hydrochloride and 3.1 g of triethylamine were suspended in 100 ml of tetrahydrofuran, and 3.2 g of 2-chloroethyl isocyanate was added thereto and stirred for 2 hours. The reaction solution was concentrated, and the resulting crystals were washed with water and n-hexane to obtain 7.9 g (Yield 83%) of 2-[N-{(2-chloroethyl)carbamoyl}-DL-leucyl]amino-1,3,4-thiadiazole was obtained as slightly yellow crystals having a melting point of from 162° to 166° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:5][C:4]2[CH:6]=[C:7]([F:20])[C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:27]=1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)cc(Nc2cc(F)c(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
162 mg (0.55 mmol) of 3,5-difluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 90 mg (0.55 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 6 ml of water/ethanol 1:1. 56 μl (0.65 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux for 3 h. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:28])[C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)([O:3]C)=[O:2].C(O)(=O)C.O>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:28])[C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:24])([CH3:25])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)c3ccc(C(=O)O)cc3)ccc21
Yield: 85.1 %

Procedure:
3.9 g (10 mmol) of 1-(4-Carbomethoxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanedione (Example 6) were refluxed in a mixture of 5 ml of concentrated sulfuric acid, 80 ml of glacial acetic acid and 40 ml of water for 8 h. The mixture was then poured into 500 ml of water, and the crystalline precipitate was filtered off with suction and washed with water until the washings were neutral. The dried crude product was recrystallized from cyclohexane, yielding 3.1 g of the title compound of melting point 148°-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:14]OB(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COB(O)O
Reactant: COC(=O)c1cc(Br)cnc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cnc1OC
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
1.2 g of methyl 5-bromo-2-methoxy-3-pyridinecarboxylate was dissolved in 20 ml of N,N-dimethylformamide, 440 mg of methylboric acid, 4.79 g of anhydrous cesium carbonate, and 564 mg of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), to give 461 mg of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:5](=[O:7])[CH3:6])[CH3:3].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:2]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH2:11][CH2:10]1)[C:5](=[O:7])[CH3:6])[CH3:3]
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CCN(CC1CCNCC1)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCN(c2ccnc(C(F)(F)F)n2)CC1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
A mixture of N-ethyl-N-[(4-piperidinyl)methyl]acetamide hydrochloride (Example 4; 2.14 g, 10 Mole), 4-chloro-2-trifluoromethylpyrimidine (1.83 g, 10 mmole), and sodium carbonate (2.65 g, 25 mmole) in DMF (30 ml) was stirred for 18 hrs at room temperature. The mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (50 ml), filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give formula I product as a yellow oil (2.17 g, 67%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C1CCNCC1
Product: COc1ccc(Nc2ncc(CN3CCCCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (264 mg, 0.457 mmol) and piperidine (Aldrich, St. Louis, Mo.) (67.7 μL, 0.686 mmol). 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.72 (d, J=2.35 Hz, 1H); 8.35 (d, J=2.54 Hz, 1H); 8.21 (d, J=2.35 Hz, 1H); 8.14 (dd, J=8.90, 2.84 Hz, 1H); 6.77 (d, J=9.00 Hz, 1H); 5.56 (br. s., 2H); 3.94 (s, 3H); 3.45 (s, 2H); 2.56 (s, 3H); 2.41 (br. s., 3H); 1.60 (dt, J=10.95, 5.48 Hz, 5H); 1.39-1.46 (m, 2H). m/z (ESI, +ve ion) 407.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH:21](Br)[CH3:22]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH:21]([N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2)[CH3:22]
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: CC(Br)c1cc(F)ccc1F
Product: CC(c1cc(F)ccc1F)N1C(=O)CNc2ncc(I)cc21

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.030 g) was alkylated with 2,5-difluoro-alpha-bromoethylbenzene as in General Procedure 1 to give the title compound as a yellow solid. LCMS: m/z=415.93 (M+H+)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[C:7]([PH2]=O)=[C:8]([CH3:16])[CH:9](OCC)OCC)[CH3:4].[Br:20][C:21]1[CH2:25][CH2:24][CH2:23][C:22]=1[CH:26]=O>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:16])/[CH:9]=[CH:26]/[C:22]1[CH2:23][CH2:24][CH2:25][C:21]=1[Br:20])[CH3:4]
Reactant: CCOC(=O)C([PH2]=O)=C(C)C(OCC)OCC
Reactant: O=CC1=C(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(C)/C=C/C1=C(Br)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2.03 g of NaH (50% in mineral oil) was suspended in 120 ml of DMF. 4-(Diethoxy-phosphinyl-3-methyl-but-2-enoic acid ethyl ester (12.9 g) was added at 0° C. The mixture was stirred for 15 minutes at 0° C. and for 30 minutes at RT. After recooling to 0° C., 2-bromo-cyclopent-1-ene-carbaldehyde (5.72 g), dissolved in 11 ml of DMF, was added drop by drop and allowed to react for 10 minutes at 0° C. and for 2 hours at RT. The mixture was then poured into crashed ice. extracted with EtOEt, washed with sat. NaCl-solution, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/AcOEt=97/3) and crystallization from hexane/trace amounts of AcOEt yielded finally 3.408 g of pure (2E,4E)-5-(2-bromo-cyclopent-1-enyl)-3-methyl-penta-2,4-dienoic acid ethyl ester as yellowish crystals of mp. 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])C.C(N(CC)CC)C>C(O)C>[ClH:1].[N+:8]([C:7]1[C:2]([NH:17][C@H:16]([C:15]([OH:19])=[O:14])[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), (S)-alanine ethyl ester hydrochloride (100 g, 0.651 mole) and triethylamine (103.7 g, 1.03 mole) in 95% ethanol was heated at reflux for 4.5 hours, during which time a dark yellow solution formed. The reaction mixture was stirred at room temperature overnight and then refluxed for an additional 2 hours. The solvents were evaporated under reduced pressure, and the resulting solid was triturated in ethyl acetate, filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed three times with water, dried over sodium sulfate, filtered, and evaporated to an oil weighing 107 g (quantitative yield). The oil was eluted through 600 g of silica gel, using ethyl acetate as the eluent, and evaporated to an oil. A 3.5-g portion of the oil was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. The mixture was evaporated and redissolved in acetonitrile. Addition of isopropyl ether caused a solid to precipitate. The solid was collected by filtration and its mother liquor was evaporated and the residue was triturated in ethereal hydrogen chloride. A yellow solid formed which was collected by filtration. Upon standing, more solid formed in the mother liquor. This solid was collected by filtration, rinsed with diethyl ether and dried under high vacuum to give 0.14 g of title compound, mp>260° C. (darkens 178°-185° C.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(C#N)cc1)C(=O)O

Procedure:
In analogy with Example 1i), 0.50 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(p-cyanophenyl)methyl]dihydrofuran-2-(3H)-one in 19 ml of dimethoxyethane and 10 ml of water is hydrolysed with 4.8 ml of a 1M lithium hydroxide solution to form the title compound: TLC Rf (B)=0.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([O:38]COC)[C:29]=1[CH:42](OC)[O:43]C)(=O)=O>>[CH:42]([C:29]1[C:30]([OH:38])=[C:31]([C:34]([F:35])([F:37])[F:36])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1)=[O:43]
Reactant: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)C)c1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)cc2)c(C(C)C)c1

Procedure:
According to a method similar to Example (40-2) and Example (8-3), from crudely purified methyl (4′-hydroxy-2-isopropyl-1,1-biphenyl-4-yl)acetate (147 mg) obtained in Example (42-3) and 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate (252 mg, 0.65 mmol) obtained in Example (26-5), crude methyl (4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-2-isopropyl-1,1′-biphenyl-4-yl)acetate was obtained (169 mg).
Reaction SMILES: [C:1]1([P:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18]O.O>CC(C)=O>[C:1]1([P:7](=[O:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([F:11])([F:9])[F:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: FC(F)(F)P(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=P(c1ccccc1)(c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A solution of 1.0g (3.9 mmol) of diphenyltrifluoromethylphosphine (4) in 5 mL of acetone was treated with 0.5 mL (4.9 mmol) of 30% hydrogen peroxide. Within a few minutes an exothermic reaction occurred which caused the solution to reflux. After this had subsided, the solution was allowed to stand for 4 hours at room temperature and poured into 15 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of cichloromethane. The organic layers were combined, dried (MgSO4), and concentrated to give 0.85g (80% yield) of diphenyltrifluoromethylphosphine oxide as a colorless liquid: 19F NMR (CDCl3 relative to CF3CO2H) 5.86 ppm (d, JPF =89 Hz); mass spectrum (70 eV) m/z (relative intensity) 201 (100, M-CF3), 77 (23), 51 (16).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reaction time: 2 h

Procedure:
To (trans)-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 44.5 mmol) in 1,4-dioxane (75 ml) and water (75 ml) was added dropwise benzyl chloroformate (6.99 ml, 49.0 mmol). The pH was kept between 7 and 8 by adding saturated aqueous sodium carbonate. After stirring for two hours the reaction mixture was concentrated in vacuo till half volume, 1M sodium hydroxide (aq) was added till pH=9 and the mixture was extracted with diethylether. 2M Hydrochloric acid was added till pH=1 was the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to yield (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (12.03 g)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][N:21]=[CH:20]2)(=[O:31])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-1,3-propylenediamine (2.09 g, Tokyo Kasei Kogyo) and triethylamine (3.4 ml, Tokyo Kasei Kogyo) in dichloromethane (20 ml) was added with a solution of isoquinoline-5-sulfonyl chloride (2.73 g, prepared according to Japanese Patent Unexamined Publication (Kokai) No. 61-227581) in dichloromethane (15 ml) with stirring and ice cooling and stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. Then, the residue was purified by flash column chromatography (chloroform:methanol=50:1) to obtain the title compound (4 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N=C=N.CO>C(Cl)(Cl)Cl>[C:1]([NH:8][C@H:9]([C:13]([NH:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: N=C=N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
Boc-valine was coupled to the resultant compound of Example 69 using the carbodiimide coupling procedure of Example 55 to provide, after silica gel chromatography using 3% methanol in chloroform, the desired compound (82%, Rf 0.7, 10% methanol in chloroform) as a white solid, m.p. 184°-184° C. Mass spectrum: (M+H)+ =703.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:30][C:20]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:17]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:19]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
1-methylpiperazine (0.111 mL, 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). the reaction vessel was heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (60-100%) in heptane furnished 0.120 g (63%) of the title compound.