Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:17]([O:19]C)=[O:18])[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To dimethyl malonate (102 mL), a solution of sodium methoxide in methanol (28%, 90.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 30 minutes. The white suspension was cooled to room temperature. Then, tert-butyl (3-bromopropyl)carbamate (106 g) was added thereto at once, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, water was added, and organic matter was extracted with diethyl ether. The organic layer was washed with a 1 N aqueous sodium hydroxide and saturated sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of dimethyl {3-[(tert-butoxycarbonyl)amino]propyl}malonate. The obtained ester (94 g) was dissolved in methanol (100 mL). To the solution, a solution of lithium hydroxide monohydrate (13.6 g) in water (300 mL) and methanol (300 mL) was added at 0° C., and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure, and organic matter was extracted with ethyl acetate. 2 N hydrochloric acid (160 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=10/1) to obtain the title compound (69.1 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1>[CH2:19]([C:18]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 79.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (119.1 g, 0.48 mole) was cyclized using trimethyl orthovalerate (93 g, 0.57 mol) in the presence of pyridine hydrochloride (1.1 g, 0.0095 mol) to provide 120 g of 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline as an ivory powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9](OC)=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:10][CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)c1ncccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccnc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Heat a mixture of 3-hydroxypicolinic acid (5.3 g, 38 mmol), potassium carbonate (15.8 g, 114 mmol), and iodomethane (9.6 mL, 153 mmol) in acetone (100 mL) and DMF (10 mL) overnight at 60° C. Cool the reaction mixture to ambient temperature, pour into brine, extract three times with ethyl ether, dry over anhydrous MgSO4 and concentrate in vacuo. Pass through a short plug of silica gel eluting with ether to provide 3-methoxy-2-methoxycarbonylpyridine as a pale yellow liquid (6.3 g, 100%). To a solution of 3-methoxy-2-methoxycarbonyl-pyridine (2.34 g, 14.0 mmol) in dry THF (25 mL) add slowly with stirring a solution of 1M lithium aluminum hydride in THF (10 mL, 10 mmol) and continue stirring overnight at ambient temperature. Quench cautiously with sodium sulfate decahydrate, filter under suction and rinse the solids with additional THF. Concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:1) to provide the desired intermediate as a white solid (350 mg, 18%).
Reaction SMILES: ClC1C(Cl)=C(/C=C(/[N+]([O-])=O)\CC)C=CC=1OCCCC(O)=O.[Cl:23][C:24]1[C:37]([Cl:38])=[C:36](/[CH:39]=[C:40](/[N+:43]([O-:45])=[O:44])\[CH2:41][CH3:42])[CH:35]=[CH:34][C:25]=1[O:26][C:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.NCC(O)=O.[NH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55]>>[Cl:23][C:24]1[C:37]([Cl:38])=[C:36](/[CH:39]=[C:40](/[N+:43]([O-:45])=[O:44])\[CH2:41][CH3:42])[CH:35]=[CH:34][C:25]=1[O:26][C:27]1([C:31]([NH:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: CC/C(=C\c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]
Reactant: NCCC(=O)O
Agent: CC/C(=C\c1ccc(OCCCC(=O)O)c(Cl)c1Cl)[N+](=O)[O-]
Agent: NCC(=O)O
Product: CC/C(=C\c1ccc(OC2(C(=O)NCCC(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
By carrying out the reaction essentially as described in Example 9, except that the (E)-4-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]butyric acid is replaced by an equimolar quantity of (E)-1-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]cyclobutane-1-carboxylic acid and the glycine is replaced by an equimolar quantity of β-alanine, there is obtained N-{(E)-1-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]-cyclobutane-1-carbonyl}-3-aminopropionic acid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C(O)=O.[Na].CN1CCCC1=O>[Cu]I.CCCCCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([F:17])([F:16])[C:11]([F:19])([F:18])[F:10])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1ccc(I)cc1C
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1C
Temperature: 170 °C

Procedure:
Into a nitrogen purged, flame dried round bottom flask was added 4-iodo-o-xylene (15.0 g, 64.7 mmol), sodium pentafluoropropionic acid (16.8 g, 90.5 mmol), copper (I) iodide (12.3 g, 64.6 mmol) and 100 mL of anhydrous N-methylpyrrolidinone. The reaction mixture was heated at 170° C. for 16 hours, then cooled to room temperature, and run through a thick silica gel plug with hexane. The collected yellow liquids were then evaporated to dryness on a rotary evaporator, and the oil distilled at 60° C. (10−1 Torr) to collect the desired product (9.14 g, 63%) as a colorless liquid. Analysis of the product provided the following data: 1H NMR (200 MHz, CDCl3) δ=2.347 (s, 6H), 7.247 (d, J=7.8 Hz, 1H), 7.357 (s, 1H), 7.401 (s, 1H). 13C NMR (50 MHz, CDCl3) δ=19.810, 19.840, 124.013 (t, J=6.1 Hz), 127.472 (t, J=6.1 Hz), 130.158, 137.563, 141.205. GC-MS: m/z: 224 (C10H9F5).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:3]=O.[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]([N+:19]([O-:20])=[CH:3][CH:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C=[N+]([O-])C(C)(C)C)Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.18 %

Procedure:
To a mixture of [2-methyl-3-(4-isopropylphenyl)-propionaldehyde] (3.0 g, 15.8 mmol, 1.0 equiv), N-tert-butylhydroxylamine (1.76 g, 19.7 mmol, 1.3 equiv) and toluene (60 ml) was added p-TsOH (50 mg), and the mixture was stirred at rt for 18 h. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography (EtOAc:hexane 1:1) to give N-tert-butyl-C-[2-(4-isopropylphenyl)-1-methyethyl]nitrone (1.04 g, 25.18%) as a white solid: 1H NMR (CDCl3) δ 7.12 (d, J=1.0, 4H), 6.63 (d, J=7.2 1H), 3.47–3.31 (m, 1H), 2.89–2.80 (m, 2H), 2.71–2.63 (dd, 1H), 1.44 (s, 9H), 1.25 (d, J=6.9, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].S(=O)(O)[O-].[Na+]>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[C:12]#[N:13])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)c1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(C(O)C#N)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 4-isopropylbenzaldehyde (21.4 g) and sodium cyanide (6.9 g) in water (25 ml) at 0° was added saturated sodium bisulfite (40 ml) dropwise over a period of 30 minutes. During the addition about 50 g of ice was also added in small portions. After the addition the mixture was warmed up to room temperature gradually. Resulting waxy 4-isopropylmandelonitrile was separated by decantation and the aqueous layer was extracted with benzene. The benzene extract was evaporated and, the residue was combined with the waxy material. The 4-isopropylmandelonitrile was dissolved in concentrated hydrochloric acid (25 ml) and the mixture was stirred at room temperature overnight. It was then stirred in a 100° oil bath for 3 hours. After cooling was added water to dissolve the solid material and the product was extracted with ethyl ether throughly. The combined extracts were washed with brine, dried (sodium sulfate) and evaporated to give 4-isopropylmandelic acid as an oil (17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:10]=1)=[O:5])[CH3:2].C(Cl)[Cl:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[C:10]=1[Cl:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)CF)nn1C
Reactant: ClCCl
Product: CCOC(=O)c1c(Cl)c(C(C)(C)CF)nn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (722 mg, 3.16 mmol, prepared as described in the previous step) was dissolved in DCM (5 mL) and SO2Cl2 (0.256 mL, 3.16 mmol) was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The resulting residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-1:4 EtOAc/heptane to yield 4-chloro-5-(2-fluoro-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCl3) δ: 4.59 (d, J=47 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.08 (s, 3H), 1.43 (d, J=1.7 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+]([CH:4](NS(C1C=CC=CC=1)(=O)=O)CCOCCC(NS(C1C=CC=CC=1)(=O)=O)[N+]([O-])=O)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:40][S:41]([O:44][CH2:45][CH2:46][CH:47]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][N:63]([S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[N+:80]([O-:82])=[O:81])(=[O:73])=[O:72])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=2)=[CH:58][CH:57]=1)[CH2:48][CH2:49][O:50][S:51]([CH3:54])(=[O:53])=[O:52])(=[O:43])=[O:42]>CN(C=O)C.C(OCC)(=O)C>[CH3:54][S:51]([O:50][C:49]1[CH:48]=[C:47]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][N:63]([S:71]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=3[N+:80]([O-:82])=[O:81])(=[O:73])=[O:72])[CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=3)=[CH:58][CH:57]=2)[CH:46]=[C:45]([O:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH:4]=1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)Cc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=[N+]([O-])C(CCOCCC(NS(=O)(=O)c1ccccc1)[N+](=O)[O-])NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1cc(Cc2ccc(CN(Cc3ccccn3)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)cc(OS(C)(=O)=O)c1
Reaction time: 30 h
Yield: 80.7 %

Procedure:
A solution of bis(3-nitrobenzenesulfonylaminopropyl)ether (190 mg, 0.38 mmol) and finely ground, freshly oven-dried cesium carbonate (320 mg, 1.14 mmol) in anhydrous DMF (60 mL) was heated to 80° C. Methanesulfonic acid, 5-methanesulfonyloxy-3-(4-{[(2-nitro-benzenesulfonyl)-pyridin-2-ylmethyl-amino]-methyl}-benzyl)-pentyl ester (250 mg, 0.38 mmol) in DMF (20 mL) was then added to the reaction over a 30 hour period via syringe pump. After complete addition, the reaction was stirred another 30 hours. The mixture was then cooled, diluted with 300 mL ethyl acetate and extracted repeatedly with water. The organic phase was then dried and concentrated, and the residue was purified by column chromatography on silica gel using 25% ethyl acetate in dichloromethane as eluant to afford the desired product (203 mg, 51%). 1H NMR (CDCl3) δ 1.47–1.71 (m, 9H), 2.42 (d, 2H, J=6.1 Hz), 3.15–3.32 (m, 12H), 4.53 (s, 2H), 4.55 (s, 2H), 6.94 (d, 2H, J=6.4 Hz), 7.03 (d, 2H, J=6.4 Hz), 7.05 (d, 1H, J=5.8 Hz), 7.52 (m, 4 H), 7.64 (m, 6 H), 7.91 (m, 5H), 8.44 (d, 1H, J=5.4 Hz).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]1[O:15][CH:9]1[CH2:10]2)(=O)C.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C@@H:8]1[CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[OH:4])[CH2:10][C@H:9]1[OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Oc1cccc2c1CC1OC1C2
Reactant: NCc1ccccc1
Product: Oc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2

Procedure:
A mixture of 5-acetoxy-2,3-epoxy-1,2,3,4-tetrahydronaphthalene (prepared in the manner disclosed in U.S. Pat. No. 4,076,843, 20.4 g) and benzylamine (85 mL) was heated in a bomb at 120° C. for 18 h. After cooling, excess amine was distilled off under high vacuum using a 70° C. bath. The semi-solid residue was triturated with chloroform (70 mL) and filtered. The filtercake was washed with chloroform, then with diethyl ether, and dried under vacuum to provide crude product. The crude product was recrystallized from a mixture of methanol and ethyl acetate to yield the title product (10 g) as a white solid. The regioisomeric product (trans 3-benzylamino-2,8-dihydroxy-1,2,3,4-tetrahydronaphthalene) was largely contained in the chloroform extract and wash.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][CH:30]3[CH2:31][CH2:32]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)NC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
TFA (0.5 mL, 7.20 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-cyclopropylurea (10 mg, 0.024 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 7.69-7.67 (m, 2H), 7.59 (d, 1H, J=8.8 Hz), 7.27 (m, 3H), 3.91 (t, 2H, J=5.6 Hz), 3.62 (m, 1H), 2.64 (t, 2H, J=6.0 Hz); ESI-MS [M+H]+: 333.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[N:5]=1)(=[O:3])[CH3:2].[SiH3]O[SiH3].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [SiH3]O[SiH3]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CO)n1
Reaction time: 0.67 h
Yield: 99.2 %

Procedure:
To a THF (10 mL) solution of the silyl ether 2-Acetyl-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (0.8 g, 3.0 mmol) was added tetrabutylammonium fluoride hydrate (870 mg, 3.3 mmol) at room temperature, and the mixture was stirred for 40 min. It was extracted with EtOAc (150 mL) and washed with water (6 mL×3) and brine (6 mL). The extract was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane/EtOAc 4:1 to give the title compound (450 mg, 99%) as an oil. 1H NMR (CDCl3) δ 8.00 (d, 1H, J=7.2 Hz, H-3), 7.88 (m, 1H, H-4), 7.49 (d, 1H, J=7.7 Hz, H-5), 4.88 (d, 2H, J=5.0 Hz, CH2), 3.84 (d, 1H, J=3.2 Hz, OH), 2.78 (s, 3H, CH3); 13C NMR (CDCl3) δ 200.0 (CO), 159.1 (C-6), 152.7 (C-2), 138.0 (C-4), 124.4 (C-5), 120.8 (C-3), 64.3 (CH2), 26.3 (CH3).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Yield: 87 %

Procedure:
N-Hydroxyphthalimide and cyclopropyl-methanol were reacted as described for compound LIX in Example 27, to afford LXXXVI in 87% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 7.86 (4H, s), 3.97 (2H, d, J=7.4 Hz), 1.22-1.11 (1H, m), 0.61-0.48 (2H, m), 0.34-0.22 (2H, m).
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([CH3:16])[O:17][C:26]3=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(CC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 4-(1-adamantylmethylamino)butan-2-ol (50 mg, 0.21 mmol) and Et3N (42.4 mg, 0.42 mmol) in CH2Cl2 (5 mL) at 0° C. under N2, a solution of triphosgene (25 mg, 0.084 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stirred at rt for 1 h. The mixture was concentrated to give crude product, which was purified by preparative TLC to afford 3-((1-adamantyl)methyl)-6-methyl-1,3-oxazinan-2-one (12 mg, 21%). 1H NMR (CD3OD, 400 MHZ): δ=1.46 (d, 3H), 1.72˜2.18 (m, 17H), 3.02 (d, 1H), 3.34 (d, 1H), 3.44 (m, 1H), 3.63 (m, 1H), 4.58 (m, 1H); MS m/z=264
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[OH-].[K+].[CH2:9]1[O:11][CH2:10]1>>[F:1][CH2:2][CH:3]([CH2:4][F:5])[O:6][CH2:9][CH2:10][OH:11]
Reactant: C1CO1
Reactant: OC(CF)CF
Agent: [K+]
Agent: [OH-]
Product: OCCOC(CF)CF
Reaction time: 12 h
Yield: 38 %

Procedure:
112 g (1.0 mol) of 1,3-difluoro-2-propanol and 3 g of potassium hydroxide are initially introduced and 50 ml of ethylene oxide are condensed in a V4A autoclave (volume : 300 ml) at -78° C. The reaction mixture is then shaken for 12 hours at +80° C. to +90° C. (initial pressure about 9000 hPa). After depressurizing and venting unreacted ethylene oxide, the residual contents of the autoclave are fractionally distilled in a water jet vacuum. 59 g (38 % of theory) of 2-(2-fluoro-1-fluoromethyl-ethoxy)-ethanol are obtained as a main fraction of boiling range 98° C. to 105° C./24 hPa.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@@H:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:11])=O)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]([CH3:81])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][NH:71][C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:64][CH:63]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1>C(Cl)Cl>[CH3:81][N:55]([CH3:54])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][N:71]([C:9](=[O:11])[C@@H:8]([NH:7][C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[O:6])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:66][CH:67]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccc(N(C)C)cc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
(S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (62 mg, 0.217 mmol), DIEA (0.076 mL, 0.434 mmol) and HATU (61 mg, 0.159 mmol) were added to a solution of (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (55 mg, 0.145 mmol) in DCM (3 mL). The reaction was stirred at r.t. for 2 hrs. The reaction was evaporated and purified on the Biotage (10-45% EtOAc:Hex) to give (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-1-((S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (61 mg, 0.094 mmol, 65% yield) as a yellow oil. LCMS: rt=2.00 min. [M-OMe]+=616 and [M+H]+=648; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:21])=[C:9]2[Cl:12])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1nccc2ccc(Br)cc12
Solvent: ClCCl
Product: [O-][n+]1ccc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
To a solution of 7-bromo-1-chloroisoquinoline (4.0 g, 15.8 mmol) in DCM (100 mL) at 0° C. was added mCPBA (˜77%, 7.46 g, 33.3 mmol). The reaction was allowed to stir at room temperature for 24 hours, diluted with DCM (100 mL) and washed with 1N NaOH and brine. The DCM extracts were dried over Na2SO4, filtered, concentrated and chromatographed on silica eluting with 5 to 15% acetone/DCM to give the title compound (1.43 g). LRMS (M+H)+=258.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[N:14][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)nc2)c1C
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ccc(C3CC3)nc2)c1C
Temperature: 0 °C
Yield: 55.8 %

Procedure:
A suspension of 1-(6-chloropyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.6 g), cyclopropylboronic acid (776 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (124 mg), palladium acetate (67.6 mg) and tripotassium phosphate (3.83 g) in 1,4-dioxane (13 ml) was stirred under reflux. After completion of the reaction, the mixture was allowed to cool, ice water and a saturated aqueous solution of ammonium chloride were added thereto, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(6-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (911 mg) as a brown oil. MS (ESI) m/z: 272 (M+H)+.