Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C[O:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:30](=[O:29])[C:31]([CH3:36])([CH3:35])[CH2:32][OH:33])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: COCC(C)(C)C(=O)O
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 43.7 %

Procedure:
The title compound was prepared by following the procedure as described in Example-107 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.130 g, 0.33 mmol), DMF (5 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.060 g, 0.50 mmol), BOP (0.224 g, 0.50 mmol), TEA (2.0 mL) to afford 0.070 g of the desired product. MS (m/z): 486.22 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1)[CH3:4].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O1CCOCC1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:10]2[CH:6]([O:5][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: CCOC1CCC(=O)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Yield: 44.5 %

Procedure:
2.6 g of sodium hydride (dispersed at 55-60% in oil) is added to a solution of 7 g of 5-ethoxy pyrrolidin-2-one in 150 cm3 of dioxane, with agitation for 1 hour. A solution of 9.25 g of 4-methoxy benzoyl chloride in 60 cm3 of dioxane is added with agitation for 4 hours. After filtering, the dioxane is evaporated under reduced pressure. The residue is chromatographed on 500 g of silica gel (eluent: acetone-n-hexane 1-2) and 6.35 g of expected product is obtained. b.p. =210° C. under 0.09 mbar.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([NH:20][NH2:21])([C:15]([O:17]CC)=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO[C:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)=[C:25]([C:28]#[N:29])[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([N:20]3[N:21]=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)[C:25]([C:26]#[N:27])=[C:28]3[NH:29][C:15]2=[O:17])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C1(NN)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Yield: 58.9 %

Procedure:
A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate hydrochloride (350 mg, 1.0 mmol), 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (276 mg, 1.0 mmol) and K2CO3 (414 mg, 3.0 mmol) in MeOH (20 mL) was heated to reflux for 16 hr. The mixture was filtered and the filtrate was concentrated to give the crude product (280 mg, 58.9%) as a yellow solid. MS (ESI, m/e) [M+1]+ 475.9.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.C(O)=O.[C@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>CCOCC>[C@H:10]1([NH:20][CH:4]=[O:6])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(=O)OC=O
Solvent: CCOCC
Solvent: O=CO
Product: O=CN[C@@H]1CCCc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of acetic formic anhydride (0.056 mol) (prepared by stirring acetyl anhydride (7.36 ml, 78.0 mmol) and formic acid (2.94 ml, 78.0 mmol) at 50-60° C. for 2 h then cooling to room temperature) was added (r)-1,2,3,4-tetrahydro-1-naphthylamine (8.20 g, 55.7 mmol) dropwise with stirring at such a rate that the temperature never rose above 40° C. After stirring for 30 min, 300 mL of ether was added, and the solution was stirred at room temperature overnight. The reaction was diluted with ether, washed twice with water, twice with Sat. NaHCO3, with 5% HCl, and finally with water. The organic layer was dried with Na2SO4, filtered, and evaporated to dryness. flash chomatograph (SiO2, hexane/EtOAc=1:1 to pure EtOAc) afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide as a white solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[C:13]=[O:14]>CN(C=O)C>[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][NH:12][C:13](=[O:14])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4]
Reactant: OCCNCCO
Reactant: O=C=NCc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1Cl)N(CCO)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of 2,2′-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 mL) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (1.3 g, 65%). LRMS (M+H+) m/z 272.1.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O.Cl.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 56.6 %

Procedure:
9.10 Milliliters of WSC was gradually added to 100 ml of a solution of 12.47 g of Boc-Leu-OH.H2O, 6.98 g of HCl.H-Gly-OEt and 6.76 g of HOBT dissolved in dichloromethane, with ice-cooling. The mixture was stirred for 42 hours at room temperature. The reaction mixture was mixed with 100 ml of 1N hydrochloric acid, and the resulting precipitate was removed by filtration. The filtrate was washed with 100 ml of 1N hydrochloric acid, two 100-ml portions of a saturated aqueous sodium bicarbonate solution and 100 ml of a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to crystallize the residue. The resulting crystal was recrystallized from ethyl acetate-petroleum ether to obtain 8.68 g (yield: 56.6%) of the above objective compound. Melting point: 79.5°-82.5° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1)[CH3:2].[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH2:1]([C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([NH:17][CH:14]([CH3:16])[CH3:15])[N:8]=1)[CH3:2]
Reactant: CC(C)N
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Product: CCc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Yield: 79.3 %

Procedure:
111 g (0.5 mole) of 2-ethyl-4,6-dichloro-5-nitro-pyrimidine are reacted with 59.1 g (1.0 mole) of isopropylamine. To yield 97 g of 2-ethyl-6-isopropylamino-5-nitro-4-chloro-pyrimidine of m.p. 51°-52° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:33]([F:35])[CH:34]=1>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.O>[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/[C:2]2[N:7]=[N:6][C:5]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[O:11][C:4]=3[CH:3]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Reactant: CC1(C)OB(/C=C/c2cc(F)cc(F)c2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(F)cc(/C=C/c2cc3c(nn2)Oc2ccccc2O3)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Under an argon atmosphere, to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (500 mg) were added 1,2-dimethoxyethane (7.5 ml), 2M aqueous sodium carbonate solution (3.0 mL), 2-[(E)-2-(3,5-difluorophenyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 mg) and tetrakis(triphenylphosphine)palladium (130 mg). The reaction mixture was stirred at 100° C. for 3 hr and cooled to room temperature. Water was added, and the obtained solid was collected by filtration and dried under reduced pressure to give 3-[(E)-2-(3,5-difluorophenyl)vinyl][1,4]benzodioxino[2,3-c]pyridazine (700 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1>CN(C=O)C.O>[CH3:18][S:17][C:13]1[N:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:11][N:12]=1
Reactant: Oc1ccccc1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccccc2)n1

Procedure:
To a suspension of sodium hydride (0.3 g,6.85 mmol, 50% dispersion in oil pre-washed with n-hexane) in dry DMF (4 ml) was added dropwise a solution of phenol (0.59 g, 6.23 mmol) in dry DMF (1 ml). The resulting mixture was stirred under an atmosphere of nitrogen until effervescence had ceased. The resulting mixture was diluted with dry DMF (3 ml) and then added dropwise to a stirred solution of 4-chloro-2-methylthiopyrimidine (1.00 g, 6.23 mmol) in dry DMF (3 ml) at 0° C. An exothermic reaction took place and the temperature of the reaction mixture rose to 5° C. After stirring under nitrogen for 30 minutes at 10° C., GC analysis indicated the formation of a single product (98.8%). The reaction mixture was diluted with water (15 ml) and extracted with ether (2×20 ml). The combined ether extracts were washed with 5% sodium hydroxide solution (2×15 ml) and brine (15 ml) and then dried. Evaporation of the solvent gave 2-methylthio-4-phenoxypyrimidine as a pale yellow oil (1.40 g, 94% pure by GC) which was used directly in the next stage. 1H NMR delta: 2.37(3H,s)ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14]
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Reactant: ClCCCCCBr
Product: O=C1OCC(c2ccc(F)c(F)c2)N1CCCCCCl

Procedure:
Prepared by Procedure G and Scheme C1 using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 1-bromo-5-chloropentane.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:27])=[N:24][O:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[C:23]([CH3:27])=[N:24][O:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 23 %

Procedure:
3-Methyl-isoxazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.935 g, 2.59 mmol) and ethyl formate (0.62 mL, 7.72 mmol) were dissolved in anhydrous ethanol (25 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.83 mL, 12.94 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.232 g, 0.595 mmol, 23%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[OH-].[Na+].[F:13][CH:14]([F:16])Cl>O1CCOCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH:14]([F:16])[F:13])[CH:6]=[C:5]([CH3:10])[N:4]=1
Reactant: FC(F)Cl
Reactant: CSc1nc(C)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1nc(C)cc(OC(F)F)n1
Temperature: 80 °C
Yield: 27.4 %

Procedure:
218.7 g (1.4 mols) of 2-methylthio-4-hydroxy-6-methylpyrimidine are suspended in 1.12 litres of dioxane, and 1500 g (11.2 mols) of 30% aqueous sodium hydroxide solution are added. The suspension is heated to 80° C., and into this hot suspension are passed, in the course of 3 hours, 242 g (2.8 mols) of difluorochloromethane. The pale yellow suspension obtained is cooled to 20° C. and filtered. The residue is washed with dioxane and dried to thus yield 210 g of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine. The filtrate is extracted with methylene chloride, and the organic phase is washed with water and concentrated by evaporation to obtain, as crystalline residue, a further 79 g of the desired product. The overall yield obtained in this manner is 289 g of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine (100% of theory), m.p. 40-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:47].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:40])[CH3:41])[O:13][N:12]=1)=[O:47]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CSc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (20 mg, 0.033 mmol) in dichloromethane (1 mL) at 0° C. was added meta-chloroperoxybenzoic acid (15 mg, 0.066 mmol). The mixture was stirred at 0° C. for approximately 30 minutes. Aqueous sodium bicarbonate was added and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution) to afford ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (12 mg, 0.019 mmol, 57%). 1H-NMR (400 MHz, CDCl3) δ 8.39 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz, 2H), 8.05-8.03 (m, 2H), 7.68 (d, J=9 Hz, 2H), 7.31 (s, 3H), 7.07 (d, J=9 Hz, 2H), 5.10-4.90 (m, 2H), 4.80-4.58 (m, 2H), 3.22 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). LRMS m/z 623 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH:16]=[CH2:17].Cl>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH:16]=[CH2:15]
Reactant: OB1OCc2ccc(O)cc21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
H181 (200 mg, 1.33 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 213 mg, 5.33 mmol) and 3-bromoprop-1-ene (0.46 mL, 5.33 mmol). The reaction mixture was stirred for 5 h then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (160.5 mg, 63.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.1 & 2.4 Hz, 1H), 6.12-6.02 (m, 1H), 5.42 (dd, J=17.2 & 1.6 Hz, 1H), 5.29 (dd, J=17.2 & 1.6 Hz, 1H), 5.06 (s, 2H) and 4.57 (d, J=2.8 Hz, 2H) ppm; Mp: 79-81° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][OH:9].F[C:11]([C:13]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[F:14])=[O:12]>>[C:13]([C:11]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][O:9][C:11]([C:13]([C:15]([F:16])([F:17])[F:18])([C:19]([F:20])([F:22])[F:21])[F:14])=[O:12])=[O:12])([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[F:14]
Reactant: OCCCOCCCO
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Product: O=C(OCCCOCCCOC(=O)C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.1 %

Procedure:
HO(CH2)3O(CH2)3OH (10 g) was loaded into an autoclave and stirred in a sealed state, and FCOCF(CF3)2 (36.95 g) was fed over 7 hours at room temperature with occasional pauses for bubbling with nitrogen gas under unsealed conditions. After the feeding, the reaction solution was stirred at room temperature for 1 hour and bubbled with nitrogen gas under unsealed conditions. The reaction solution was neutralized with saturated aqueous NaHCO3 (100 mL) and extracted with R-225 (100 mL) in twice. The organic phase was washed with saturated aqueous NaHCO3 (50 mL) and further with saturated aqueous NaCl (50 mL). The organic phase was dried over magnesium sulfate and filtered to give 36.13 g of a crude liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9](O)[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCC(O)c2sccc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCC=Cc2sccc21
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of 0.90 g of 4-(2-chloro-4-nitrobenzoyl)-8-hydroxy-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 5 ml of dichloromethane cooled to -10° C. is added under argon 533 μl of triethylamine and dropwise 296 μl of methanesulfonyl chloride. After one hour the cooling bath is removed and the mixture allowed to stand at room temperature overnight. The mixture is diluted with 10 ml of dichloromethane and 5 ml of water. The organic layer is separated, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give an oil which is crystallized by adding hexane. Filtration gives light yellow crystals (0.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([OH:14])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH3:19])=[O:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1Cc2ccc(O)cc2CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccc(O)cc2cn1
Yield: 46 %

Procedure:
To a solution of 4.36 g (22.6 mmol) of 7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid in 100 mL of MeOH was added 4.95 mL (67.7 mmol) of thionyl chloride and the solution was refluxed for 1 hr. After evaporation of the solvent, the residue was stirred vigorously in a mixture of 200 mL of EtOAc, 500 mL of H2O and 100 mL of saturated Na2CO3 (aq) until all solids dissolved. The aqueous layer was then saturated with sodium chloride and extracted twice with EtOAc. The combined organics were then washed with brine, dried over Na2SO4 and concentrated to a solid. To this solid was added 200 mL of xylenes and 3.0 g of palladium on carbon (10%) and the suspension was refluxed for 16 hr. The suspension was filtered through a pad of Celite® and silica gel. The pad was then washed with 50 mL of xylenes. The filtrate was discarded and the filter cake washed with 500 mL of a 4:1 mixture of CH2Cl2:MeOH. This filtrate was then evaporated to give 2.09 g (46%) of methyl 7-hydroxy-3-isoquinolinecarboxylate as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.08 (s, 1H), 8.49 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.39 (d, J=9 Hz, 1H), 7.36 (s, 1H), 3.87 (s, 3H). ESI-LCMS m/z 204 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([N:20]2[CH2:21][CH2:22][C@H:18]([C:15]([OH:14])([CH3:17])[CH3:16])[C@@H:19]2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCCc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-propylbenzonitrile (538 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (615 mg) and lithium carbonate (259 mg), the title compound was obtained as a yellow solid (yield: 69 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28]([OH:30])=O)=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][NH:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:30])[N:33]([CH3:34])[CH3:32])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)N(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (30 mg, 0.071 mmol), dimethylamine (0.1 mmol) and HOBT (0.2 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(0.2 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated, taken up with 1 mL of methanol and purified on preparative HPLC to give 29-1: LC-MS 467.4 (MH).