Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[NH2:4][CH2:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C(O)C>[C:5]([CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])#[N:4]
Reactant: CCOP(=O)(CCCN)OCC
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCC#N)OCC
Yield: 30 %

Procedure:
A mixture of diethyl[3-(N-phthalimido)]propylphosphonate (ex. 5) (3.72 g; 11.4 mmoles), absolute ethanol (46 ml) and hydrazine hydrate (0.78 ml of 98% purity; 15.7 mmoles) is stirred at reflux for 35 min. The mixture is filtered and the solvent is distilled under vacuo. The resulting oil is dissolved in CHCl3 (10 ml) and is filtered again. Solvent removal in vacuo gives a colorless liquid (0.7 g; yield 30%). According to example 4, diethyl 3-aminopropylphosphonate (6) is also obtained from diethyl 2-cyanoethylphosphonate in an analogous fashion followed by vacuum distillation at about 115° C. and 0.18 mbar (yield 80%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)=[O:4]>CO.C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cccc(C(O)CBr)c1

Procedure:
The above-identified compound (50.76 g) was obtained by processing Intermediate 14 (45 g) through reaction and after-treatment in accordance with the procedures of synthesis of Intermediate 41. Rf=0.27 (methanol/chloroform of 1/10).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=3)#[N:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[C:16]2[C:8]1=[CH:7][CH:6]=[C:5]([C:3]#[N:4])[CH:17]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c1cc(C#N)ccc1n2Cc1ccccc1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
A slurry of sodium hydride (50% in oil, 960 mg) in 100 ml of dimethylformamide is treated with 3,6-dicyanocarbazole (4.34 g, see Example 1) and heated at 110° C for two hours. The reaction mixture is then treated dropwise with benzylbromide (3.42 g) and heated at 110° C for an additional 18 hours. The reaction mixture is poured into water and extracted several times with dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and filtered through 200 ml of silica gel to yield 4.9 g of the title compound, melting point 265°-267° C.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Reaction time: 28 h
Yield: 41 %

Procedure:
Potassium fluoride (69.6 g; 1.2 mole) and benzyltriethylammonium chloride (10.7 g; 0.05 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1.0 mole). After stirring at 140° C. for 28 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 41% yield together with 7% recovered 2-chloronitrobenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([OH:12])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[S:23](O)(=[O:25])=[O:24]>ClCCl>[CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([O:12][S:23]([C:22]([F:28])([F:27])[F:21])(=[O:25])=[O:24])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCc1cc2c(O)cc(F)cn2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(OS(=O)(=O)C(F)(F)F)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Example 46 (2.88 g) was dissolved in dichloromethane (100 mL). To this solution, triethylamine (4.51 mL) was added, followed by addition of anhydrous trifluoromethanesulfonic acid (2.97 mL) at 0° C. The mixture was stirred at room temperature for 1 hour. Subsequently, the reaction was terminated by adding water and the mixture was extracted three times with ethylacetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=20:1) afforded the title compound as a yellow oil (4.25).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH:24](N1CCOCC1)=[O:25].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:24]=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2c(C=O)cccc2C1
Yield: 13.6 %

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 19a (3.87 g, 12.39 mmol) in diethyl ether (60 mL) was cooled to −100° C. A solution of 1.7 M tert-butyllithium in hexanes (16.04 mL, 27.27 mmol) was added dropwise. After the addition, stirring was continued for 30 min to −100° C. 4-Formylmorpholine (1.87 mL, 18.59 mmol) in diethyl ether (10 mL) was added all at once and the reaction was stirred for an additional 1 h. The mixture was then allowed to reach room temperature. Ammonium chloride saturated solution was added and the product was extracted with dichloromethane (3×70 mL). The combined organics were dried with magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes, to yield 0.44 g of 5-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 20a.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1OS(C(F)(F)F)(=O)=O)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[C:40]1[CH:44]=[C:43]([CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[O:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(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>[CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1[C:50]1[CH:49]=[N:48][C:47]([O:46][CH2:45][C:43]3[O:42][N:41]=[C:40]([C:33]4[C:34]([F:39])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=4[Cl:31])[CH:44]=3)=[CH:52][CH:51]=1)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
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: CCOC(C)=O
Product: CCOC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
(rac.)-(1R*,5S*)-9-Methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 1.00 g, 2.18 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.41 g, 3.27 mmol) were dissolved in DME (14.5 mL), and aq. 2M Na2CO3 (11.0 mL) was added. The mixture was degassed with N2 (5 min). Pd(PPh3)4 (126 mg, 0.109 mmol) was added, and the mixture was rapidly heated to 80° C. The mixture was stirred at this temperature for 1 h, and was allowed to cool to rt. The mixture was diluted with EtOAc (100 mL), and was washed with water (100 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (1.12 g, 81%). LC-MS: tR=0.91 min; ES+: 631.34.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:28])[NH:19][CH2:20][CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]1=[O:29])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[CH:21]1([CH2:20][NH:19][C:18]([C:14]2[C:15]3[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9](=[O:29])[C:10]=3[CH:11]=[CH:12][CH:13]=2)=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3CCCCCC3)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3CCCCCC3)cccc2c1=O

Procedure:
(R)-2-(5-(Cycloheptylmethylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (170 mg, 0.00043 mol) and Potassium carbonate (100 mg, 0.0008 mol) were stirred in methanol (5 mL, 0.1 mol) at room temperature overnight. The volatiles were removed under vacuo and the residue was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2) to give a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[CH:2].C([Li])CCC.[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([CH:36]=[O:37])=[CH:30][C:29]=1[O:38][CH3:39].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([C:36](=[O:37])[C:2]#[C:1][C:3]2[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[O:16][CH3:17])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: C#Cc1cc(-c2cccs2)c(OC)cc1OC
Reactant: COC(=O)COc1c(OC)cc(C=O)cc1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)COc1c(OC)cc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
Ex-3: A solution of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene (1.0 g, 4.09 mmol) from Ex-1B in THF (35 mL) was cooled to −78° C. n-Butyllithium (4.62 mmol, 1.85 mL of a 2.5 M solution in hexanes) was added over 15 min while maintaining an internal temperature below −50° C. After aging for 15 min at −78° C., the reaction was transferred via cannula over 5 min to a cold (−78° C.) solution of (4-formyl-2,6-dimethoxy-phenoxy)-acetic acid methyl ester (1.15 g, 4.52 mmol) from Ex-3A in THF (25 mL). The resulting solution was slowly warmed to room temperature and then quenched with a saturated NH4Cl solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure The resulting crude {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester was dissolved in dichloromethane (50 mL), charged with pyridinium dichromate (3.00 g, 7.97 mmol) and aged at room temperature under nitrogen for 2.5 h. The reaction was then filtered through a pad of celite using additional dichloromethane and then ethyl acetate. The combined organic was concentrated under reduced pressure. Silica gel chromatography (ethyl acetate/hexane, 3:2) gave 1.0 g (49%) of the desired {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester as a yellow solid, m.p. 153–155° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.60 (s, 2H), 7.41 (dd, 1H, J=3.6 and 1.5 Hz), 7.35 (dd, 1H, J=5.3 and 1.5 Hz), 7.09 (dd, 1H, J=5.3 and 3.6 Hz), 6.54 (s, 1H), 4.77 (s, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.97 (s, 6H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:26][CH:11]3[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9]([CH3:18])([CH3:17])[CH2:10]3)[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1

Procedure:
The product is prepared as described in Example II-1, by reaction of 126.7 g (0.5 moles) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-oxopiperidine and 30.2 g (0.26 moles) of 1,6-hexanediamine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[Cl:15].[CH:16](=[O:18])[CH3:17].O>CCCCCC.C1COCC1>[Cl:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC=O
Reactant: COc1ccc(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(C)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (4 ml) was added to a solution of 4-bromo-3-chloroanisole (CAS Reg. No. 50638-46-5, 1.3 g) in THF (20 ml) at −78° C. The mixture was stirred for 30 min at −78° C. Acetaldehyde (0.7 ml) was added to the mixture. The mixture was allowed to warm to room temperature. Water (50 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil to give the title compound (983 mg) as colorless oil. MS (m/e)=186 [M+].
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH:32][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:25])(=[O:26])[N:22]([CH3:23])[CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Product: CN(C)S(=O)(=O)c1ccccc1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dichlorobenzylamine (0.13 mL, 1.0 mmol). The title product was obtained as white needles (0.0569 g, 56% yield). 1HNMR (500 MHz, CDCl3) δ: 11.93 (1H, s), 7.91 (1H, dd, J=7.32 Hz), 7.74 (1H, t, J=5.80 Hz), 7.72–7.67 (2H, m), 7.38 (2H), d, J=7.93 Hz), 7.32 (1H, d, J=1.83Hz), 7.11 (1H, dd, J=8.24, 1.83 Hz), 4.60 (1H, dd, J=15.26, 7.02 Hz), 4.41 (1H, dd, J=15.26, 5.80 Hz), 3.24 (3H, s), 2.69 (6H, s). HRMS (ESI) calcd for C21H21SCl2N4O5 (M+H): 511.0610; found: 511.0612.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[O:29]=[S:25]1(=[O:30])[CH2:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.984, m/z=520.1; 1H NMR (CDCl3) 1.52 (d, 3H), 2.11-2.29 (m, 5H), 2.32 (m, 2H), 2.81 (s, 3H), 2.83-2.96 (m, 2H), 2.98-3.08 (m, 3H), 3.11-3.22 (m, 2H), 5.67 (m, 1H), 7.06 (d, 2H), 7.24-7.36 (m, 5H), 7.38 (d, 2H), 7.61 (s, 1H), 7.69 (m, 1H), 8.73 (d, 1H).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1ccnn1
Yield: 65 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 65, (2S,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (60.2 mg, 65%). 1H-NMR (400 MHz, CDCl3): σ 8.95 (s, 1H), 7.77 (d, 2H), 7.43 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 6.76 (d, 1H), 6.63 (d, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 4.80 (d, 1H), 3.79 (dd, 1H), 3.30 (t, 1H), 3.04-2.93 (m, 2H), 2.87-2.78 (m, 1H), 2.68 (dd, 1H), 1.75-1.68 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:6]
Reactant: O=C(O)c1ccc(Br)cc1Br
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Br)CC2)c(C)c1
Yield: 85.4 %

Procedure:
Using 2,4-dibromobenzoic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (343 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (691 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[S:17][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+].[OH-].[Na+].C(N)CN>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)C.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[C:9]2[S:17][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)sc2ccncc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: NCCN
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a mixture of cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methanone (864 mg) synthesized above, methyl 4-aminobenzoate (553 mg), triethylamine (3.71 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (439 μL) at 0° C., and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (268 μL) and sodium cyanoborohydride (419 mg), and the mixture was stirred at room temperature stirred for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give a pale-brown solid. To a mixture of the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux. Tetrahydrofuran (5 mL), ethanol (5 mL) and 1N aqueous sodium hydroxide solution (5.00 mL) were additionally added, and the mixture was stirred with heating under reflux for 2.5 hr, and ethylenediamine (1.00 mL) was added. The mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. The residue was acidified with 1N hydrochloric acid to pH=4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% ethyl acetate/hexane) to give the title object compound (432 mg, 34%) as a pale-yellow solid.
Reaction SMILES: O[CH:2]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:4]=1.CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[F:34][CH:2]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:4]=1
Reactant: CCOP(=O)(OCC)C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of diethyl hydroxy(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylphosphonate (1.3 g, 3.2 mmol) in dry CH2Cl2 at −78° C. was added DAST (0.3 mL, 3.82 mmol) dropwise very slowly. The reaction mixture was allowed to reach RT, and stirred for 2 h. After completion of the reaction, excess DAST was quenched with water at 0° C. The mixture was extracted with CH2Cl2, dried and concentrated to dryness, and the residue was purified by column chromatography to give the pure title compound (940 mg). 1H NMR (500 MHz, CDCl3): δ 1.2 (m, 6H), 4.1 (m, 4H), 5.7 (dd, 1H, J=45 Hz, 5 Hz), 7.0 (d, 1H, J=10 Hz), 7.1 (d, 1H, J=5 Hz), 7.2-7.4 (m, 4H), 7.9 (m, 1H), 8.4 (s, 1H).