Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]#[N:18])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-cyano-5-dimethylamino-2-(3-oxo-3-{3-[5(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M82) (0.35 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (149 mg, 64%).
Reaction SMILES: [C:1]([O:4][CH:5]1[N:9]([CH3:10])[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:13])=[N:7][C:6]1=[O:22])(=O)C.Cl>CCOCC.C1COCC1.O>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[N:9]([CH3:10])[CH:5]([O:4][CH3:1])[C:6](=[O:22])[N:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1C(=O)N=C(NC(=O)Nc2cccc(Cl)c2)N1C
Temperature: 70 °C
Yield: 35 %

Procedure:
A solution of 10.00 g (0.031 mol) of N-(5-acetyloxy-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl)-N'-(3-chlorophenyl) urea. The compound from Example 1a, in 200 ml of anhydrous ether was treated with anhydrous HCl until no more precipitation occurred. The solid was filtered, with anhydrous ether and dissolved in 200 ml of warm (70° C.) methanol. The reaction mixture was cooled to room temperature and after 1 hr filtered. Concentration of the filtrate gave additional material which was combined with the first crop, dissolved in THF/water and extracted with ether. The combined ether layers were washed with water to pH 5-6, dried (MgSO4) and evaporated in vacuo. Crystallization of the residue from methanol and finally methanol/pentane (5:1) afforded 3.22 g (37%) of the title compound, mp 147°-149° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:36]=[CH:35]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:29][CH3:28])[CH:31]=[CH:32][CH:33]=4)[N:38]=3)[CH2:41][CH2:42]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: COc1cccc2ccc(N3CCNCC3)nc12
Product: COc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)nc12

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-methoxy-2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]([C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([O-:7])=[O:6])#[N:2].[Na+].S(OC)(O[CH3:17])(=O)=O>>[C:1]([C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH3:17])=[O:6])#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: N#CC(F)(F)C(F)(F)C(=O)[O-]
Agent: [Na+]
Product: COC(=O)C(F)(F)C(F)(F)C#N
Reaction time: 8 h
Yield: 58 %

Procedure:
After being maintained at about 25° for 2 more days, the reaction mixture, which contained sodium 3-cyanotetrafluoropropionate, was treated with 69.3 g (0.55 mole) of dimethyl sulfate, stirred, and allowed to stand overnight. Fractionation of the volatile products gave 53.3 g (58%) of methyl 3-cyanotetrafluoropropionate, bp 90°-97°.
Reaction SMILES: [O:1]=[C:2]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[CH2:29](N1CCCC(N)C1)C1C=CC=CC=1.C(N1CC[C@@H](N)C1)C1C=CC=CC=1>>[O:1]=[C:2]([NH:17][CH:18]1[CH2:22][CH2:21][CH2:29][N:20]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: NC1CCCN(Cc2ccccc2)C1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CCN(C2CCOCC2)C1
Agent: N[C@@H]1CCN(Cc2ccccc2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CCCN(C2CCOCC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-(2-oxo-2-{[1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide whereby 1-benzylpiperidin-3-amine was substituted for (3R)-1-benzylpyrrolidin-3-amine as was isolated as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=CCCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
The crude amide was dissolved in ether and cooled in an ice bath and treated with LAH (1.35 g, 35 mmol) and stirred for 1 hour. The reaction was quenched with 1 N HCl, extracted with ethyl acetate and washed successively with water and brine, dried over MgSO4. The extract was filtered and evaporated under vacuum to give 4.3 g of 3-(4-fluorophenyl)propanal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:26][OH:27]>C(O)C.O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=[N:26][OH:27])[CH2:14][CH2:13]1)[CH2:5]2
Reactant: O=C1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ncc(Br)cc2CC12CCC(=NO)CC2
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a stirred solution of 6′-bromo-1′H-spiro[cyclohexane-1,3′-[1,8]naphthyridine]-2′,4(4′H)-dione (P) (0.35 g, 1.13 mmol) in ethanol/water (18 mL/2 mL) were added Na2CO3 (0.6 g, 5.68 mmol) and hydroxylamine hydrochloride (0.39 g, 5.68 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 4 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get the desired compound as an off-white solid (200 mg, 95%); 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.28 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 2.99 (s, 2H), 2.30-2.16 (m, 4H), 1.84-1.66 (m, 2H), 1.50-1.38 (m, 2H).
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].Cl>CO.O>[NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.5 Grams of Z-Arg(Tos)-Ser-Ser-OMe was dissolved in 50 ml of methanol and 10 ml of water, and 8.06 ml of 1N-sodium hydroxide was added thereto, the mixture was stirred at a room temperature for 45 minutes, next 7.24 ml of 1N-HCl was added to neutralize the reaction mixture, then methanol was removed by distillation, and the residue was extracted with n-butanol. The extract was washed with water, and n-butanol and water were removed by distillation, the residue was crystallized by adding ether, reprecipitated from methanol-ethyl acetate to obtain 2.60 g of Z-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH3:18])[CH:7]([CH3:17])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][CH:7]1[CH:6]([CH3:18])[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:16])[CH2:8]1
Reactant: CC(O)C(C)CNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1CN(C(=O)OC(C)(C)C)S(=O)OC1C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a stirred solution of thionyl chloride (5.4 g, 45.4 mmol) in acetonitrile (25 mL) cooled to −45° C. is added a solution of tert-butyl (3-hydroxy-2-methylbutyl)carbamate (3.7 g, 18.1 mmol) in acetonitrile (35 mL) by syringe over about 15 min, keeping the internal temperature below −40° C. When the addition is completed, solid 4-dimethylamino pyridine (222 mg, 1.8 mmol) is added in one portion followed by pyridine (7.3 mL, 90.8 mmol), keeping the temperature below −40° C. The mixture is stirred at −40° C. to −35° C. for 1 h. Ethyl acetate (100 mL) is added and the mixture is filtered at −35° C. The solid is washed with EtOAc and discarded. To the filtrate is added saturated Na2HPO4 solution (20 mL) and the mixture is stirred vigorously for 3 h. The organic layer is separated, washed with 1M NaHSO4, dried (MgSO4) and concentrated to afford the title compound (4.4 g) which is used in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]([C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]1[N:10]=[C:11]([S:18][CH3:19])[S:12][C:13]=1[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(=O)CC(OCC)=O)C1N(C2C=CC=CC=2)N=CC=1C(OCC)=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:20](=[O:27])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([OH:15])[C:13]2[S:12][C:11]([S:18][CH3:19])=[N:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)N(Cc1ccccc1)c1nc(SC)sc1C(=O)OC
Agent: CCOC(=O)CC(=O)N(Cc1ccccc1)c1c(C(=O)OCC)cnn1-c1ccccc1
Product: CCOC(=O)c1c(O)c2sc(SC)nc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared according to the procedure of Example 138C substituting the product of Example 139B for the product of Example 138B (0.11 μg, 82%). MS (ESI−) m/z 375 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ccc(Br)c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(Cl)ccc1Br
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 3-bromo-2,6-dichloropyridine (3.00 g, 13.2 mmol) in acetonitrile (20 mL) was added sodium methoxide (methanol solution, 4.83 mol/L, 3.0 mL) dropwise at 0° C. The mixture was stirred at room temperature over night. To the mixture was added 30 mL of water, and the organic was evaporated. The resulting suspension was filtered, and the pad was washed with water for several times. The pad was dried under reduce pressure to give title compound (2.74 g, 93.2%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[CH2:14]=O>Cl>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:8])[O:7][CH2:14]2
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: C=O
Agent: Cl
Product: COc1cc2c(cc1OC)C(=O)OC2
Temperature: 90 °C

Procedure:
A mixture of 3,4-dimethoxy-benzoic acid (10 g) in 37% HCl (150 ml) and formaldehyde (25 ml, 37 wt. % solution in water) was heated to 90° C. for 4¾ hours, and then insoluble material was removed by filtration. The filtrate was quenched with water (200 ml) and extracted three times with ethyl acetate (200 ml). The combined organic layers were washed with aqueous NaOH (40 ml, 2.5 M) and water (100 ml). The organic solvent was dried over anhydrous Na2SO4, filtered and evaporated to dryness
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[S:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e]-[1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[O:24]C)=[O:11])[CH:4]=1.Br.[OH-].[Na+]>O1CCOCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[OH:24])=[O:11])[CH:4]=1
Reactant: COc1nnc(OC)c2cc(C(=O)Nc3cc(C(F)(F)F)ccn3)ccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1nnc(O)c2cc(C(=O)Nc3cc(C(F)(F)F)ccn3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.2 %

Procedure:
A mixture of 1,4-dimethoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide (0.24 g, 0.634 mmol), dioxane (3 mL) and 48% HBr (0.1 mL) was stirred at room temperature for 18 hours. The reaction was poured onto water, neutralized with 2N NaOH and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 4-hydroxy-1-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide (5 mg), m/z (M+1) 379.11; and 1-hydroxy-4-methoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide (16 mg), 1H NMR (600 MHz, CDCl3) δ: 3.94 (s, 3H), 7.26 (d, 1H), 8.29 (dd, 1H), 8.41 (d, 1H), 8.46 (d, 1H), 8.50 (s, 1H), 8.62 (s, 1H), 9.75 (s, 1H), 10.53 (s, 1H) ppm. m/z 364.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:31][N:32]1[C:36]([CH2:37][CH2:38]O)=[CH:35][CH:34]=[N:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:38][CH2:37][C:36]1[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (43.5 mg, 0.34 mmol), triphenylphosphine (89 mg, 0.34 mmol), and diisopropyl azodicarboxylate (0.07 mL, 0.34 mmol) in THF (5 mL) was stirred at room temperature for 18 h. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with EtOAc/hexanes to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water:TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 29 mg of 5-(5-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yflethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile as a beige solid. LCMS [M+1]+ 545.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1O[C@H](CO)CN1c1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at 25° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled down to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1019: 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz); C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Na+].[I-].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CCC(C)=O>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1)([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOC(=O)c1cn2cccc(CCl)c2n1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2cccc(CP(=O)(OCC)OCC)c2n1
Yield: 45 %

Procedure:
By the method of Example 6, the product from Example 21 was dissolved in MEK (130 mL) and treated with NaI (3.4 g, 23 mmol) and triethyl phosphite (5.32 g, 32 mmol). Final purification via flash chromatography (95/4.5/0.5 EtOAc/EtOH/Et3N) provided 3.23 g (45%) of title compound.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[Br-].[Li+].[CH3:11][C:12]([O:15][C:16]([N:18]1[C@@H:22]2[CH2:23][C:24]([CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:25])=[O:17])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:15][C:16]([N:18]1[CH:19]2[CH2:20][CH2:21][CH:22]1[CH2:23][C:24]([OH:25])([CH3:4])[CH2:26]2)=[O:17])([CH3:11])([CH3:13])[CH3:14]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: C[Mg]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
A solution of methyl magnesium bromide in diethyl ether (3 M, 3.7 mL, 11.09 mmol) was diluted with anhydrous THF (5 mL). Lithium bromide (1.93 g, 22.1 mmol) was slowly added to the solution at rt, followed by addition of a solution of Boc-nortropinone (500 mg, 2.21 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at 50° C. for 2 hours and stirring was continued overnight at rt. The reaction was quenched with water and the mixture partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50:50), afforded 3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (168 mg, 31%). The obtained product was dissolved in 2 M HCl in diethyl ether (5 mL). After 4 hours stirring at rt the mixture was left on standing overnight. The formed participate, 3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride, was isolated by filtration and dissolved in a mixture of dichloromethane and methanol (90:10). PS-Trisamine was added to the solution and it was left standing overnight. The resin was removed by filtration and washed with dichloromethane. The filtrate was evaporated to dryness affording pure 3-methyl-8-azabicyclo[3.2.1]octan-3-ol. 1-Cyano-4-fluoronaphthalene (37.1 mg, 0.22 mmol) was added to a solution of 3-methyl-8-azabicyclo[3.2.1]octan-3-ol (91 mg, 0.64 mmol) in DMF (1 mL), followed by addition of pyridine (1 mL). The reaction mixture was stirred overnight at 100° C., cooled down to rt and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50:50), and by reverse phase preparative HPLC afforded the title compound (58 mg, 90%).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1ccccc1F

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 2-fluorobenzyl bromide instead of benzyl bromide.