Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:27])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NCN(c2cccc([N+](=O)[O-])c2)c2ncccc21
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CN(c2cccc([N+](=O)[O-])c2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2.7 g of 1-(m-nitrophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dry dimethylformamide was added 0.48 g of approximately 55% sodium hydride and the mixture was stirred at room temperature for 30 minutes. To this was added dropwise 2.52 g of dimethyl sulfate and the whole was stirred at room temperature for 3 hours. The reaction mixture was neutralized with sodium carbonate and concentrated under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was collected by filtration and recrystallized from a mixture of dimethylformamide and methanol to give 1.96 g of 1-(m-nitrophenyl)-3-methyl-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as yellow needles, melting at 247° - 248° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].[CH2:11](Cl)Cl>CS(C)=O>[CH2:11]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: ClCCl
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc2c(c1)OCO2
Yield: 80 %

Procedure:
A solution of 110 g. of catechol, 160 g. of 50 percent aqueous sodium hydroxide, and 100 ml. of DMSO was stirred and heated to 95°-100° C. for 15 minutes. The temperature of the solution was maintained in the same range while the solution was added over a period of 30 minutes to a refluxing solution of 100 ml. of methylene dichloride in 400 ml. of DMSO. After the addition, the temperature of the refluxing reaction mixture reached 120° C., and was maintained at this level for 2.5 hours. Following the same isolation procedures as indicated in (A) above, 99.7 g. (80 percent) of methylenedioxybenzene was isolated.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([NH2:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([N:30]=[C:41]=[O:43])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (125 mg, 0.29 mmol) (see Example 102 for preparation) and DIPEA (109 uL, 81 mg, 0.63 mmol) in THF (6 mL) was added to a solution of triphosgene (34 mg, 0.14 mmol) in THF (6 mL) at 0° C. The reaction mixture was stirred for 30 at 0° C. and 30 min at room temperature, then directly used for next step.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:10]=1[C:11]([N:13]1[CH2:17][CH:16]2[CH2:18][N:19]([C:21](=[NH:23])[NH2:22])[CH2:20][CH:15]2[CH2:14]1)=[O:12].C[O-].[Na+].[F:36][C:37]([F:48])([F:47])[C:38](=O)[CH2:39][C:40](=O)[C:41]([F:44])([F:43])[F:42]>C(O)CCC>[F:36][C:37]([F:47])([F:48])[C:38]1[CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[N:22]=[C:21]([N:19]2[CH2:18][CH:16]3[CH:15]([CH2:14][N:13]([C:11]([C:10]4[C:24]([N:28]5[N:32]=[CH:31][CH:30]=[N:29]5)=[CH:25][CH:26]=[CH:27][C:9]=4[F:8])=[O:12])[CH2:17]3)[CH2:20]2)[N:23]=1
Reactant: N=C(N)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3nc(C(F)(F)F)cc(C(F)(F)F)n3)CC2C1
Yield: 6.2 %

Procedure:
Crude 5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide—TFA salt (66 mg) was diluted with n-butanol (4 mL) and treated with sodium methoxide (51.9 mg, 0.961 mmol). The reaction is heated to reflux for 1 hour, then cooled and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (400 mg, 1.92 mmol) is added prior to re-heating the reaction to reflux for 19 hours. The mixture was then cooled and concentrated, then diluted with DCM and saturated sodium bicarbonate. Extract with DCM and concentrate. Reverse phase HPLC gave the title compound (4.6 mg). MS (ESI): mass calculated for C21H16F7N7O, 515.39; m/z found 416.2 [M+H]+. Rotamers observed in 1H NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO.O1CCCC1>[C:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
1-Phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.1 g) synthesized in Reference Example 16 was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL), aqueous sodium hydroxide solution (1 mol/L, 40 mL) was added, and the mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under reduced pressure, aqueous hydrochloric acid solution (1 mol/L, 50 mL) was added, and the precipitated solid was filtrated. The solid was dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1-phenyl-1H-pyrazole-4-carboxylic acid (2.5 g) as a white solid. This carboxylic acid (8.72 g) and 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (14 g) synthesized in Example 7 were dissolved in N,N-dimethylformamide (225 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (10.65 g) and 1-hydroxybenztriazole (HOBt) monohydrate (10.62 g) were successively added thereto, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (16.2 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.ClCCCOC1C=CC(C2(C#N)CCCCC2)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>CN1C(=O)CCC1>[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][N:52]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:51]1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Reactant: CO[C@H]1CCNC1
Agent: N#CC1(c2ccc(OCCCCl)cc2)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CO[C@H]1CCN(CCCOc2ccc(C3(C#N)CCCCC3)cc2)C1
Temperature: 160 °C
Yield: 41 %

Procedure:
A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[NH2:20][OH:21].Cl.[OH-].[Na+]>CCO.O>[OH:21][N:20]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=NO)C(C3)C2
Temperature: 80 °C
Yield: 90 %

Procedure:
The mixture of ketone 1C (3 0 mmol), NH2OH—HCl (5 mmol), and NaOH (5 mmol) was diluted with EtOH (5 mL) and H2O (1 mL) and the reaction mixture was heated at 80° C. for 16 h. Upon cooling, the reaction mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na2SO4) and concentrated to provide oxime 14A in 90% yield as a solid. The material was used in the next step without further purification. Data: LC/MS (ESR) m/z 281 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methane-sulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylformamide (10 ml), to which 1H-1,2,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50° C. for 20 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), 1N-hydrochloric acid (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml). The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate). The desired fraction was concentrated and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH:25]=[O:26])=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:34])(=O)=O.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH3:37][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH:25]=[O:26])=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:34]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 85.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (176 mg, 0.336 mmol) was dissolved in dimethoxyethane (8.8 mL), and the solution was treated with trimethylboroxine (0.140 mL, 1.01 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (32.9 mg, 0.0403 mmol), potassium carbonate (231 mg, 1.68 mmol) and water (0.121 mL), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=4/1) to obtain 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (112 mg, yield 86%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C=C.[C:23]1(OC2C=CC=CC=2)[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:10]1[CH:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:23]=[CH2:24]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: CCOCC
Product: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The product from step (i) (5 g) was heated under argon in gently refluxing diphenyl ether (15 g) for 21/2 hours. The mixture was cooled to room temperature and ether (70 ml) was added. The solid material was filtered and purified by flash chromatography on silica gel, eluting with methanol/dichloromethane (1/4 v/v) to give 2-allyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.88 g) as a solid, m.p. 180°-182° C.; NMR (d6 -DMSO) δ8.88(1H,s), 8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m), 5.88-6.03(1H,m), 5.0(2H,m), 3.44(4H,t), 3.28(2H,d), 3.05(4H,t); m/e 296 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[F:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: CC(C)(C)CC1NC(C(=O)Nc2cccc(F)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-fluoro-aniline (Aldrich, 38 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 60 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1F
Agent: Cl
Product: COC(=O)Cc1ccccc1F
Temperature: 68 °C

Procedure:
To a stirred solution of 2-fluorophenylacetic acid (9.6 g, 62 mmol) in MeOH (100 mL) was added concentrated HCl (0.7 mL, 19 mmol). The solution was heated at 68° C. for 4 hours, and then the reaction was concentrated in vacuo to remove MeOH. The residue was dissolved in ether and then washed with saturated NaHCO3 solution (1×50 mL). The organic extracts were separated, dried with Na2SO4, filtered and concentrated to give a yellow oil (10 g). MS m/e=169.0 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([O:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([O:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To 2 mL of a chloroform solution containing 87 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-((methylamino)carbonylmethyloxy)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 49 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)-N-methylacetamide as a pale yellow foam.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.Cl.[CH:12]12[O:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.[OH-].[Na+]>O>[C:2]([N:14]1[CH2:13][CH:12]2[O:19][CH:16]([CH2:17][CH2:18]2)[CH2:15]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: C1CC2CNCC1O2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1cccnc1)N1CC2CCC(C1)O2
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Nicotinoyl chloride hydrochloride (17.81 grams, 0.1 mole) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1) octane hydrochloride (15 grams, 0.1 mole) and sodium hydroxide (15 grams) in 300 ml of water, at 10° C. After the addition of nicotinoyl chloride hydrochloride, the reaction mixture was stirred for 2 hours and then left overnight at room temperature. The product was extracted from the reaction mixture with diethyl ether and the extract treated with DARCO G60 (activated carbon). After the removal of ether, the product was obtained as a clear liquid (10 grams, 46% yield) which crystallized. The product 3-nicotinoyl-8-oxa-3-azabicyclo(3.2.1)octane was recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v) to white crystals having a melting point of 48°-49.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([NH:30][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)=[CH:32][CH:33]=1)#[N:36]
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C#N)cc3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 4-aminobenzonitrile according to the procedure from Example 137C substituting 4-aminobenzonitrile for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (51.5 mg, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 11.11 (s, 1 H), 10.62 (s, 1 H), 9.11 (s, 1 H), 9.00 (d, J=5.51 Hz, 1 H), 8.57-8.80 (m, 1 H), 7.97 (d, J=8.82 Hz, 2 H), 7.68-7.90 (m, J=8.82 Hz, 3 H), 7.38-7.52 (m, 2 H), 6.88-7.12 (m, 3 H), 6.45-6.71 (m, 1 H), 3.77 (s, 3 H).
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.[C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])(O)=[O:13]>C(Cl)Cl>[NH2:3][C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:13]
Reactant: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(N)=O
Reaction time: 1 h
Yield: 35.7 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00318 mole) was added to a solution of compound 105 (0.00159 mole) in DCM (160 mL) at room temperture. N,N′-methane-tetrayl-biscyclohexanamine (0.00206 mole) was added neat at room temperature. After 60 minutes, NH3 gas was bubbled in for 5 minutes, and a solid precipitated out. The mixture was allowed to sit over the weekend. The mixture was filtered, and the filtrate was extracted with saturated NaHCO3. The organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography, yielding 0.21 g of 1,1-dimethylethyl 2-[4-(aminocarbonyl)-5-propyl-1H-imidazol-2-yl]-2,3-dihydro-1H-indole-1-carboxylate (compound 106).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20](C5C=CN=C(OC)C=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.[CH3:36][OH:37]>C(C#N)(C)=O>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:10]5[CH:7]=[CH:6][C:36](=[O:37])[NH:15][CH:13]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CO
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)ccc2C)ccn1
Agent: CC(=O)C#N
Agent: C[Si](C)(C)I
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 55 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
To a slurry of 1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (25 mg, 0.062 mmol) in AcCN (1.5 mL) was added TMS-I (35.45 μL, 0.24 mmol) and stirred at 55° C. for 7 h. The reaction was diluted with methanol (1.0 mL) and stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum, and taken into ethyl acetate (10 mL. The organic solution washed with sodium bisulphate (2×2 ml) water (2×3 mL), dried over sodium sulphate and concentrated under vacuum. The solid was stirred with methanol (1.0 mL) at 40° C. for 10 min and collected by filtration, washed with methanol (1.0 mL) and dried under vacuum to yield 18.0 mg (74%) of the desired product. ESI-MS m/z calc. 387.4. found 388.2 (M+1)+. Retention time 1.32 minutes.