Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([S:25][CH3:26])[CH2:16][N:15]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:14]1=[O:24].C(N(CC)CC)C.N1C=CC=CC=1.[O:40]([CH2:47][C:48](Cl)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[Si:17]([N:15]1[CH2:16][C:13]([S:25][CH3:26])([NH:12][C:48](=[O:49])[CH2:47][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:14]1=[O:24])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CSC1(N)CN([Si](C)(C)C(C)(C)C)C1=O
Reactant: O=C(Cl)COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1(NC(=O)COc2ccccc2)CN([Si](C)(C)C(C)(C)C)C1=O

Procedure:
A suspension of (23) (830)mg) in dry dichloromethane (20 ml) at -10° C. was treated with triethylamine (220 mg) and pyridine (172 mg), followed by a solution of phenoxyacetyl chloride (372 mg) in dry dichloromethane (~4 ml). The mixture was washed with very dilute HCl, followed by brine. The organic phase was dried and the solvent evaporated. Chromatography on silica yet gave the product (24) (730 mg). νmax (CHCL3) 3400, 1745, and 1690 cm-1 ; δppm (CDCl3) (90 MHz) 0.25 and 0.27 (both s, together 6H), 0.98(S, 9H), 2.22(S, 3H), 3.36 and 3.81 (ABq, 2H, J 7.0 Hz), 4.50(S, 2H), 6.80 to 7.50 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH2:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(N)C(O)C3)c(F)cc2c1=O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 199A (0.12 g) and benzaldehyde (0.063 mL) in methanol (10 mL) and acetic acid (2 drops) was stirred for 30 minutes at 25° C., treated with sodium triacetoxyborohydride (0.196 g), stirred for 18 hours, and concentrated; and the concentrate chromatographed on silica gel with 5% methanol/dichloromethane.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>C(Cl)Cl>[NH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:1]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:2])[NH:25]1
Reactant: C1CCNNC1
Reactant: OCCCCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCCCCc1ccccc1)C1CCCNN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 1,1′carbonyl diimidazole (0.893 g, 5.5 mmol) in 5 ml CH2Cl2 was added slowly to a solution of CH2Cl2 containing phenylbutyl alcohol (0.89 ml, 5.77 mmol). After stirring at room temperature for 1 hour, this solution was then added slowly to a solution containing perhydropyridazine mentioned above. The reaction was allowed to stir for overnight. The crude mixture was then concentrated and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.COC1C=CC([N+]([O-])=O)=C2C=1C=NC=C2.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:40]=[CH:39][C:34]([CH2:35][N:36]=[C:37]=[O:38])=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:37]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:42])[F:41])=[CH:40][CH:39]=2)=[O:38])=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(N)c2ccncc12
Agent: COc1ccc([N+](=O)[O-])c2ccncc12
Product: COc1ccc(NC(=O)NCc2ccc(C(F)(F)F)cc2)c2ccncc12

Procedure:
Prepared from 8-methoxyisoquinolin-5-amine which was prepared from 8-methoxy-5-nitroisoquinoline (J. Het. Chem. 37(5), 1293) according to Description 43 and immediately used in reaction with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N, 4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N, 4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:30]1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.[CH3:51][O:52][C:53](=[O:57])[CH2:54][CH2:55]N.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:30][CH:54]([CH3:55])[C:53]([O:52][CH3:51])=[O:57])=[O:25])=[CH:22][CH:21]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)NC(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-butylcyclohexyl)amino]methyl}benzoic acid (22.0 g, 56.5 mmol) and 1-hydroxybenzotriazole (8.6 g, 57.0 mmol, containing 12% w/w water) was dissolved in DMF (300 mL). N-Dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), β-alanine methyl ester (8.4 g, 60 mmol) and diisopropylethylamine (25 mL, 142 mmol) were added and the clear solution stirred at 20° C. for 16 hours. Solvent was removed by rotary evaporation and the residual oil re-dissolved in ethyl acetate (500 mL). The organic phase was washed with 5% aqueous sodium hydrogen carbonate solution (2×500 mL), 0.5 M citric acid (2×250 mL) and brine before being dried with anhydrous Na2SO4. Solvent was removed and the residual oil evaporated twice from acetonitrile. The oil was used without further purification. Yield: 24.0 g (89%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:33])[C:21](OC4C=CC([N+]([O-])=O)=CC=4)=[O:22])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35].[CH3:36][NH2:37]>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:33])[C:21]([NH:37][CH3:36])=[O:22])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3Cl)cccn2c1Br
Reactant: CN
Solvent: CO
Product: CNC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(4-nitrophenyloxycarbonyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (63 mg) and 30% solution of methylamine in methanol (2 ml) was heated under reflux for 3 hours. After addition of 30% solution of methylamine in methanol (1 ml), the mixture was heated under reflux for additional 1 hour. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate. The extract was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (5% solution of methanol in dichloromethane) followed by crystallization from diethyl ether to give 3-bromo-8-[2,6-dichloro-3-(N-methyl-N'-methylureido)benzyloxy]-2-methylimidazo[1,2-a]pyridine (28 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH:13]=O.[N:15]1[C:24]2[CH:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[CH2:13][N:25]([CH:23]1[C:24]2[N:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:20][CH2:21][CH2:22]1)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: Cn1c(C=O)nnc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(CN(CCCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)nnc1-c1ccccc1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-carbaldehyde, 36, (0.41 g, 2.20 mmol) in 1,2-dichloroethane (4 mL) was added tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (0.76 g, 2.40 mmol), sodium triacetoxyborohydride (0.84 g, 3.95 mmol), and AcOH (10 drops). The reaction mixture was heated to 65° C. and stirred for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3 (15 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine then dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) to yield 37: 1H NMR (400 MHz, CDCl3) δ 8.40, (d, J=5.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.48-7.44, (m, 3H), 7.31, (d, J=7.2 Hz, 1H), 7.0, (dd, J=8.0, 5.2 Hz, 1H), 5.01, (bs, 1H), 4.20-3.92, (m, 3H), 3.20-2.60, (m, 6H), 2.20-1.85, (m, 4H), 1.75-1.30 (m, 13H); ESI+ MS: m/z (rel intensity) 491 (100, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=[O:20])[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(OCC)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:20])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CCOCC
Product: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 1.5 h

Procedure:
4.8 Parts of 4-chloro-2-fluoroaniline were added to a solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 150 parts of diethyl ether and stirred for 1.5 hours. The solution was evaporated under reduced pressure of 300 mm. Hg at 25° C to isolate 9 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-cyclohexene-1-carboxylic acid as white crystals melting at 91°-93° C.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:27]1([B-](F)(F)F)[CH2:29][CH2:28]1.[K+]>>[C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:27]2[CH2:29][CH2:28]2)=[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2]
Reactant: F[B-](F)(F)C1CC1
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Oc2ccc(F)cc2)n1)C(N)=O
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(Oc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 166 b, using 5-bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 177 b) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=386.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](=[O:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)([OH:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Cc1ccc([Mg]Br)cc1C
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1C
Temperature: -25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-dimethylphenyl magnesium bromide in tetrahydrofuran (0.5 M, 3.3 mL, 1.65 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.2 g, 1.1 mmol) in tetrahydrofuran (5 mL) with cooling in a −25° C. bath. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 3 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3,4-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as a yellow solid. This was used in the next step without further purification.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[C:10]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:6]=[CH:5][N:4]=1.O[O:27][S:28]([O-:30])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:40]([O-])(O)=O.[Na+]>C1COCC1.O.CO>[CH3:40][S:28]([C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[C:10]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:6]=[CH:5][N:4]=1)(=[O:30])=[O:27]
Reactant: CSc1nccc(-c2c(Oc3ccccc3C)c(=O)n3n2CCC3)n1
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1c(-c2ccnc(S(C)(=O)=O)n2)n2n(c1=O)CCC2

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-2-o-tolyloxy-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 2, (0.20 g, 0.56 mmol) in THF:methanol (6 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (1.37 g, 2.24 mmol) in H2O (6 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is extracted three times with EtOAc, the organic phases are combined, dried (MgSO4), filtered and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Br)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[CH:29]([NH2:31])[CH3:30])[CH:16]=[N:17][CH:18]=1.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[CH:29]([NH:31][C:4]2[N:3]=[C:2]([NH2:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH3:30])[CH:16]=[N:17][CH:18]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1ccc2ccccc2c1-c1cncc(F)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1ccc2ccccc2c1-c1cncc(F)c1

Procedure:
A mixture of 2-amino-6-bromopurine (0.030 g, 0.14 mmol), 1-[1-(5-fluoropyridin-3-yl)-2-naphthyl]ethanamine (0.019 g, 0.07 mmol), and N,N-diisopropylethylamine (0.01465 mL, 0.084 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a mixture of rotomers (bis-TFA salt). LCMS calculated for C22H19FN7(M+H)+: m/z=400.2; found: 400.0.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: COc1cc(C=O)ccn1
Reactant: Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(CNc2ccccc2C(=O)O)ccn1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (1.37 g, 1.0 mmol), 2-methoxy-pyridine-4-carbaldehyde (1.37 g, 1.0 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 30 mL of anhydrous toluene was stirred at reflux for 1 h, cooled to RT, and NaBH4 (0.9 g) was added. The mixture was stirred at RT for 30 min, and quenched with MeOH. The volatiles were removed under reduced pressure, and the residue was taken up in water. AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and condensed. The residue was purified by flash column chromatography to give the titled compound. MS (ES+): 259.0 (M+H)+. Calc'd for C14H12N2O3-258.10.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[CH2:17]([N:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][N:31]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(C)=O.O>C1COCC1>[CH2:17]([N:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[N:31]=[CH:32][C:33](/[CH:34]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:36][CH:37]=2)[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 15 °C
Yield: 88.6 %

Procedure:
A solution of diethylphosphonoacetic acid ethyl ester (896 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (170 mg) in THF (20 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g) in THF (10 ml) solution was added the above mixture, and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylate (0.83 g).
Reaction SMILES: [I-].[C:2]([NH:6][C:7]([C:9]1([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH:14]2[NH2+:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[C:23]([N:27]1[CH2:32][CH2:31][C@@H:30]([C:33](O)=[O:34])[C@H:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:28]1)([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:56].CCN(C(C)C)C(C)C>ClCCl>[Cl-:56].[C:23]([NH+:27]1[CH2:32][CH2:31][C@@H:30]([C:33]([N:16]2[CH:11]3[CH2:12][CH2:13][CH:14]2[CH2:15][C:9]([C:7]([NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8])([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10]3)=[O:34])[C@H:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:28]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)N1CC[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: CC(C)(C)NC(=O)C1(C2CCCCC2)CC2CCC(C1)[NH2+]2
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@@H]1CC[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8-azoniabicyclo[3.2.1]octane iodide (1-9) (42.0 mg, 0.100 mmol) in dichloromethane (5.0 mL) was added (3R,4R)-1-tert-butyl-3-(2,4-difluorophenyl)piperidine-4-carboxylic acid (1-12) (35.7 mg, 0.120 mmol), HOBt (16.2 mg, 0.120 mmol), EDC (23.0 mg, 0.120 mmol), and DIEA (38.8 mg, 0.300 mmol). The mixture was stirred at room temperature overnight, quenched with a saturated aqueous solution of NaHCO3, and extracted with dichloromethane (3×20 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by high-pressure liquid chromatography (gradient elution; 15%-95% acetonitrile/water as eluent) and addition of a solution of 1 N HCl solution in ether afforded (1-13) as a white solid (m/z (ES) 572 (MH+)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH2:8][OH:9])[CH:7]=1.N1[CH:19]=[CH:18]N=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([NH:1][C:19]2[CH:18]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:3]=[CH:4][C:5]=1[O:10][C:11]([F:12])([F:13])[F:14])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: Nc1ccc(OC(F)(F)F)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Nc2ccccc2)ccc1OC(F)(F)F
Reaction time: 16 h
Yield: 104.1 %

Procedure:
(5-Amino-2-trifluoromethoxyphenyl)methanol (1.2 g, 5.8 mmol) was dissolved in DMF (5 mL) and imidazole (0.48 g, 7.1 mmol) and tert-butyldimethylsilylchloride (0.99 g, 6.6 mmol) were added and the mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL) and water (20 mL). The aqueous phase was extracted once more with ethyl acetate (20 mL). The combined organic phases were washed with water (10 mL), aqueous citric acid (10 mL, 10%) and water (2×10 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (110 g, silica gel) using ethyl acetate and heptane (1:3) as eluent to give 1.2 g of 3-(tert-butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenylaniline.