Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:16][CH2:15]1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[F:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:3]2[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2CN1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 9 h
Yield: 16.5 %

Procedure:
Powdered zinc (2.97 g) is added at a temperature in the region of 20° C. to a stirred solution of (RS)-3-hydroxy-2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}isoindolinone (3.4 g) in acetic acid (21 cc). The mixture is heated to boiling for 9 hours and then cooled to a temperature in the vicinity of 20° C. After the addition of distilled water (30 cc), the solution is alkalinized to pH 7-8 with sodium bicarbonate. The organic phase is extracted with dichloromethane (4×30 cc), washed with distilled water (30 cc), dried over anhydrous magnesium sulphate, treated with vegetable charcoal, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column under a stream of argon at moderate pressure (0.5-1.5 bar) with ethyl acetate and then a mixture of ethyl acetate and methanol (98:2 by volume) as eluents. After recrystallization in ethyl acetate (40 cc), 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}isoindolinone (0.54 g), m.p. 175° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:8]=1
Reactant: COC(=O)c1ccccc1C=CC1CCCCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1C=CC1CCCCC(OC)=N1

Procedure:
The product of Example 79 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[C:18]([CH3:20])[CH:19]=3)=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]N2C(C)=CC(I)=N2)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[C:18]([CH3:20])[N:17]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:22][CH:23]=1
Reactant: Cc1cc(-c2nc(C)c(C(=O)NCc3ccc(F)cc3)s2)[nH]n1
Reactant: Cc1cc(I)nn1CCc1ccc(F)cc1
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-[5-methyl-2H-pyrazol-3-yl]-thiazole-5-carboxylic acid 4-fluoro-benzylamide and 1-[2-(4-fluoro-phenyl)-ethyl]-3-iodo-5-methyl-1H-pyrazole as described in Example 93 and isolated as a white solid (0.035 g, 14% yield). 1H NMR (400 MHz, CDCl3) δ 7.23-7.27 (m, 2H), 6.98 (t, J=8 Hz, 2H), 6.82-6.90 (m, 4H), 6.41 (s, 1H), 5.92-6.00 (bm, 1H), 4.50 (d, J=4 Hz, 2H), 4.15 (t, J=6 Hz, 2H), 3.05 (t, J=6, 2H), 2.68 (s, 3H), 1.84 (s, 3H); MS (M+H)+=452.9; Rt=1.56 min; HRMS (M+H)+=453.16.
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][CH:6]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:7][CH:8]=[N:9][OH:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:4][O:5][C@@H:6]1[CH2:7][C:8]2=[N:9][O:10][CH2:14][C@@H:13]2[CH2:12][CH2:11]1
Reactant: C=CCCC(CC=NO)OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2CON=C2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A sodium hypochlorite solution (5%, 18.5 mL) was added to a solution of 3-methoxyhept-6-enal oxime obtained in Preparation Example 57-(3) (1.95 g) in dichloromethane, and the mixture was stirred at room temperature for one hour and 10 minutes. The excess of sodium hypochlorite was decomposed with sodium thiosulfate, followed by extraction with chloroform three times. The resulting organic layers were dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (796 mg).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:31]([CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:32])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: O=C(O)C1CCOCC1
Product: O=C(NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1)C1CCOCC1

Procedure:
Compound 290 is synthesized from Intermediate M and Tetrahydro-pyran-4-carboxylic acid according to the procedure used to synthesize Example 261. (LC/MS method 16: ES+m/z 438.4 [M+H]+, Rt=1.44 mM)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([N:25]([CH3:33])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=O)[CH2:18][C:17]4[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:25]([CH3:33])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH2:18][C:17]4[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CC(=O)N(C)Cc1cccnc1)Cc1ccccc1-3
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)Cc1cccnc1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 14-cyclohexyl-6-{2-[methyl(pyridin-3-ylmethyl)amino]-2-oxoethyl}-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in THF (0.05 M), BH3.Me2S (20 eq, 2 M solution in THF) was added. The solution was stirred overnight at RT. The solution was carefully quenched by adding 1.25 N HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was used directly in the next step; MS (ES+) m/z 537 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[F:12][C:3]1[C:4]([F:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
A mixture of 1,2,3-trifluoro-4-nitrobenzene (4.0 mL, 35 mmol), morpholine (3.1 mL, 35 mmol), and K2CO3 (4.8 g, 35 mmol) in DMSO (35 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt and washed with water and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (11.5 g, 67% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.09-3.51 (4H, m), 3.58-4.08 (4H, m), 6.98 (1H, ddd, J=9.8, 8.1, 2.1 Hz), 7.94 (1H, ddd, J=9.9, 8.0, 2.1 Hz). LC-MS (ESI) m/z 245 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][N:13]=3)=[O:10])=[CH:4][C:3]=2[C:24]([F:27])([F:26])[F:25])[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2ccccc2)cn1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4ccccc4)cn3)cc2C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46-7 (73 mg, 0.17 mmol), 2-methylpyridin-4-ylboronic acid (35 mg, 0.255 mmol), Pd(PPh3)4 (12 mg, 0.017 mmol), toluene (0.8 mL), ethanol (0.2 mL) and 2M Na2CO3 (0.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 aqueous solution and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46 as white solid. MS m/z 448.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.48-8.45 (m, 2H), 8.28 (d, 1H, J=8.4 Hz), 7.92 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz), 7.75 (s, 1H), 7.61 (dd, 1H, J1=8.0 Hz, J2=1.2 Hz), 7.54-7.52 (m, 2H), 7.47-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.28 (d, 1H, J=7.6 Hz), 7.14 (s, 1H), 7.10 (d, 1H, J=5.2 Hz), 3.86 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][CH3:15])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([OH:30])=O)[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([N:14]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]5)[CH3:15])=[O:30])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CNc1ccc2[nH]c(C(C)(C)C)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)C1(c2ccc3c(c2)OCO3)CC1)c1ccc2[nH]c(C(C)(C)C)cc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 μL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80° C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 3913(M+1)+. Retention time of 3.41 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26]C(OCC1C=CC=CC=1)=O)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (7S)-7-benzyloxycarbonylamino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (11.0 g, 21.8 mmol) in EtOAc and MeOH was added 10% Pd/C. The reaction was charged with H2, degassed and refilled with hydrogen three times. The slurry was stirred at RT for 2 h at balloon pressure, then filtered through a plug of Celite, and solvent was removed under reduced pressure. The hydrogenolysis of the ester yielded 8.0 g (99%) of a thick oil solid after 19 h. 1H NMR (CDCl3) δ 8.9-7.3 (7H, m), 3.96 (1H, m), 2.31 (2H, t), 2.0-1.2 (17H, m). MS (ESI): (MH+) 372.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]([C:19]([OH:21])=O)[CH2:9][S:8]2)[CH:2]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[C:26]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:11]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:21])[CH:36]=[CH:35][CH:34]=1)(=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C(=O)Nc2cccc(C(=O)c3ccccc3)c2)CSC1c1cccnc1
Yield: 115 %

Procedure:
To a solution of 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxylic acid (944 mg; 1.2 eq.; 3.05 mmoL), prepared as described above, and 3-aminobenzophenone (500 mg; 2.54 mmol) in methylene chloride (0.15M) was added triethylamine (0.46 mL) at room temperature under nitrogen with stirring, followed by addition of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (773 mg; 1.2 eq) and the resulting mixture was stirred at ambient temperature for 16 hours. This mixture was concentrated to an oil on a rotory evaporator which was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (30 mL). The aqueous phase was extracted twice with ethyl acetate and the resulting combined organic layers were washed with brine and dried magnesium sulfate. After filtering, the solvent was removed to yield the title compound (1.43 g) as a thick orange oil. The compound was further purified by flash chromatography on silica gel to yield 1010 mg (82% yield) N-(3-benzoylphenyl) 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxamide as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:39]>>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:39]=2)[CH2:14][N:13]([CH2:29][C:30]([F:31])([F:33])[F:32])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1 h

Procedure:
{1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (148 mg, <257 mmol) was dissolved in m-xylenes (4.0 mL) and heated at 135° C. Solid ammonium acetate (150 mg, 1.9 mmol) was added and the reaction was stirred at 135° C. After 60 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[4-(4-Bromo-phenyl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (15.1 mg) as the TFA salt: LCMS-ESI+: calc'd for C21H25BrF3N5O3: 532.3 (M+); Found: 532.1/534.2 (M+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=3)=[N:12][CH:13]=2)=[N:4]1>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[CH3:2][N:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=3)=[N:12][CH:13]=2)=[N:4]1
Reactant: Cn1cnc(-c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccc(C3=CCNCC3)nc2)n1
Reaction time: 3 h

Procedure:
4M HCl in dioxane (20 ml) was added to a solution of Tert-butyl 4-(5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4BX) (4 g, 11.67 mmol) in CH2Cl2 (50 ml) at room temperature. The mixture was stirred for 3 hours then solvent was evaporated yielding title product as a white solid (3.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 36.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,6-dichlorobenzenesulfonylchloride (0.0479 g, 0.195 mmol) to obtain 4-(2,6-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 37%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O-:19])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1)=[O:36]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C([O-])N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-chloro-benzoyloxy)-ethoxy]-phenyl]-3 -(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 616 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:10]3=[CH:9][C:8]=2[CH:7]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]3[N:11]4[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[C:10]4=[CH:9][C:8]=3[CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1NCCCn2c1cc1cc(OCCCCl)ccc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 2, from 9-(3-chloro-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, pyrrolidine (commercially available) and potassium carbonate, to give the desired product as a light yellow solid (50%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)=[CH:19][CH:18]=1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: Nc1ccc(Cl)cc1
Product: Cc1nc(Nc2ccc(Cl)cc2)nnc1-c1ccccc1
Yield: 75.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (4.15 g) and p-chloroaniline (4.22 g) was heated at 150° to 160° C. for 18 hours. After cooling, the resulting solid was washed successively with ethyl acetate, chloroform and methanol, and then dried to give 3-(4-chloroanilino)-5-methyl-6-phenyl-1,2,4-triazine (4.26 g).
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:3].[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[C@@H:30]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@@H:31]2[OH:32])=[C:23](N)[N:22]=1.P([O-])([O-])([O-])=O>>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[C@@H:30]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@@H:31]2[OH:32])=[C:23]([OH:3])[N:22]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc(O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Reaction time: 2 h

Procedure:
A suspension of 10 mg/ml of an adenosine deaminase enzyme (prepared from intestinal calf mucosa) was assayed to have an activity of 210 μ moles/min. at 38° C. To a solution of 191 mg. of 2,6-diamino-9-(β-D-arabinofuranosyl)purine in 800 ml of a 1 millimole phosphate buffer of pH 7.1 was added 50 micrograms of adenosine deaminase. After two hours at 38° C. the reaction mixture was freeze dried. The resulting powder was extracted with hot methanol which was filtered and evaporated to give a solid. This solid was triturated with methanol, filtered and the methanol evaporated. The solid was dissolved in 25 ml. of warm methanol and cooled to crystallize the product, 2-amino-6-hydroxy-9-(β-D-arabinofuranosyl)purine, m.p. < 300° C.