Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.02 mL, 0.137 mmol, 3 eq.) and ethyl isocyanate (0.005 mL, 0.068 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 15 mg (65%) of (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03-1.34 (m, 3 H) 1.56-1.96 (m, 4 H) 2.18 (br. s., 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.73-4.42 (m, 3 H) 5.05 (br. s., 1 H) 6.02 (d, J=5.84 Hz, 1 H) 7.09-7.63 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:31]([N-:34]C(C)C)(C)[CH3:32].[Li+].BrCC#N.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:32][C:31]#[N:34])[CH3:2]
Reactant: CCOC(=O)CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: N#CCBr
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Treat a −78° C. solution of [4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-acetic acid ethyl ester (4.71 g, 11.49 mmol) in THF (40 mL) with a 1.6M solution of lithium diisopropylamide in THF (7.18 mL, 14.36 mmol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (1.71 g, 14.36 mol) and stir at −78° C. for 2 hours. Warm the reaction to room temperature and stir for 2 hours. Quench the reaction with 1N HCl at 0° C. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 25% to 40% ethyl acetate in hexanes gradient to afford 2.62 g (50%) of the titled product. MS (m/z): 450 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[N:19]1.N1C2C=CC=C(N)C=2C=N1>>[CH3:17][N:18]1[C:26]2[C:21](=[C:22]([NH:27][C:2]([NH:1][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)=[O:3])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: O=C=NCc1ccc(N2CCCCC2)cc1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)+364.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1
Reactant: CC1(C)CC(Cc2nnc(Br)s2)CC(C)(C)N1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: C1COCCO1
Product: COc1cc(-n2cccn2)ccc1-c1nnc(CC2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 4] [39 mg, 0.128 mmol) and 2-bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole (34 mg, 0.107 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol), followed by a solution of Na2CO3 (34 mg, 0.32 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as a brown oily residue. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a slightly off-white solid 28.6 mg, 65% yield). LC-MS: Rt 0.88 min; MS m/z 412.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, J=2.53 Hz, 1H), 8.39 (d, J=8.59 Hz, 1H), 7.83 (d, J=1.01 Hz, 1H), 7.73 (d, J=1.52 Hz, 1H), 7.67 (dd, J=8.59, 2.02 Hz, 1H), 6.64-6.61 (m, 1H), 4.11 (s, 3H), 3.01 (d, J=6.57 Hz, 2H), 2.17-2.28 (m, 1H), 1.53 (dd, J=12.63, 2.53 Hz, 2H), 1.09 (s, 6H), 1.00 (s, 6H), 0.86 (t, J=12.38 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][N:6]1[C:2]([C:17]2[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=2)=[CH:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)n(C)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)n(C)c1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (950 mg, 4.36 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol)[prepared according to Preparation 3], potassium carbonate (3011 mg, 21.78 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) in 1,4-Dioxane (18.200 ml) and Water (3.64 ml) was stirred at 80° C. in a sealed tube for 1 h. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) were added and the solution stirred for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylate (300 mg, 1.341 mmol, 30.8% yield) as a clear oil: LCMS m/e ES 220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=4)[N:12]=[C:11]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>CC(N(C)C)=O>[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH:63][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[C:14](=[O:15])[C:10]3=[CH:9][S:8][C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:11]3=[N:12]2)=[CH:17][CH:18]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(6-Fluoro-3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (41 mg, 0.12 mmol) was dissolved in anhydrous dimethyl-acetamide(1 ml). Diisopropyl-ethyl amine (46 mg, 0.36 mmol, 62 μl) was added followed by [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol) and 3-dimethylaminopropylamine (12 mg, 0.12 mmol). The mixture was stirred at room temperature overnight and purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 425 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[C:15]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:26]2[CH2:27][CH2:28][N:23]([C:15]3[C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][C:18]([CH:20]4[CH2:22][CH2:21]4)=[CH:17][N:16]=3)[CH2:24][CH2:25]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 99.8 %

Procedure:
Using 5-bromo-2-picolinic acid (378 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (500 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (798 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH2:17][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1C(F)(F)F
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccccc4)CC3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 702.8 %

Procedure:
To a solution of 1.46 g (5.6 mmol) of 1-benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine and 0.13 g (0.67 mmol) of 4-(4-fluorophenyl) piperidine (Example 1, Step 1) in 30 mL of dichloroethane at rt was added 2.37 g (11.2 mmol) of sodium triacetoxyborohydride. After stirring for 18 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone:hexanes, 1:8) to give 1.98 g of the title compound. 1H NMR (key peaks) (CDCl3) δ7.28-7.37 (m, 5H), 7.19-7.22 (m, 2H), 7.01 (t, 2H, J=8.5 Hz); Mass Spectrum (ESI) m/e=421 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](Cl)=[O:13])=[CH:7][CH:6]=1>O.C1C=CC=CC=1>[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:2]([CH3:3])[CH3:1])=[O:13])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Solvent: O
Solvent: c1ccccc1
Product: CN(C)C(=O)c1cccnc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a rapidly stirred mixture of 10 mL of benzene and dimethylamine (2.6 mL of a 40% solution) was added a slurry of 2-(4-chlorophenoxy)nicotinoyl chloride (0.536 g, 2 mmol, Maybridge Chemical Co.) over 5 min. The biphasic mixture was stirred at room temperature for 18 h and then diluted with water and benzene. The aqueous layer was further extracted with benzene and the organic layers were combined and washed (brine, water), dried (Na2SO4) and concentrated in vacuo to produce the product as a pale yellow oil (0.432 g); δH (CDCl3, 400 MHz) 8.14 (dd, 1H), 7.72 (dd, 1H), 7.33 (m, 2H), 7.03 (m, 3H), 3.12 (s, 3H), 2.99 (s, 3H); MS m/z279, 277 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1.C(O)(=O)C>[Zn].CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate (1.58 g), zinc powder (1.5 g) and glacial acetic acid (1.5 ml) were added to anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour under ice-cooling. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (30 ml) and ethyl acetate (30 ml) and then extracted. The aqueous layer was further extracted twice with ethyl acetate (30 ml). The ethyl acetate layer was combined, and the combined solution was washed with 5% hydrochloric acid and water, and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, followed by filtration, and dried to give amorphous 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-caboxylic acid (1.0 g).
Reaction SMILES: [I-:1].[Na+].[C:3]1([C:9]2([CH2:14]CS([O-])(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(C(C)=O)C(C)C>[C:3]1([C:9]2([CH2:14][I:1])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: O=S(=O)([O-])CCC1(c2ccccc2)CCCC1
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: ICC1(c2ccccc2)CCCC1
Yield: 44.8 %

Procedure:
5.00 g (33.3 mmol) of sodium iodide were added to a solution of 1.00 g (3.93 mmol) of (1-phenylcyclopentyl)methylmethanesulfonate [prepared as described in step (ii) above] in 10 ml of methyl isobutyl ketone, and the resulting mixture was heated under reflux for 18 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between diethyl ether and water. The organic phase was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:1 by volume mixture of methylene chloride and hexane as the eluent, to give 504 mg (yield 45%) of the title compound as an oil.
Reaction SMILES: [Li]CCCC.[Si:6]([C:13]1[O:14][CH:15]=[CH:16][C:17]=1[CH2:18][OH:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl-].[Li+].CN(C)[CH:24]=[O:25]>CCCCCC.C(COC)OC>[Si:6]([C:13]1[O:14][CH:15]=[C:16]([CH:24]=[O:25])[C:17]=1[CH2:18][OH:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)c1occc1CO
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)c1occ(C=O)c1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (a 1.6M solution in hexane; 2.7 ml, 4.28 mmol) was added dropwise to a solution of 3-(2-tert-butyldimethylsilyl-furylmethanol (430 mg, 2.0 mmol) in dimethoxyethane (5 ml) at -78 degrees C. under argon. After stirring at 0 degrees C. for 15 minutes, lithium chloride (860 mg, 20.4 mmol), followed by N,N-dimethylformamide (0.35 ml, 4.48 mmol) was added. Stirring continued at 0 degrees C. for 16 hours and the mixture was quenched with ammonium chloride. Extraction with ethyl acetate and evaporation of the dried (magnesium sulfate) extracts gave a solid, which was recrystallized from hexane to give the titled aldehyde.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.Cl.CC[O:26]CC>C(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: N#Cc1cc(C(F)(F)F)ccc1I
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (INTERMEDIATE 2, 42 g) in CH2Cl2 (300 mL) at −78° C. was added a solution of DIBAL in CH2Cl2 (175 mL, 1M) over 30 minutes. A precipitate formed. The reaction was warmed to 0° C. An additional 25 mL of the DIBAL solution was added dropwise over 30 minutes. The reaction was poured into 200 mL 2N aqueous HCl, diluted with ether and stirred 1 hour. TLC analysis indicates imine still present and an additional 100 mL 2N aqueous was added and the reaction stirred overnight. Imine was still present by TLC analysis and 200 mL 2N aqueous HCl was added and the mixture stirred 2 hours. The layers were separated and the aqueous layer back extracted with ether. The ether extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with 95:5 hexanes/EtOAc to give 2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid. 1H NMR (500 MHz, CDCl3): (10.00 (s, 1H), 8.12 (s, 1H), 8.11 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, 8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:26][CH:27]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: C=CCN
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 31, 8-bromo-1-(chloromethyl)- 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [ClH:1].C1(CN[CH2:10][C:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])C=CC=CC=1.C[C@@H](C1C=CC=CC=1)NCC1C=CC=CC=1.[C:45](=[O:48])([O-:47])[NH2:46]>>[ClH:1].[O:12]=[C:11]([N:13]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:10][NH:46][C:45](=[O:47])[OH:48]
Reactant: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNCc1ccccc1
Reactant: NC(=O)[O-]
Agent: C[C@H](NCc1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNC(=O)O

Procedure:
2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride: By following the procedure of Example 1(a) but replacing dibenzylamine with α(S)-methyl-N-(phenylmethyl)benzene methanamine, ((S)-N-benzyl-α-methylbenzylamine, Oxford Asymmetry Ltd., Abingdon Oxon, UK), tert-butyl N-{2-oxo-2-{(phenylmethyl)1(S)-phenylethyl}amino}ethyl}carbamate was made. The Boc group was removed following the procedure of Example 1(b) to give N-{2-oxo-2-{(phenylmethyl)(1(S)-phenylethyl}amino}ethyl}carbamate hydrochloride, which was subjected to reductive amination with benzaldehyde according the procedure of R. F. Borch, Org. Synth., 1972, 52, 124, to give 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methoxypiperidine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49 (br. s., 2 H) 1.75-1.97 (m, 2 H) 2.33 (d, J=1.95 Hz, 3 H) 3.11-3.68 (m, 7 H) 3.92 (br. s., 1 H) 7.64 (br. s., 1 H) 7.70-7.79 (m, 1 H) 8.07 (d, J=7.81 Hz, 1 H) 8.12-8.65 (m, 3 H). ESI-MS m/z [M+H]+ 436.3.
Reaction SMILES: Br[C:2]1([CH2:20][C:21]([OH:23])=[O:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:9]([O:18][CH3:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1.[N+:24]([O-:29])([N+]([O-])=O)=[O:25]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]1[C:9]([O:18][CH3:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3][C:2]1([N+:24]([O-:29])=[O:25])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC1=C2C=CC=C2OC(Br)(CC(=O)O)C1c1ccccc1F
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: COC1=C2C=CC=C2OC(CC(=O)O)([N+](=O)[O-])C1c1ccccc1F

Procedure:
Using the method of Example 17, 2-bromo-3-(2-fluorophenyl)-4-methoxy-7-benzofuranacetic acid is reacted with dinitrogen tetroxide to provide 3-(2-fluorophenyl)-4-methoxy-2-nitro-7-benzofuranacetic acid. Recrystallization of the acid from benzene provides yellow crystals, m.p. 185°-195° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[CH:20]1([NH:25][C:26]([CH3:33])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[CH:20]1([NH:25][C:26]([CH3:33])=[C:27]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:9]=2[F:8])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)C=C(C)NC1CCCC1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)c1cc(F)c(F)cc1F)=C(C)NC1CCCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloride were added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate in dioxane, for stirring at ambient temperature for 30 minutes and at 65° C. for one hour, to obtain ethyl 3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate.