Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCO>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)C3)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNC3)nc1
Yield: 11.9 %

Procedure:
Combine 6-(2-Benzyl-2,3-dihydro-1H-isoindol-5-yloxy)-nicotinamide (230.0 mg, 0.67 mmol), EtOH (5 mL), 10% Pd—C (45.0 mg), and a Hydrogen balloon. Stir the reaction at room temperature for 168 hours at atmospheric pressure. Filter the reaction mixture through a pad of Celite using MeOH eluent and then concentrate the filtrate under reduced pressure. Add the mixture to a 2 g SCX column, wash with MeOH, and elute using 1N NH3-MeOH. After concentrating under reduced pressure, purify the mixture by flash chromatography using 10% 1N NH3-MeOH/DCM eluent to afford 19.2 mg, 0.08 mmol (11% yield) of the title compound as a white solid: 1H NMR (500 MHz, d-Methanol); 4.1-4.3 (4H, br m), 6.9-7.1 (3H, m), 7.3-7.4 (1H, m), 8.2-8.3 (1H, m), 8.6 (1H, s); MS m/z 254 (M).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[CH2:42]([CH2:44][NH2:45])[OH:43]>>[OH:43][CH2:42][CH2:44][NH:45][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:24])([CH3:23])[N:16]([O:21][CH3:22])[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][C:32]([CH3:41])([CH3:40])[N:33]([O:38][CH3:39])[C:34]([CH3:37])([CH3:36])[CH2:35]2)[N:3]=1
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:44](=[O:48])[N:45]([CH3:47])[CH3:46])[NH:13][C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH3:40])[C:24]([NH:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])(C)(C)C.[ClH:50]>O1CCOCC1.C(Cl)Cl>[ClH:50].[ClH:50].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:13][C:14]([CH2:15][NH:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH3:40])[C:24]([NH:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])=[O:43])[C:44](=[O:48])[N:45]([CH3:46])[CH3:47]
Reactant: CN(C)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](CCCCN)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [((S)-5-amino-1-dimethylcarbamoyl-pentylcarbamoyl)-methyl]-amide dihydrochloride (150 mg) was prepared by following General Procedure L starting from [((S)-5-dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamic acid tert-butyl ester (200 mg) in 4M HCl in dioxane (1 mL) and DCM (2 mL). LC/MS: m/z 547.8.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: Cc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-bromo-5-methylpyridine (888 mg) in toluene (10 mL) were added phenylmethanethiol (705 mg), N,N-diisopropylethylamine (1.47 g), tris(dibenzylideneacetone)dipalladium(0) (189 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (239 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) to give the title compound as a yellow oil (yield 1.06 g, 95%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C:23]([O:22][CH3:21])([CH3:31])[CH3:32])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: COC(C)(C)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 56.8 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 0.1 g, 0.37 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 0.065 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.19 g, 0.44 mmol) in methylene chloride (10 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) and the resulting solution stirred at room temperature for 19 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution, and dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF15-40 g column, 50%-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (0.063 g, 0.21 mmol, 41%) as an off white solid; [α]29D=−47.5° (c=0.28, chloroform); HR-ES(+) m/e calcd for C24H32N4O3 [M+Na]+ 447.2366, observed 447.2368; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.62 (m, 2H), 7.48 (d, J=2.3 Hz, 1H), 7.45-7.54 (m, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.05 (dd, J=10.7, 5.0 Hz, 1H), 4.87 (d, J=17.8 Hz, 1H), 4.53 (d, J=17.8 Hz, 1H), 3.99 (s, 2H), 3.15 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.98-2.10 (m, 11H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH:12]2[OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][C:12]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CC2CC1CN(Cc1ccccc1)C2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CC2CC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A solution of 3-benzyl-3-aza-bicyclo[3.2.1]octan-6-ol (8 mmol) in anhydrous dichloromethane at 0° C. under nitrogen was treated with of N-methyl morpholine N-oxide (12 mmol), 1 weight equivalent of oven dried 4 angstrom sieves and TPAP (tetrapropylammonium perruthenate) (0.2 mmol). The reaction mixture was stirred for 30 min. at 0° C. then allowed to warm to room temperature with stirring for an additional 1 h. The reaction was filtered through a plug of silica gel and eluted with ethyl acetate then striped to an oil. Purification by silica gel chromatography eluted with 15% ethyl acetate/hexanes produced an oil (7.7 mmol). APCl MS m/z 216.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[C:20]([CH:25]=O)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][N:28]1[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:14]=1
Reactant: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2cccc(-c3ccccc3CN3CCc4ccccc4C3)c2)c2ccccc2n1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 100 (166 mg, 0.49 mmol) and 40 (0.06 mL, 0.473 mmol) in dichloroethane (4.9 mL) were sequentially added NaBH(OAc)3 (155 mg, 0.73 mmol) and HOAc (0.03 mL, 0.52 mmol). The reaction was stirred for 48 hours and then extracted with dichloromethane (2×30 mL). The dichloromethane extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give desired product as a yellow solid (51 mg, 23.7%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Sn](C)(C)C)[N:7]=[C:6]([C:14]#[N:15])[N:5]=1)[CH2:2][CH3:3].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20](Br)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([C:8]2[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]([C:14]#[N:15])[N:7]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C#N)n1
Yield: 35.1 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under a nitrogen atmosphere to a mixture of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (155 mg, 0.50 mmol) and 3,5-bis-trifluoromethyl-bromobenzene (0.10 mL, 0.58 mmol) in dimethylformamide (3 mL). The mixture was refluxed for 4 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: DCM) to afford a solid which was triturated in pentane. After filtration, 4-(3,5-bis-trifluoromethyl-phenyl)-6-propyl-pyrimidine-2-carbonitrile (63 mg, 35%) was obtained as an off white solid (mp=112° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:35][C:36](C)=[O:37]>C(O)C>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]([CH:13]2[N:17]=[C:14]([O:37][CH2:36][CH3:35])[CH2:15][S:16][CH:11]3[N:12]2[C:33](=[O:34])[CH:10]3[NH:9][C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:25][CH:26]=1)([O-:32])=[O:31]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CC(C)=O
Solvent: CCO
Product: CCOC1=NC(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3cccs3)C2SC1

Procedure:
A solution of 2.53 g of p-nitrobenzyl 7β-[(2-thienylacetyl)amino]-3-azido-3-cephem-4-carboxylate in 50 ml. of acetone and 50 ml. of ethyl alcohol was heated at the reflux temperature for 1.25 hr. and thereafter the solution was evaporated to dryness. The crude product showed three spots on a thin layer chromatogram. The predominant 4-ethoxy-1,3-diaza isomer (title compound) was separated from the other isomer by chromatography over 15 g. of silica gel using 600 ml. of toluene vs 600 ml. of 75% ethyl acetate-toluene. The title compound was obtained crystalline as fine white needles (0.713 g.) melting at about 154° C. to about 155° C. after recrystallization from methylethyl ketone-hexane.
Reaction SMILES: [OH:1][CH:2]1[C:18]([CH3:20])([CH3:19])[C:17](=[O:21])[CH:16]([CH3:22])[CH:15]([OH:23])[CH:14]([CH3:24])[CH2:13][CH2:12][CH2:11][CH:10]2[CH:8]([N:9]2[CH2:25][CH2:26][OH:27])[CH2:7][CH:6]([C:28]([CH3:36])=[CH:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[O:5][C:4](=[O:37])[CH2:3]1.[C:38](=O)([O-:59])[O:39][CH2:40][CH:41](N1C2C=CC=CC=2N=N1)[S:42][S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:38](=[O:59])([O:39][CH2:40][CH2:41][S:42][S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[O:27][CH2:26][CH2:25][N:9]1[C@@H:8]2[C@H:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:24])[C@H:15]([OH:23])[C@@H:16]([CH3:22])[C:17](=[O:21])[C:18]([CH3:19])([CH3:20])[C@@H:2]([OH:1])[CH2:3][C:4](=[O:37])[O:5][C@H:6](/[C:28](/[CH3:36])=[CH:29]/[C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)[CH2:7]2
Reactant: CC(=Cc1csc(C)n1)C1CC2C(CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1)N2CCO
Reactant: O=C([O-])OCC(SSc1ccccn1)n1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCOC(=O)OCCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-17-[2-hydroxyethyl]-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione in anhydrous dichloromethane at 0° C. was added DMAP (1.2 eq.) and benzo[d][1,2,3]triazol-1-yl2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (1.0 eq.) in tandem. The reaction mixture was stirred at 0° C. under argon and monitored by TLC every 10 min. Additional DMAP (1.2 eq.) and Compound I (2)(1.0 eq.) were added as necessary until all of Compound G was consumed. The reaction was quenched with MeOH (1 mL) at 0° C., the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel, 2.5-5% MeOH in DCM) to afford the title compound as a beige solid. Compound amounts and recoveries are listed below in Table 2. Total yield from 2.95 g of Compound G was 2.80 g (67.9%) of Compound I.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][N:38]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCN(S(C)(=O)=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 1-methanesulfonylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]([N:20]([CH2:28][CH3:29])[CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:27][CH:24]1[CH2:23][CH2:22][CH:21]([N:20]([CH2:28][CH3:29])[CH2:18][CH3:19])[CH2:26][CH2:25]1
Reactant: CCN(CC)C1CCC(N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 77.5 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.01 g, 3.25 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (660 mg, 3.90 mmol) to afford the desired product (1.12 g, 78%) as a yellow wax: ESI MS m/z 523 [C23H30BrN3O+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[ClH:26].CN(C)CCCOC1C(C)=C2N(C=1)N=CN=C2OC1C=CC(N[C:50]([NH:52][C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[O:51])=CC=1F>>[ClH:26].[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:50]([NH:52][C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[O:51])=[CH:18][C:17]=1[F:23]
Reactant: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Yield: 19 %

Procedure:
4-(6-(2-(Dimethylamino)ethoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (20 mg, 0.06 mmol) was converted to the title compound (6.5 mg, 19%) in a manner similar to the preparation of Compound C of Example 32.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=O)[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:30]>P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:28][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:22]([Cl:23])[C:17]=1[N:5]1[C:6](=[N:8][CH:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[Cl:30])[CH:7]=[C:3]([C:1]#[N:2])[NH:4]1
Reactant: N#Cc1cc(NC(=O)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(=NC(Cl)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 139 g (0.33 mol) of N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-5-yl]pyrazine-2-carboxamide, 72.6 g (0.35 mol) of phosphorus pentachloride, and 300 ml of toluene was heated under reflux for 2 hours. Further, 5 g of phosphorus pentachloride was added thereto, followed by heating under reflux for 1 hour. The mixture was cooled to room temperature and allowed to stand overnight. After stirring for 30 minutes, crystals were filtrated and washed with toluene. The crystals were dissolved in 1 L of chloroform and the solution was extracted after the addition of water. The organic layer was washed twice with water, and with saturated saline, and then, dried over anhydrous sodium sulfate. The solvent was removed by distillation and the resulting crystals were washed with hexane to obtain 112.3 g (yield 79%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylchloromethylimino)pyrazole-3-carbonitrile.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[H-].[Na+].[F:11][C:12](Cl)([F:17])[C:13]([Cl:16])([Cl:15])[Cl:14]>CS(C)=O>[F:11][C:12]([F:17])([O:8][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=1)[C:13]([Cl:16])([Cl:15])[Cl:14]
Reactant: FC(F)(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.0 g (18.3 mmol) of p-aminophenol was added over a period of 10 minutes to a mixture of 0.48 g (20.1 mmol) of sodium hydride in 20 ml of dry DMSO. The mixture was stirred for 20 minutes. 3.73 g (18.3 mmol) of 1,1-difluoro-tetrachloroethane was added causing an exotherm to 47° C. The mixture was stirred at 60° C. for 2 hours, then poured into ice water. The brown solid was collected by filtration, dried, dissolved in ether and then HCl gas was bubbled into the solution causing the above-named aniline to precipitate as the hydrochloride salt. The white solid (4.4 g, 87 percent of theoretical d 250° C.) was collected by filtration.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>ClCCl>[CH2:11]([O:13][C:14](=[O:15])/[CH:16]=[CH:4]/[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:1]=[O:10])[CH3:12]
Reactant: O=Cc1ccccc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of phthalaldehyde (6.7 g) in dichloromethane (30 ml) was added ethoxycarbonylmethylenetriphenylphosphorane (17.42 g) and the mixture was stirred for 30 minutes at room temperature. The solvent was evaporated and the residue was dissolved in diethyl ether. After the mixture was filtered, the filtrate was evaporated. The residue was distilled under vacuum (125° C., 0.6 mmHg) to give (E)-3-(2-formylphenyl)propenoic acid ethyl ester (6 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1C#N
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
Trifluoroacetic acid (0.856 mL) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D19) (105 mg) in dichloromethane (1.5 mL) at RT. The resulting solution was stirred for 1.5 hours. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[6-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E7) (69 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.65 (2H, t), 2.97 (2H, t), 4.98 (1H, m), 7.36 (1H, d), 7.56 (1H, d), 7.72 (2H, t), 8.12 (1H, s), 8.42 (1H, dd), 8.51 (1H, d), 11.22 (1H, s), 12.12 (1H, br s). MS (ES): C23H20N4O4 requires 416. found 416.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[OH-].[Na+].[I:18]I>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: II
Reactant: Nc1nc(O)cc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(O)c(I)c(-c2ccccc2)n1
Yield: 78 %

Procedure:
Following the procedure of Example 16 but substituting 21.4 g. (0.113 M) of 2-amino-6-phenyl-4-pyrimidinol, 200 ml. water, 500 ml. chloroform, 5.6 g. sodium hydroxide and 28.8 g. I2, a yield of 29.0 g. (78%) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol is obtained.