Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(C(F)(F)F)(=O)=O.C(BCCCC)CCC.C(N(C(C)C)CC)(C)C.[Br:54]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[C@H:15]([Br:54])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: CCCCBCCCC
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCC[C@@H](Br)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
(4R)-4-Benzyl-3-[5-(4-methoxyphenyl)pentanoyl]-1,3-oxazolidin-2-one (Reference Example 19) (1.4 g) was dissolved in dichloromethane (25 ml), and dibutylborane triflate (1M, 8.3 ml) and diisopropylethylamine (1.6 ml) were added thereto under ice-cooling. After 30 minutes, the reaction mixture was cooled to −78° C. and added dropwise to a solution of N-bromosuccinimide (NBS) (1.1 g) in dichloromethane (25 ml) which had been cooled to −78° C., via a cannula. After 2 hours, an aqueous sodium sulfite solution was added thereto and the resulting mixture was stirred at room temperature for 30 minutes. Chloroform was added to the reaction mixture to effect separation and extraction. The organic layer was dried, concentrated, and then the residue was purified by a silica gel chromatography (150 g, ethyl acetate:hexane=1:4) to obtain (4R)-4-benzyl-3-[(2R)-2-bromo-5-(4-methoxyphenyl)pentanoyl]-1,3-oxazolidin-2-one (0.9 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:35])([F:34])[F:33])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.[O-][Mn](=O)(=O)=O.[K+].[CH3:43]CN(CC)CC.CO.C(Cl)Cl>O1CCOCC1.CO>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]2[C:17]3[C:16](=[O:36])[N:15]([C:12]4[CH:11]=[CH:10][C:9]([C:6]5([C:2]6[N:1]([CH3:43])[CH:5]=[CH:4][N:3]=6)[CH2:7][CH2:8]5)=[CH:14][CH:13]=4)[CH2:20][CH2:19][C:18]=3[C:21]([C:32]([F:33])([F:34])[F:35])=[N:22]2)=[CH:25][CH:26]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5)CC4)cc2)CC3)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(c5nccn5C)CC4)cc2)CC3)cc1
Temperature: 80 °C
Yield: 72 %

Procedure:
The product from Example 144 (0.08 g, 0.18 mmol) was dissolved in 1,4-dioxane (2.0 mL) and KMnO4 (spatula tip) was added. The reaction was heated to 80° C. for 12 h at rt. The reaction was filtered, concentrated, and purified via flash chromatography (silica, 100% EtOAc then 0.5% Et3N:10% MeOH/CH2Cl2 then 100% MeOH) to yield the title compound (0.06 g, yield: 72%). 1H NMR δ 7.44 (d, J=9.1 Hz, 2H), 7.24 (d, J=8.7 Hz, 2H), 6.98 (m, 4H), 4.07 (dd, J=2.9, 3.7 Hz, 2H), 3.81 (s, 3H), 3.48 (s, 2H), 3.12 (t, J=6.2 Hz, 2H), 1.44 (m, 2H), 1.21 (t, J=7.3 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14].O>CN(C=O)C>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(N=C=S)cc2N1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (0.20 g, 1.2 mmol) in DMF (5.2 mL) was added dropwise to a solution of 1,1′-thiocarbonyldiimidazole (0.22 g, 1.2 mmol) in DMF (2.1 mL) at room temperature over 1 hour. The mixture was stirred for 30 minutes and then water was slowly added. The resulting precipitate was collected by filtration (rinsed with water) and dried under vacuum to afford the title compound (0.21 g, 83% yield), which was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[C:31]([CH:38]1CCN(N)CC1)(OC(C)(C)C)=O>>[NH2:8][CH:12]1[CH2:38][CH2:31][N:13]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(C)(C)OC(=O)C1CCN(N)CC1
Product: NC1CCN(C(=O)c2sccc2Nc2ccnc3[nH]ccc23)CC1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-Boc-aminopiperidine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 342 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (1H, s) 10.36 (1H, s) 8.18 (1H, d, J=4.10 Hz) 8.04 (1H, d, J=7.03 Hz) 7.87 (1H, d, J=5.08 Hz) 7.33-7.37 (1H, m) 7.15 (1H, d, J=5.27 Hz) 6.53 (1H, d, J=7.03 Hz) 3.54 (4H, s) 2.81-2.94 (1H, m) 1.82 (2H, d, J=9.96 Hz) 1.70-1.76 (1H, m) 1.25-1.39 (2H, m)
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([SH:15])[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:3][CH3:4])[CH3:2]>[Fe].C(O)(=O)C>[NH2:12][C:11]1[C:6]([NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([CH3:16])=[N:9][C:10]=1[SH:15]
Reactant: CCOC(=O)c1c(C)nc(S)c([N+](=O)[O-])c1NC(C)CC
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC

Procedure:
6.2 g. of 4-sec.butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 50 ml. of acetic acid. Iron dust is added carefully at reflux temperature until the mixture is colorless. The excess of iron is filtered off and the filtrate is evaporated to dryness. The oily residue is dissolved in 10 ml. of methanol and precipitated by the addition of aqueous ammonia to obtain 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester, yield 3 g. (53%); m.p. 88°-89° (ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30]CC4C=CC=CC=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)n1COCC[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3cc[nH]c(=O)c3)cc2)n1COCC[Si](C)(C)C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g) in DMF (5.0 mL) at 0° C. was added 60% sodium hydride (0.047 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxylmethyl chloride was added and reaction mixture stirred for 2 hours. Saturated ammonium chloride was added and mixture was extracted with ethyl acetate (2×). Organic layer was washed with 5% lithium chloride solution (2×), brine and dried (MgSO4). Concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g). LCMS-ESI+: calc'd for C36H47N4O4Si: 627.87 (M+H+). Found: 627.1 (M+H+). A mixture of 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g) and 10% Pd/C (0.023 g) in ethanol (5.5 mL) was stirred under hydrogen atmosphere for 1 hour. Reaction mixture was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated and purifed by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[5-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3027 g): LCMS-ESI+: calc'd for C29H41N4O4Si: 537.47 (M+H+). Found: 537.0 (M+H+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(OC)(c2ccc(-c3ccccc3)cc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (150 mg, 0.482 mmol), (S)-2-(tert-butoxycarbonylamino)non-8-enoic acid (144 mg, 0.530 mmol), and HATU (260 mg, 0.723 mmol) in DCM (5 ml) was added N,N-diisopropylethylamine (0.252 ml, 1.445 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 18 h. It was then diluted with DCM, washed with 5% citric acid, and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to yield 2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylate (140 mg, 51.5% yield) as white foam.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[NH:27][CH:26]=1>>[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([S:5]([CH2:4][CH:1]6[CH2:3][CH2:2]6)(=[O:7])=[O:6])[CH:9]=5)[N:22]4[N:21]=3)=[CH:33][C:28]=2[NH:27][CH:26]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Product: O=S(=O)(CC1CC1)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 3H-benzimidazol-5-ylamine (45.2 mg, 0.340 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 39 mg (43%) of brown powder; LC/MS: 445 (M+H); HPLC: 97% pure, RT=2.46 min; 1H NMR: (DMSO, δ) 9.85 (s, 1H), 9.33 (s, 1H), 9.02 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=7.7, 1H), 8.00 (s, 1H), 7.90 (dd, J=9.2, 1.5, 1H), 7.83 (d, J=7.7, 1H), 7.75 (m, 2H), 7.27 (d, J=4.8, 1H), 6.97 (d, J=4.8, 1H), 3.21 (d, J=7.1, 2H), 0.77 (m, 1H), 0.34 (m, 2H), 0.01 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(SC(F)(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidin-2-one (1.30 g, 3.50 mmol) in ethanol (3 ml) was added 8N aqueous sodium hydroxide solution (1.31 ml,10.5 mmol), and the mixture was stirred at 80° C. for 4 hrs. To the reaction solution was added water (20 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (0.8 g, 77%).
Reaction SMILES: Cl[C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[C:4]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:18][C:16]1([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14][B:13]([C:4]2[CH:3]=[CH:2][C:11]3[O:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH3:12])[O:17]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(Cl)c2c1CCCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CCCO2
Temperature: 25 °C
Yield: 94.1 %

Procedure:
Palladium on activated charcoal (10% Pd by weight, 120 mg) was added to a solution of 2-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7f) (1.20 g, 3.89 mmol) and ammonium formate (2.45 g, 38.89 mmol) in methanol (20 mL). The mixture was refluxed for 60 minutes. The mixture was then cooled to room temperature, filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo to provide 4,4,5,5-tetramethyl-2-(5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1,3,2-dioxaborolane (7g) (1.00 g, 3.66 mmol, 94%) as a white solid, which was used without further purification.
Reaction SMILES: C1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])CC1.Br[C:18]1C=CC(C)=C(C=1)C(O)=O.BrC1C=C(C=CC=1C1CC1)C(O)=O>>[CH3:18][C:11]1[CH:12]=[CH:4][C:5]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=C(O)c1ccc(C2CC2)c(Br)c1
Product: CCC(=O)c1ccc(C)c(C(=O)O)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 10.6, except 5-bromo-2-methylbenzoic acid was used in place of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:17](Cl)#[C:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[N:12]([CH2:17][C:18]#[C:19][CH2:20][CH3:21])[N:13]=2)=[N:6][CH:7]=1
Reactant: CCCC#CCl
Reactant: O=C1CCC(c2ccc(Cl)cn2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCN1N=C(c2ccc(Cl)cn2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a 100 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 200 milligrams (mg) of 6-(5-chloropyridin-2-yl)-4,5-dihydropyridazin-3(2H)-one (0.95 mmol), 3.8 mg of 60% sodium hydride (oil dispersion) (0.95 mmol), and 20 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the dropwise addition of 0.1 ml of pentynyl chloride (0.95 mmol) in about 5 mL of dry DMF. The reaction was stirred overnight at ambient temperature, and checked by TLC and GC the next morning. No starting material remained, and one new product was formed. The reaction was poured into about 100 mL of water, and extracted with 3×50 mL of ethyl acetate. The combined ether extract was washed with 100 mL of water, 100 mL of saturated aqueous sodium chloride solution, dried, and stripped to afford 240 mg of a tan solid 92% isolated yield. The NMR data is a 1 follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 1.15 (t, 3H); 2.20 (m, 2H); 2.60 (t, 2H); 3.25 (t, 2H); 4.70 (s, 2H); 7.75 (d, 1H); 8.15 (d, 1H); 8.50 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])=O.[OH-].[Na+].[N+:14]([CH3:17])([O-:16])=[O:15].Cl>O>[N+:14]([CH2:17][CH:1]1[O:11][B:9]([OH:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=2)([O-:16])=[O:15]
Reactant: O=Cc1ccccc1B(O)O
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2ccccc21
Temperature: 25 °C
Yield: 87.1 %

Procedure:
2-Formylphenylboronic acid (25 g, 0.167 mol) was added to a cooled solution of sodium hydroxide (7.0 g, 0.175 mol, 1.05 eq) in 83 mL of water at 10° C. Nitromethane (10.17 g, 1 eq) was added to this solution and then warmed to room temperature with stirring. This mixture was stirred for 3.5 hours. The reaction was then cooled in an ice bath and acidified with 3M HCl to a pH of 2. A white precipitate was collected and filtered, washed with water and air dried to obtain 28 g (87%) of 3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (off-white solid).
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH:5]=[C:6]2[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(O)(=O)C>O1CCCC1.C(Cl)Cl.[Zn]>[C:14]1([CH:13]([O:12][C:10]([C:6]2[CH:7]3[CH:3]([CH2:4][CH:5]=2)[CH2:2][C:8]3=[O:9])=[O:11])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2CC(=O)C12
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 50 g of 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, from Example 4, in 75 mL of tetrahydrofuran, was added 500 mL of acetic acid and 100 g of zinc dust. This mixture was stirred mechanically for 6 hr at room temperature and then diluted with 1 L of methylene chloride and filtered. The filtrate was evaporated to a residue which was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give a colorless solid which, when triturated with 150 mL of ether-petroleum ether (1:1), afforded 35.1 g (85.5%) of crystalline 7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid diphenylmethyl ester: IR (Nujol mull): 1625, 1715, 1785 cm-1 ; NMR (220 MHz; CDCl3): δ 2.57 (1H, m), 2.89 (3H, m), 3.27 (1H, m), 4.48 (1H, m), 6.80 (1H, s), 6.86 (1H, m) and 7.1-7.4 (10H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(Nc2nccs2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Thiazol-2-amine 52-1 (2.0 g, 20.0 mmol) was dissolved in THF and 1 equivalent of sodium hydride (0.8 g, 60% dispersion in oil) was added. This was stirred for 30 min at room temperature. Then 4,6-dichloropyrimidine 7-1 (2.97 g, 20.0 mmol) and the other equivalent of sodium hydride were added simultaneously. This was refluxed for 30 minutes. The reaction was quenched with methanol and water and then evaporated. The residue was partitioned with DCM:MeOH:water (50:5:50). The organic layer was drawn off, dried and evaporated to afford crude material which was purified on a silica column eluted with 99:1:0.1 (DCM:MeOH:NH4OH). Rf=0.4 (DCM:MeOH:NH4OH 98:2:0.2). 1H-NMR(DMSO-d6): 11.96 (s, 1H); 8.71(s, 1H); 7.49(d, 1H); 7.25(d, 1H); 7.13(br s, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1COCC1>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([OH:10])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ−116.52 (m).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[O:23]=[C:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-butanesulfonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 2H), 1.55-1.70 (m, 2H), 2.40 (t, J=5.9 Hz, 4H), 2.94 (t, J=7.6 Hz, 2H), 3.54 (t, J=5.9 Hz, 4H), 7.00 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 9.34 (s, 1H); MS (ES) m/z: 311.0 (MH+); HRMS Calcd. for C15H22N2O2S(M+): 310.1351. Found: 310.1375. Anal. Calcd. for C15H22N2O2S: C, 58.04; H, 7.14; N, 9.02. Found: C, 57.78; H, 6.95; N, 8.83.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]>CCO>[CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1n[nH]c2cc([N+](=O)[O-])ccc12
Solvent: CCO
Product: CC(C)Nc1n[nH]c2cc(N)ccc12
Temperature: 78 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
Isopropyl-(6-nitro-1H-indazol-3-yl)-amine (0.070 g, 0.318 mmol) and SnCL2.2H2O (0.365 g, 1.62 mmol) were added to 5 mL EtOH, and the reaction mixture was heated to 78° C. and stirred for four hours. The reaction mixture was cooled and concentrated under reduced pressure. The resulting oil was dissolved in 5 mL EtOH and the solution was treated with 5 mL saturated aqueous NaHCO3. The resulting solid was removed by filtration, and the filtrate was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-100%) to give 0.036 g of N*3*-Isopropyl-1H-indazole-3,6-diamine, MS (M+H)=219.