Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].CN1C(=O)N(C)CCC1.C(O[Li])(C)(C)C.[C:39]([CH2:43]OS(C(F)(F)F)(=O)=O)([F:42])([F:41])[F:40]>C1COCC1>[CH3:1][C@H:2]1[N:7]([CH2:43][C:39]([F:42])([F:41])[F:40])[C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Li]OC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 37 (50 g, 0.164 mol) and DMPU (25 g, 0.2 mol) in THF (500 mL) was added tert-BuOLi (16.5 g, 0.2 mol) in portions at 20° C. for 0.5 h. After the mixture was degassed for 30 min at 20° C., CF3CH2OTf (45.8 g, 0.2 mol) was added at 20-25° C. The reaction was stirred for 24 h at 20-25° C. After the reaction was complete, the mixture was quenched by water, and then partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give product 38 (50 g, 78% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.18-7.13 (m, 4H), 4.17 (m, 1H), 4.11 (br, 1H), 3.67 (m, 3H), 2.66 (s, 1H), 2.33 (d, 3H), 1.83 (t, 1H), 1.41 (s, 9H), 0.96 (d, 3H); MS (ESI) m/e [M+H]+ 405.17.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound 3-(4-bromo-phenyl)-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME were added 58.0 mg (0.3 mmol) of 3-(trifluoromethyl)phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated at 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% DCM) to give 29 mg (50%) of the title compound. LC/MS (m/z): 572 (M+1)+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OO)=[O:22]>>[O:22]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: O=COO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCC1OC1CCCCCCCC(=O)O

Procedure:
9,10-Epoxyoctadecanoic acid is prepared according to a method described in “Salimon et al., (2009), European Journal of Scientific Research, 32(2), 216-222” and in which 71 mmol of oleic acid are treated with freshly prepared performic acid at ambient temperature for 3 hours with magnetic stirring (400 rpm). A white powder of 9,10-epoxyoctadecanoic acid (51 mmol) is obtained, with a degree of purity of 65% and a yield of 72%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[S:46][C:47]2[C:53]([N:54]([CH3:58])[C:55](=[O:57])[CH3:56])=[CH:52][CH:51]=[C:50]([O:59][CH3:60])[C:48]=2[N:49]=1>C1COCC1>[C:55]([N:54]([CH3:58])[C:53]1[C:47]2[S:46][C:45]([NH:44][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:49][C:48]=2[C:50]([O:59][CH3:60])=[CH:51][CH:52]=1)(=[O:57])[CH3:56]
Reactant: COc1ccc(N(C)C(C)=O)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a stirred solution of 31 mg (0.22 mmol) 4-fluoro-benzoic acid in 2 ml THF were added 89 mg (0.23 mmol) HATU and 0.07 ml (0.44 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 28 mg (0.11 mmol) N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-methyl-acetamide was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (dichloromethane/methanol 50/1) followed by trituration in ether afforded 10 mg (24%) N-[7-(acetyl-methyl-amino)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as a white crystalline solid. ES-MS m/e (%o): 374 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]([CH3:13])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloro-6-trifluoromethylpyrimidine (XXVII) (1.00 g, 4.6 mmol) was dissolved in dry THF (5 mL). To this solution was added N-methyl-4-trifluoromethoxyaniline (0.88 g, 4.6 mmol) and diisopropylethylamine (0.8 mL, 4.6 mmol). The resulting solution was stirred at room temperature for 18 hrs, then the volatiles were removed in vacuo and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with 2N HCl, dried over MgSO4, filtered and then concentrated in vacuo to give a brown color oil. Purification of the brown oil by chromatography (silica, hexane/EtOAc) afforded the product (XXVIII) as a yellow solid (0.95 g, 56%): 1H NMR (CDCl3) δ 7.42-7.27 (m, 4H), 6.4 (s, 1H), 3.5 (s, 3H); GC/MS m/z (relative intensity) 374 (26), 373 (45), 372 (76), 370 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxy-phenyl-acetic acid (2.26 g, 10 mmol) and dichloromethane (50 mL). Cool to -5° C. using a ice-salt bath. Add 2 drops of dimethylformamide followed by dropwise addition of oxalyl chloride (1.74 mL, 20 mmol). after 1 hour, warm the reaction mixture to ambient temperature. After 2 hours, evaporate the reaction mixture in vacuo to give the title compound as a liquid.
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[S:6]([C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])(=[O:8])=[O:7])[CH2:2][CH:3]=[CH2:4].B.C1C[O:32]CC1.O.B(O[O-])=O.[Na+]>C1COCC1>[OH:32][CH2:4][CH2:3][CH2:2][CH2:1][N:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[S:6]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])(=[O:7])=[O:8]
Reactant: C=CCCN(c1ccc(OC)cc1)S(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: C1CCOC1
Agent: B
Agent: O=BO[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(CCCCO)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at −78° C. was added BH3.THF (1.00 mL of a 1 M solution in THF, 1.00 mmol). After stirring at −78° C. for 1 h and at 0° C. for 1 h, the reaction mixture was treated with H2O (20 mL) and sodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, the mixture was poured onto H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgSO4). Concentration followed by chromatography (2:1/hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid, mp 88-90° C. 1H NMR (CDCl3): d 7.08 (m, 2H), 6.85 (m, 2H), 3.80 (s, 3H), 3.77 (m, 2H), 3.64 (t, J=6.0; 2H), 1.63-1.55 (m, 5H), 1.50 (bs, 1H). Anal. Calcd. for C17H16F5NO4S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21]([CH:28]=O)=[CH:20][CH:19]=1.O>O1CCCC1>[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:20][CH:19]=1
Reactant: Cn1cc2c(C=O)ccc(F)c2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(F)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (0.467 g, 11.7 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.34 mL, 11.7 mmol) in tetrahydrofuran (3 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 7-fluoro-2-methyl-2H-indazole-4-carbaldehyde (1.60 g, 8.98 mmol) in tetrahydrofuran (5 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.85 g, yield 83%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[BrH:13].[CH2:14]=O>>[BrH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Br:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: C=O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: Br
Product: NC(C(=O)O)c1ccc(O)c(CBr)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (0.6 mole) in a minimum amount of concentrated hydrobromic acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen bromide gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes. The title compound is collected and washed with ether and acetone.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>C(O)C>[CH3:6][NH:8][CH2:9][CH2:10][C@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]1=[O:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(CC[C@@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 16 h
Yield: 103.3 %

Procedure:
1′-[(1S)-3-(tert-butoxycarbonyl-methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (70 mg, 0.15 mmol) was dissolved in ethanol (3 mL) and 2N HCl in ethyl acetate (0.3 mL, 0.6 mmol) was added. The mixture was stirred 16 hours then concentrated under a stream of nitrogen. The residue was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 54 mg of 1′-[(1S)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one. The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (0.16 mL, 0.16 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 54 mg of 1′-[(1S)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].S([O-])([O-])(=O)=O.[Mg+2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([NH:1][C:2]1[NH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1c(-c2ccccc2F)[nH]c(NCc2ccccc2)c1C#N

Procedure:
To a solution of 2-amino-3-cyano-4-methyl-5-(2fluorophenyl)pyrrole (Compound No. 1) obtained in Example 5 (0.21 g) in methylene chloride (5 ml) was added a small amount of magnesium sulfate and the mixture was stirred under ice-cooling. Then, a solution of benzaldehyde (0.11 g) in methylene chloride (5 ml) was added dropwise at the same temperature and the mixture was stirred at room temperature for 5 days. The magnesium sulfate was then filtered off and the filtrate was concentrated under reduced pressure. After the residue was dissolved in methanol (15 ml), sodium borohydride (76 mg) was added thereto under ice-cooling. This mixture was stirred at room temperature for 1 hour and the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the ethyl acetate layer was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 50 g; eluent: chloroform/methanol=50/1) and the resulting crystals were recrystallized from benzene/n-hexane to provide the title compound as light-yellow powder (0.17 g). m.p. 151-152° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].Cl[Si:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:9][Si:8]([CH3:11])([CH3:10])[O:5][CH:4]=[CH:3][C:2]([CH3:6])=[CH2:1]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)=CC=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C=CO[Si](C)(C)C

Procedure:
3-methyl-2-butenal is reacted with chlorotrimethylsilane using the method of P. Cazeau et al., Tetrahedron 43, 2075-2088 (1987), in acetonitrile containing triethylamine and anhydrous sodium iodide at 40°-45° to yield 1-trimethylsilyloxy-3-methyl-1,3-butadiene 2;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>>[NH2:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][C:2]=1[Br:1]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br
Product: CCOP(=O)(Cc1ccc(N)c(Br)c1)OCC
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Di-tert-butyl [2-bromo-4-(bromomethyl)phenyl]imidodicarbonate (Compound 108B, 6.0 g, 13 mmol) was taken up in triethyl phosphite (5.0 mL, 29 mmol) and stirred at 120° C. for 16 h. The reaction mixture was transferred to a microwave vial and was irradiated in the microwave for 4 h at 190° C. The reaction mixture was concentrated in vacuo. The compound was purified on an Isco Combiflash eluting with 10 to 100% EtOAc in heptane. The product was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J=2.27 Hz, 1H), 7.04 (ddd, J=2.27, 2.40, 8.21 Hz, 1H), 6.71 (dd, J=0.76, 8.08 Hz, 1H), 3.97-4.06 (m, 4H), 2.96-3.04 (m, 2H), 1.26 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 322.00, 323.96 [MH+]. HPLC: tR=2.83 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([F:33])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(F)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a stirred solution of 1.34 g (4.5 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 199 mg (5.0 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 2.14 g (6.75 mmol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielding 0.40 g (28%) of (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+) and 0.52 g (37%) of (RR,SS)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH3:13])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[C:11]=3[N:12]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cn1c(=O)c(N)c(N)c2ccccc21
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
To a suspension of 3,4-diamino-1-methyl-1H-quinolin-2-one (0.60 g, 1.59 mmol) in CH2Cl2 (10 mL) were added Et3N (0.177 g, 1.74 mmol) and 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (0.45 g, 1.60 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h, and then excess acid chloride was quenched by addition of MeOH. The mixture was concentrated in vacuo, and the amide intermediate was taken up in 5 mL of HOAc and heated at reflux for 7 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The cyclized product was purified by flash chromatography, to give 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.12 g, 18% yield). 1H-NMR (DMSO): δ 8.08 (m, 1H), 7.60 (m, 1H), 7.43 (m, 1H), 7.32 (m, 6H), 5.02 (s, 2H), 3.91 (m, 2H), 3.34 (s, 3H), 2.81 (m, 3H), 1.78 (m, 2H), 1.39 (m, 2H). MS: calculated for C24H24N4O3+H 417.2; found: 417.4.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([O:8][C@H:9]1[C@H:14]([N:15]=[C:16]=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6].C(N(CC)CC)C>C(#N)C>[C:5]([O:8][C@H:9]1[C@H:14]([NH:15][C:16]([NH:4][O:3][CH3:2])=[S:17])[C@@H:13]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:11]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:10]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a suspension of methoxyamine hydrochloride (180 mg, 2.16 mmol) in acetonitrile (7 mL) was added (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (560 mg, 1.44 mmol) followed by triethylamine (300 μL, 2.16 mmol). The mixture was stirred at room temperature for 2 h. Solvents were removed by concentration. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methoxythioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (545 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H), 2.09 (s, 3H), 2.10 (s, 6H), 2.13 (s, 3H), 3.67 (s, 3H), 3.82-3.85 (m, 1H), 4.15 (dd, 1H, J=2.5, 12.5 Hz), 4.28 (dd, 1H, J=4.5, 12.5 Hz), 5.03 (dd, 1H, J=10.0, 13.0 Hz), 5.20-5.30 (m, 2H), 5.84 (d, 1H, J=8.5 Hz), 7.01 (d, 1H, J=10.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:38][NH:39][CH3:40]>>[C:35]([C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:25]2[O:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH2:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:39]([CH3:40])[CH3:38])[N:7]=5)[CH2:9][CH2:10]4)=[O:37])=[CH:18][CH:19]=3)=[N:27][C:26]=2[CH:28]=1)#[N:36]
Reactant: CNC
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccnc(Cl)n5)CC4)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccnc(N(C)C)n5)CC4)cc3)oc12
Yield: 48 %

Procedure:
A 5-ml microwave vial was charged with N-{[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (31 mg, EXAMPLE 7) and dimethylamine (2M in tetrahydrofuran, 3 ml). The resultant mixture was heated to 130° C. for 15 min in a microwave reactor. The mixture was concentrated in vacuo and the residue purified via flash chromatography on a Biotage Horizon 25M column, eluting with 10 column volumes of 100% ethyl acetate, to provide the title compound (15 mg, 48%). Mass spectrum (ESI) 524.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.2 Hz, 2H), 7.94 (m, 5H), 7.52 (s, 1H), 6.30 (t, J=5.8 Hz, 1H), 5.84 (d, J=6.0 Hz, 1H), 4.43 (d, J=10.8 Hz, 2H), 3.48 (sept, J=6.8 Hz, 1H), 3.45 (t, J=6.4 Hz, 2H), 3.13 (s, 3H), 2.84 (t, J=11.2 Hz, 2H), 1.93, (m, 3H), 1.46 (d, J=7.0 Hz, 6H), 1.37 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH2:11]O)=[N:9][CH:10]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.CCCCCCCCCCCCN>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH2:11][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])=[N:9][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CO)ncc1OCC(F)F
Agent: CCCCCCCCCCCCN
Product: Cc1cc(CN2C(=O)c3ccccc3C2=O)ncc1OCC(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (720 mg, white solid) from (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol (594 mg, 2.92 mmol, Step-3) and phthalimide (473 mg, 3.22 mmol) in a similar manner to Step-4 of Amine-12.