Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[C:6]([NH:25][C@H:26]([CH2:29][CH3:30])[C@@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)O
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (2.74 g, 2.2 eq, 13.33 mmol) in Et2O (100 mL) under an argon atmosphere at −70° C., was added methyllithium (1.6 M in Et2O, 16.6 mL, 4.4 eq, 26.56 mmol) dropwise, and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (2 g, 1 eq, 6.05 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h, when TLC (hexane:ether; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with ether (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (80:20) to afford the title compound as a light yellow oil. Yield: 1.91 g (91%). (80% de 2S,3R: 20% de 2R,3R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.47 & 0.55 (2×t, J=7.43 & 7.27 Hz, —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5H, —NHCH(CH2CH3)CH(CH3)OH), 2.03 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.32-3.51 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.40 (d, 1H, J=3.79 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.14-7.51 (m, 15H, 3×Ph).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:14](#[N:16])[CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>C1COCC1>[CH3:13][C:8]1([C:7]2[C:2]([CH2:15][C:14]#[N:16])=[N:3][CH:4]=[CH:5][CH:6]=2)[O:12][CH2:11][CH2:10][O:9]1
Reactant: CC#N
Reactant: CC1(c2cccnc2Cl)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(c2cccnc2CC#N)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 2-chloro-3-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (2.19 g, 11.0 mmol, 1.0 equiv) and acetonitrile (577 μL, 11.0 mmol, 1.0 equiv) in THF (75 mL) is cooled to 5° C. under nitrogen atmosphere. 2M Sodium bis(trimethylsilyl)amide solution in THF (11.0 mL, 21.9 mmol, 2.0 equiv) is added within 1 minute. This results in a bright yellow solution which turns orange over time. Stirring at 0° C. is continued for exact 1 h. According to TLC there is complete conversion. Saturated NH4Cl solution (50 mL) is added. The organic layer is separated and concentrated in vacuo. The residue is combined with the water layer and extracted with ethyl acetate (75 mL). The organic layer is washed three times with sat. NH4Cl solution, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash column chromatography (10% to 50% ethyl acetate in heptane) and gave 540 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[CH2:6][CH:7]1[CH2:9][CH2:8]1)[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[C:6]([CH:7]1[CH2:9][CH2:8]1)=[CH:14][N:15]([CH3:17])[CH3:16])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C(=O)CC1CC1
Product: CCOC(=O)C(=O)C(=CN(C)C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
A mixture of 3-cyclopropyl-2-oxo-propionic acid ethyl ester (6.4 mmol, 1.0 g) and dimethylformamide dimethylacetal (12.8 mmol, 2.0 mL) are combined and stirred at room temperature for 18 hours. The reaction is concentrated under reduced pressure to yield the title compound (1.38 g, 100%). LC-MS: 212.0 (M+1).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[S:8][C:7]([C:9](OC)=[O:10])=[C:6]([NH:13][CH3:14])[CH:5]=1.Cl.[Cl-].[NH4+].C([N:20](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CO>[Br:3][C:4]1[S:8][C:7]([C:9]([NH2:20])=[O:10])=[C:6]([NH:13][CH3:14])[CH:5]=1
Reactant: CNc1cc(Br)sc1C(=O)OC
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cc(Br)sc1C(N)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
A mixture of 3 M sodium hydroxide (2.5 mL, 7.50 mmol), MeOH (10 mL) and methyl 5-bromo-3-(methylamino)thiophene-2-carboxylate (674 mg, 2.69 mmol) was stirred at 70° C. overnight. Then, the mixture was cooled in ice-water bath, and 6 M HCl (0.9 mL, 5.40 mmol) was added. The mixture was concentrated under reduced pressure to give a yellow solid. This residue was mixed with ammonium chloride (2.88 g, 53.9 mmol), triethylamine (7.51 mL, 53.9 mmol) and DMF (27 mL). The mixture was stirred for 5 min, then 1-hydroxybenzotriazole (2.19 g, 16.2 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.10 g, 16.2 mmol) were added. The stirring was continued for 3 days. The reaction mixture was poured into saturated aqueous NaHCO3 (200 mL). Extraction with EtOAc (200 mL), washing with saturated NaHCO3, drying over MgSO4, filtration and concentration under reduced pressure gave brown oil. This oil was purified by column chromatography (Purif, silica gel, hexane to EtOAc) to afford the title compound (536 mg, 85%) as a pale brown solid:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][OH:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C(Cl)(Cl)Cl.CO.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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][OH:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(Br)ccc2c2c1nc(CO)n2CC1CCOCC1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: Nc1nc2cc(-c3cccnc3)ccc2c2c1nc(CO)n2CC1CCOCC1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a mixture of [4-amino-7-bromo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (500 mg, 1.28 mmol), 3-pyridyl boronic acid (233 mg, 1.90 mmol), potassium carbonate (579 mg, 4.20 mmol), dimethoxyethane (5 mL), and water (2.5 mL) under a nitrogen atmosphere was added Pd(PPh3)2Cl2 (18 mg, 0.026 mmol). The resulting suspension was refluxed for 2 hours. The reaction was cooled to ambient temperature. The reaction mixture was diluted with chloroform and placed directly onto a silica gel column. Chromatography (SiO2, 0-40% CMA/CHCl3) gave material that was stirred in methanol and filtered to provide 263 mg of [4-amino-7-pyridin-3-yl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol as tan crystals, m.p. 260-262° C. MS (APCI) m/z 500.3 (M+H)+; Anal. calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.49; H, 5.87; N, 17.83.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][N:15]([CH2:18][CH2:19][C@@:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([NH:23][O:24]C2CCCCO2)=[O:22])[C:14](=[O:36])[CH:13]=1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][N:15]([CH2:18][CH2:19][C@@:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([NH:23][OH:24])=[O:22])[C:14](=[O:36])[CH:13]=1
Reactant: COc1ccc(-c2ccn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c(=O)c2)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 M aqueous HCl (2.76 mL) was added slowly to a solution of (2R)-4-[4-(2,3-difluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (132 mg, 0.26 mmol) in 1,4-dioxane (15 mL) at room temperature. The reaction was allowed to stir at room temperature overnight. After 18 hours the reaction was concentrated to 25% of the original volume, resulting in a white precipitate. The precipitate was filtered via Buchner funnel and washed with hexanes (20 mL) to afford a white solid. Yield 45 mg, 41%. MS (APCI) m/z 431.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.14 (td, J=12.20, 4.88 Hz, 1H) 2.35-2.45 (m, 1H) 3.08 (s, 3H) 3.72 (td, J=12.05, 4.78 Hz, 1H) 3.90 (s, 3H) 4.09 (td, J=11.90, 5.27 Hz, 1H) 6.46 (dt, J=7.02, 1.85 Hz, 1H) 6.54 (s, 1H) 7.03-7.17 (m, 1H) 7.37 (td, J=8.63, 2.24 Hz, 1H) 7.72 (d, J=7.22 Hz, 1H) 9.22 (br. s., 1H) 11.10 (s, 1H)
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:19]=[C:18]([C:20](C)(C)C)[CH:17]=[C:16]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)[C:15]=1[OH:30])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=C(C)C=C(C)C=1>[C:24]1([C:16]2[C:15]([O:30][P:2]3[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]3)=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:19]=[C:18]([CH3:20])[CH:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC(C)(C)c1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)COP(Cl)OC1
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CCCCC2)c(OP2OCC(C)(C)CO2)c(C(C)(C)C)c1
Yield: 57.1 %

Procedure:
4.85 g (29.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added drop-wise over a period of about 15 minutes to a solution of 6.6 g (27.0 mmol) of 6-(cyclohexen-1-yl)-2-tert-butyl-4-methylphenol (compound (102), Example 1) and 4.0 ml (29.0 mmol) of triethylamine in 25 ml of mesitylene (1,3,5-trimethylbenzene). The reaction mixture is then refluxed for 18 hours, cooled, filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from dry acetonitrile gives 5.8 g (57%) of 2-[6-(cyclohexen-1-yl)-2-tert-butyl-4-methyl-phenoxy]-5,5-dimethyl-1,3,2-dioxaphosphorinane, m.p. 97°-102° C. (compound (201), Table 2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[O:9]=[C:10]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:12]1([CH2:11][C:10]([N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)=[O:9])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C(CN1CCOCC1)N1CCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ncn1

Procedure:
7-2 (0.22 g, 1.76 mmol), 42-2 (0.37 g, 1.76 mmol) and DIEA (0.23 g, 1.76 mmol) were reacted to afford 42-3, which was purified on a silica column. 1H-NMR(CD3OD): 8.00(s, 1H); 5.75(s, 1H); 3.70(m, 6H); 3.65(m, 4H); 3.56(m, 2H); 3.30(s, 2H); 2.54(br s, 4H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]([CH3:15])[C:3]=1[C:16]([O:18]C)=O.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[CH3:15][N:4]1[C:3]([C:16]([NH:20][C:21]2[S:22][C:23]([CH3:26])=[CH:24][N:25]=2)=[O:18])=[C:2]([OH:1])[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:14]
Reactant: COC(=O)C1=C(O)c2cc(C)ccc2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)C(O)=C(C(=O)Nc1ncc(C)s1)N(C)S2(=O)=O

Procedure:
4.0 gm (14 millimols) of methyl 4-hydroxy-2,6-dimethyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.0 gm (17 millimols) of 2-amino-5-methyl-thiazole were refluxed in 200 ml of anhydrous xylene for 24 hours. After cooling, the crystals which had separated out were filtered off. After recrystallization from ethylene chloride 3.6 gm (70% of theory) of 2,6-dimethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26]C3C=CC=CC=3)=O)=[CH:19][CH:18]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]1=2)=[O:4].[C:37]1([CH2:43][CH2:44][NH2:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:45][CH2:44][CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:26])=[CH:21][CH:22]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]1=2)=[O:4]
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1)Oc1ccccc1
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
To a solution of (3aR*,10aS*)-4-(chloroacetyl)-9-[4-(phenoxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (151 mg, 0.3 mmol) in DMF (1.5 mL) was added 2-phenylethylamine (38 μl, 0.3 mmol) and the mixture was stirred at room temperature for 4 hours. This reaction mixture was diluted with ethyl acetate and washed with 2 portions of water and, then, with saturated aqueous NaCl solution. This solution was dried over NaSO4 and concentrated under reduced pressure and the residue was crystallized from ethanol-diethyl ether to provide 62 mg (yield 39%) of the title compound. m.p. 224°-226° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To the product from step (iv) (1.25 g) in THF (100 mL), methyl 2-(4-formylphenyl)acetate (0.818 g) was addded followed by sodium triacetoxyborohydride (0.885 g) and acetic acid (3 drops) and stirred at rt for 16 h. The reaction was quenched with water, extracted with DCM washed with sat. NaHCO3 (200 mL), dried and solvent removed. The resulting residue was dissolved in methanol and purified on SCX to give the subtitle compound (0.73 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>CC1C=CC(S(O)(=O)=O)=CC=1.O.C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 96 %

Procedure:
A round-bottom flask was charged with 20 (1.76 g, 10 mmol), p-TsOH.H2O (38 mg, 0.2 mmol), 3,4-dihydro-2H-pyran (1.26 g, 15 mmol) and THF (20 mL). The reaction mixture was degassed with nitrogen and heated at reflux for 18 h, and then the solvent was removed under reduced pressure. The residue was diluted with DCM (250 mL) and water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1.0% MeOH) to afford 2.5 g (90%) of methyl 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylate (22) as a grey oil: MS (ESI) m/z=261.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:25])=[O:24])[C:16]([C:19](O)=[O:20])=[N:17][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:15]2[C:16]([C:19]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=4[O:10][CH2:9][CH2:8]3)=[O:20])=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)(=[O:25])=[O:24])=[CH:27][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1cccc2c1OCCN2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2c(F)cccc21

Procedure:
8-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine, 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(8-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 2.986 min. MS m/z 550.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([F:30])=[C:26](F)[CH:27]=3)[C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20]2)[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:26]1[CH:27]=[C:28]3[C:23]([C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]3[CH:16]3[CH2:18][CH2:17]3)=[CH:24][C:25]=1[F:30])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CNCCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CC(C)(C)OC(=O)NC12CC1CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 64.7 %

Procedure:
According to the procedure of Example 34A, 1-tertbutoxycarbonylamino-3-azabicyclo[4.1.0]heptane (270.0 mg, 1.27 mmol) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (275.6 mg, 1.03 mmol) were reacted to generate the title compound (304.2 mg, 0.666 mmol, 65%).
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]=[C:16]([C:18](=[NH:22])[NH:19][C:20]#[N:21])[CH:15]=[CH:14][N:13]=1.[CH2:23](Cl)[Cl:24]>C(#N)C>[Cl:24][C:23]1[N:22]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[N:17]=2)[N:19]=[CH:20][N:21]=1
Reactant: N#CNC(=N)c1ccnc(Cl)n1
Reactant: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc(-c2ncnc(Cl)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N,N-dimethylformamide (8.5 mL, 110 mmol) in methylene chloride (100 mL) was added phosphorus oxychloride (8.0 mL, 87 mmol) dropwise, and the mixture was stirred for 0.5 h. The resulting mixture was poured into a cold (0° C.) suspension of 2-chloro-N-cyano-4-pyrimidinecarboximidamide (i.e., the product of Step A) (13 g, 73 mmol) in acetonitrile (200 mL). The resulting mixture was stirred overnight in an ice bath. The mixture was passed through a short silica gel pad, eluted with 30% ethyl acetate in hexanes, and concentrated under reduced pressure to give 7 g of the title compound as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[C:31](O)=[O:32]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([CH:27]5[CH2:28][CH2:29][CH2:30][O:26]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (17.6 mg, 60.3%), MS (ISP) m/z=429.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and tetrahydrofuran-2-carboxylic acid
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC=CC=5)=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30](=[O:44])[NH:31]5)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30](=[O:44])[NH:31]5)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCCC45CC6CC(CC(C6)C4)C5)c3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Product: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCCC45CC6CC(CC(C6)C4)C5)c3)ccc(O)c2[nH]1

Procedure:
Obtained from Intermediate 33 (0.365 g, 0.62 mmol) and palladium on charcoal (10%, 0.075 g) by the same procedure described in Example 1 (reaction time: 20 hours). The crude was purified by column chromatography with silica gel, eluting with methylen chloride/methanol/ammonium (40:2.5:0.1) and the title compound was obtained as a solid (0.113 g, 65%).
Reaction SMILES: O([Si](C)(C)C)[K].I[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[CH:17](/[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Ic1cccc2ccccc12
Agent: C[Si](C)(C)O[K]
Product: CCCCC/C=C/c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (E)-21 (379 mg, 2.2 mmol, 1.1 equiv), 1-iodonaphthalene (292 μL, 2.0 mmol) and Pd(dba) (58 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 2 h, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) and Kugelrohr distillation afforded 416 mg (93%) of (E)-154a as colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cccc2n1
Yield: 21 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 17.2 mg. (21% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.6 (br s, 1H), 10.0 (br s, 1H), 9.01 (br s, 1H), 7.72 (m, 2H), 7.47 (m, 2H), 7.28 (m, 4H), 3.60 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.89 (m, 4H), 2.36 (m, 2H). ESIMS+419.8 m/z