Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([S:17]([C:4]2[CH:5]=[CH:6][C:7]([C:28]3[N:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:32][N:33]=3)=[C:2]([CH3:1])[CH:3]=2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1-c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (278 mg, 0.74 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (139 mg, 0.49 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (20 mg, 0.025 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (484 mg, 1.49 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.2 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 2% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-methylphenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (61 mg) as an off-white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11]>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][C:2]([OH:11])=[C:1]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][C:2]=3[OH:11])[C:10]2=[CH:9][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A two-neck round bottom flask (50 mL) was charged with a solution of catalyst 1c (122 mg, 0.2 mmol) in anhydrous CCl4 (10 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 2-naphthol (290 mg, 2 mmol) in anhydrous CCl4 (10 mL). The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3a, Yield 85%. 1HNMR (300 MHz, CDCl3) δ (ppm) 7.98 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.90 (d, J=7.8 Hz, 2H, 2×HC (5)), 7.38 (d, J=9.0 Hz, 2H, 2×HC (8)), 7.41–7.27 (m, 4H, 2×HC (6), 2×HC (7)), 7.16 (d,J=8.4 Hz, 2H, 2×HC (3)), 5.09 (s, 2H, 2×OH). e.e. 90% and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=90: 10; flow rate 1 mL/min; S-isomer, tR 7.78 min and R-isomer, tR 8.79 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:12]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:12])[C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: OO
Reactant: NS(=O)(=O)c1ncccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1c(Cl)ccc[n+]1[O-]

Procedure:
To a stirring solution of 3-chloro-2-pyridinesulfonamide (2.5 g, 13.0 mmol) in 35 mL of trifluoroacetic acid was added 30% H2O2 (1.2 g, 35.1 mmol). The solution was concentrated to ~15 mL, diluted with ethyl acetate, washed twice with brine, dried and concentrated. The resulting solid was flash chromatographed with EtOAc to afford the desired product, m.p. 195°-197° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[C:13]3[C:12]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH2:20]([S:19][C:17]1[CH:18]=[C:13]2[C:12]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCSc1cnc2c(c1)c(-c1cn[nH]c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCSc1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Yield: 35.2 %

Procedure:
Inhibitor 17 was synthesized following the method described for preparation of 8 using 16 (0.50 g, 1.21 mmol), ethanol (23 mL), 10% aq. NaOH (11.2 mL). Reaction time: 1 h at 90° C. Purification by SGC using CH2Cl2:MeOH (gradient elution up to 97:3, v/v) gave 17 as an orange foam (116 mg, 35%); 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.3 Hz, 3H), 1.39 (sextet, J=7.4 Hz, 2H), 1.55 (quintet, J=7.4 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 7.42 (s, 1H), 7.83 (s, 2H), 8.19 (d, J=2.0 Hz, 1H), 8.36 (dd, J=2.0, 0.3 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C@@H:8]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27](=[O:47])[C@H:28]([CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:29][C:30]([O:32][CH3:33])=[O:31])[O:7][CH2:6]1)=[N+:2]=[N-:3].[C:48]1([C:54]#[CH:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(C(C)C)C(C)C>O1CCCC1.[Cu]I>[CH3:33][O:32][C:30]([NH:29][C@H:28]([C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C@H:8]1[O:7][CH2:6][C@@H:5]([CH2:4][N:1]2[CH:55]=[C:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:3]=[N:2]2)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:9]1)=[O:47])[CH:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])CO1)C(c1ccccc1)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](Cn2cc(-c3ccccc3)nn2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of tert-butyl (2R,5R)-5-(azidomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in tetrahydrofuran (0.033M) were added phenylacetylene (3.9 eq.) and Hunig's base (5 eq.). Nitrogen was then bubbled for 5 minutes through the reaction mixture which was placed in a sealed tube. Copper(I) iodide (1.5 eq.) was added to the reaction mixture and the temperature was raised to 70° C. for 16 hrs. The reaction mixture was evaporated to dryness and the evaporation residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 10% of MeOH/CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[SH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Sc1ccncc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(CSc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 79 %

Procedure:
Using a procedure analogous to that described in Example 117, the title compound, m.p. 140°-142° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-mercaptopyridine. The yield was 79% of theory.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[C:13]([C:15]1[C:16]([O:45][C@H:46]([CH3:50])[CH2:47][O:48][CH3:49])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][NH:40][C@@H:41]([CH3:44])[CH2:42][OH:43])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C(Cl)Cl>[C:13]([C:15]1[C:16]([O:45][C@H:46]([CH3:50])[CH2:47][O:48][CH3:49])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][N:40]4[C@@H:41]([CH3:44])[CH2:42][O:43][C:1]4=[O:2])=[C:31]([CH:34]([O:35][CH3:36])[O:37][CH3:38])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(CN[C@@H](C)CO)c(C(OC)OC)nc32)ncc1C#N
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(CN4C(=O)OC[C@@H]4C)c(C(OC)OC)nc32)ncc1C#N

Procedure:
A mixture of carbonyl diimidazole (49 mg, 0.301 mmol) and N-(5-cyano-4-(((R)-1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-((((S)-1-hydroxypropan-2-yl)amino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 148, 118 mg, 0.223 mmol) in DCM (10 ml) was heated in a septum sealed vial at 45° C. for 2.5 h. The cooled reaction mixture was partitioned between DCM and aqueous citric acid solution (5% w/w), extracted 2× with DCM, the DCM layers dried over Na2SO4 and evaporated to give the title compound as a yellow-white solid. (UPLC-MS 6) tR 1.14; ESI-MS 555.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:34]C(=O)OC(C)(C)C)([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[C:15]4[CH:27]=[CH:26][CH:25]=[N:24][C:16]=4[NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:13]3=[N:12][C:11]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)[CH3:3].[ClH:42]>ClCCl.O1CCOCC1>[ClH:42].[C:28]1([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([C:2]([NH2:34])([CH3:1])[CH3:3])=[CH:9][CH:8]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(N)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of tert-butyl {1-methyl-1-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]ethyl}carbamate (41 mg) in dichloromethane (4 mL) was added hydrogen chloride in 1,4-dioxane (2.5 mL) dropwise at room temperature. After being stirred at the same temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended with ethyl acetate and filtered to give the product (37 mg, 85%). 1HNMR (DMSO-d6) 400 MHz δ: 8.72-8.62 (m, 3H), 8.11 (dd, J=4.6, 1.8 Hz, 1H), 7.96 (dd, J=7.8, 1.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.52-7.47 (m, 2H), 7.42-7.25 (m, 7H), 7.17-7.11 (m, 1H), 6.88 (dd, J=8.0, 1.8 Hz, 1H), 6.74 (dd, J=8.0, 4.6 Hz, 1H), 1.63 (s, 6H). LCMS: 444 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C@H:6]([C:19]([O:21]C)=[O:20])[N:7]2[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15].[OH-].[Li+]>O1CCCC1.O>[C:19]([C@H:6]1[CH2:5][C@H:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]1[NH:13][C:14]([CH2:16][O:17][CH3:18])=[O:15])([OH:21])=[O:20]
Reactant: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(=O)NN1c2cc(Cl)cc(Cl)c2[C@@H](c2ccccc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-phenyl(methoxy)methylcarbonylamino-1,2,3,4-tetrahydroquinoline (Isomer B) (0.140 g, 0.331 mmol) (Example 44a) in a mixture of tetrahydrofuran (10 ml) and water (5 ml) was added aqueous lithium hydroxide (0.73 ml of a 0.5M solution, 0.364 mmol) and the resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed under vacuum and the residue was diluted with sodium bicarbonate solution (50 ml) then washed with diethyl ether (1×30 ml). The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×40 ml). The combined extracts were washed with saturated bring (1×40 ml), dried (MgSO4) and evaporated to give the crude product which was recrystallised from hot ethyl acetate/petroleum ether (bp 60°-80° ) to give the title compound as colourless crystals (0.070 g), m.p. 238°-239° C. δ (360 MHz, DMSO) 1.63 (1H, ddd, J=13.2, 12.6 and 4.0 Hz, CHACHBHCCHD), 2.07 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.28 (3H, s, NHCOCH(OCH3)Ph), 3.83 (1H, dd, J=12.6 and 2.6 Hz, CHACHBHCCHD), 4.67 (1H, s, NHCOCH(OCH3)Ph), 5.04 (1H, m, CHACHBHCCHDNHCO), 6.66 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.77 (1H, s, ArNH), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.26-7.40 (5H, m, ArH), 8.49 (1H, d, J=7.4 Hz, CHDNHCO); m/e(CI+) 409 (M+H), 166 (100%); Found C, 55.77; H, 4.57; N, 6.64; C19H18Cl2N2O4 requires C, 55.76; H, 4.43; N, 6.85%.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][CH:16]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:17]>C(O)C>[CH3:17][CH:16]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CC(C)Oc1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OC(C)C)[nH]c1=O
Reaction time: 17 h
Yield: 38.3 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (15 g) and 2-(1-methylethoxy)aniline (11.5 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(1-methylethoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (8.5 g). M.p. 205°-207° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CN(C)C=O>[Si:17]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1c2ccccc2Oc2ccccc21

Procedure:
5 Grams of phenoxazine was dissolved in 100 ml of dry tetrahydrofuran, then 1.63 g of 50% sodium hydride in mineral oil was added and the mixture refluxed for 30 minutes. Then 6.19 g of t-butyldimethylsilyl chloride in dimethylformamide (2 ml) and tetrahydrofuran (8 ml) was added and reflux was continued for five more minutes. The reaction was quenched by the addition of water, the organic layer was separated and dried over sodium sulfate. Then the solvent was removed under reduced pressure and the residue purified by column chromatography (silica as solid phase, hexane:ethylacetate (95:5) as mobile phase). N-t-butyldimethylsilylphenoxane had a melting point of 57° C. after crystallization from pentane.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[C:16]1([O:22][C:23](=O)[O:24]C2C=CC=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:23]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 2 g, 9.60 mmol) and diphenylcarbonate (4.11 g, 19.21 mmol) in THF (40 ml) at −15° C. was treated with LHMDS (1M in THF, 13.3 ml, 13.3 mmol) over 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 25:75) to give the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.65 (d, 1H), 7.46-7.38 (m, 2H), 7.27-7.18 (m, 4H), 5.17 (s, 1H), 3.87-3.80 (m, 2H), 3.26 (s, 6H), 2.83 (t, 2H), 2.00-1.92 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(OC[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 213 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and (2R)-2-[(4-chlorophenoxy)methyl]oxirane using conditions outlined in procedure Y. M.p.=111-112° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.96 (brs, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.73 (d, J=8 Hz, 2H), 7.53 (t, J=7.2 Hz, 2H), 7.47 (m 1H), 7.28 (m, 2H), 6.92 (m, 2H), 4.88 (brs, 1H), 3.95 (brm, 2H), 3.84 (t, 8.8 Hz, 1H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H); LCMS: 562 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([CH3:17])[CH3:16]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 0.83 h
Yield: 70 %

Procedure:
A 300 ml glass-made three-neck flask was charged with 0.134 mol of p-vinylphenol, 0.343 mol of imidazole and 90 ml of dimethylformamide as a solvent, and a solution prepared by dissolving 0.174 mol of triisopropylsilyl chloride in 90 ml of dimethylformamide was dropwise added thereto at 0° C. in 50 minutes. Then, the reaction temperature was elevated up to room temperature to carry out reaction for 10 hours in the same condition. Water was added thereto, and the reaction product was extracted with chloroform. The solvent was distilled off, and the residue was dissolved in diethyl ether and washed with a sodium hydroxide aqueous solution and water. The product was dried on magnesium sulfate and filtered, and then it was further dried on a calcium hydride. Then, the reaction product was distilled at a reduced pressure under nitrogen flow to obtain aimed p-triisopropylsilyloxystyrene at a yield of 70%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1cccc(CN2CCOCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 500-mL 1-necked round-bottom flask was equipped with a magnetic stirring bar and rubber septum with a nitrogen inlet. The vessel was charged with the product of Example 6 (13.6 g), dichloromethane (100 mL) and triethylamine (8.43 mL). The reaction mixture was cooled to 0° C. in an ice bath, and a solution of methanesulfonyl chloride (6.93 g) in dichloromethane (10 mL) was added in drops over 30 min. The cooling was removed and the reaction mixture was allowed to warm up to room temperature. After 1 h when TLC indicated complete conversion, 50 mL ice water was added, and the reaction mixture was transferred to a 500-mL separatory funnel. The organic extract was separated and washed with aqueous NaHCO3, brine, and dried over MgSO4. After filtration, the solvents were evaporated under reduced pressure (rotary evaporator, 30° C.) to obtain the title compound as pale yellow gum (17.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:29])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:29])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol) is suspended in dichloromethane (36 L) and to this is added thionyl chloride (1345 g, 11.30 mol) dropwise over 20 minutes followed by dimethylformamide (74.4 g, 10.0 mmol). The reaction mixture is stirred at room temperature for 21 hours; after 6 hours a complete solution is obtained. The solution is concentrated in vacuo (50° C, 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid, which is then redissolved in dichloromethane (36 L) without further purification and cooled to 5° C. with an ice bath. Diisopropylamine (3077 g, 30.40 mmol) is added dropwise over a period of 1 hour. The reaction mixture is stirred at 20° C. for 3 hours and then, N,N-dimethylethylenediamine (80.3 g, 0.91 mmol) is added. The reaction is followed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no more byproduct (bis-anhydride of 4-[5-(4-cyanophenoxy)pentoxy]3-methoxybenzoic acid) is detected. The reaction mixture is then stirred overnight at room temperature. Water (18 L) is added,stirred and the layers separated. The organic layer is washed with hydrochloric acid (1.0 N, 23 L), water (18 L), ammonium hydroxide (0.5 N, 2×23 L), water (18 L) and brine solution (18 L). The separated dichloromethane solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide as a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warming and to the solution is added water (8.6 L). The product is allowed to crystallize overnight in an ice bath. The product is filtered, washed with EtOH/H2O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide, mp 90°-92° C. HPLC indicates a purity of >99.7%.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=C[S:10][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:8][C:7]1[C:6]([SH:10])=[C:5]([OH:11])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c2ncsc12
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1c(F)ccc(O)c1S
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-1,3-benzothiazol-7-ol (C14) (2.02 g, 11.93 mmol) in ethanol (20 mL) was treated with hydrazine monohydrate (12.7 mL, 167 mmol) and stirred for at 80° C. for 1 hour. The reaction was concentrated in vacuo and used directly in the following step.