Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[N:17]=[CH:16]2
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCCC[C@@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine (0.12 mmol) in dichloromethane (1.3 mL) at 0° C. was added DIEA (0.004 mL, 0.02 mmol) and acryloyl chloride (0.012 mL, 0.15 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)acrylamide (35 mg, 58%). MS (ES+) C25H26Cl2N4O3 requires: 500, found: 501.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:26])(=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.O>CN(C)C(=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:25])(=[O:26])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: CC(O)C(F)(F)F
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O)C(F)(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
(rac)-1,1,1-Trifluoro-2-propanol (Oakwood) (189.30 g, 1.66 mole) in N,N-dimethylacetamide (200 mL) was added to a stirred, ice-bath cooled mixture of hexanes washed sodium hydride (60% dispersion in mineral oil) (Aldrich) (66.40 g, 1.66 mole) and N,N-dimethylacetamide (1900 mL) under nitrogen. The reaction was stirred at ambient temperature (5-20° C.) for 0.5 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (277.78 g, 1.11 mole) in N,N-dimethylacetamide (1800 mL) was added at a bath temperature of 5-15° C. and stirred at ambient temperature for 1 hour. The reaction mixture was poured into water (8 L) and extracted with ethyl acetate (3 L, 2 L). The combined extracts were washed with water (4 L, 2 L), brine (0.5 L), dried over magnesium sulfate and filter. The volatiles were removed by spin evaporation in vacuo. The residue was stirred with hexanes (1 L) and collected by suction filtration to give 399.51 g of crude product. Recrystallization from 2-propanol (1.5 L) gave 304.62 g (79% yield) of (rac)-3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin 10,10-dioxide, m.p. 98-100 C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:44][CH2:45][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCN1CCOCC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol), (prepared as described for the starting material in Example 107), triphenylphosphine (235 mg, 0.89 mmol) and 4-(2-hydroxyethyl)morpholine (93 mg, 0.72 mmol) in methylene chloride (4 ml) cooled at 10° C. was added diethyl azodicarboxylate (140 μl, 0.89 mmol). After stirring at ambient temperature for 3 hours, the mixture was left overnight at 5° C. The mixture was poured onto a column of silica and eluted with methylene chloride followed by methanol/methylene chloride (2/98) followed by 3N ammonia methanol/methylene chloride (2/98). The fractions containing the expected products were combined and evaporated to give 4-(indol-5-yloxy)-6-methoxy-7-(2-morpholinoethoxy)quinazoline (137 mg, 55%).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10]N=[C:8]2[Cl:15])=[O:4].[CH3:16]C(C[AlH]CC(C)C)C>C1COCC1>[Cl:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=2)[N:11]=[CH:10][CH:16]=1
Reactant: COC(=O)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc2nccc(Cl)c2c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of methyl-4-chloroquinazoline-6-carboxylate (3.5 g, 0015 mol) in dry THF (35 mL) at −25° C. was added DIBAL-H (4.4 g, 0.031 mol) and stirred at −25° C. to RT for 2 h. The reaction mixture was cooled to −10° C. and quenched with 10% aqueous NaHCO3 (9 mL). The reaction mixture was extracted with ethylacetate (100 mL), washed with water, brine and dried. The solvent was removed under vacuum to give 4-chloroquinoline-6-yl methanol (2 g, 66%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH3:16].[OH2:18]>O1CCOCC1.C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:13]=[CH:14][C:4](/[CH:3]=[C:2](\[CH3:1])/[CH:17]=[O:18])=[C:5]([O:15][CH3:16])[CH:6]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(C=C(C)C)c(OC)c1
Reactant: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(/C=C(\C)C=O)c(OC)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 1.0 g (4.3 mmol) of ethyl 4-(2,2-dimethylvinyl)-3-methoxybenzoate, 1.24 g (11.2 mmol); of SeO2, and 0.2 mL of water in 15 mL of dioxane was heated in a 110° C. oil bath for 1.5 h. After cooling to room temperature, the reaction mixture was filtered through Celite (Et2O rinse) to remove excess SeO2. Concentration afforded an orange semisolid residue, which was dissolved in a small amount of toluene and chromatographed on 25 g of silica gel using 30% Et2O/hexane to afford a small amount of a yellow oil (Rf 0.64, Z-isomer) followed by 0.60 g of a yellow solid (Rf 0.56, E-isomer). This solid was rechromatographed on 20 g of silica gel (toluene) to remove colored byproducts (Rf 0.0, 0.38) and to isolate the aldehyde (Rf 0.18), which was submitted to evaporative distillation at 110°- 120° C. (0.005 mm) to afford 0.45 g (42% yield) of very pale yellow solid. The 1H NMR spectrum indicated none of the Z-isomer was present. A sample was purified by crystallization from EtOAc/hexane: white prisms, mp 59°-61° C.; IR (CHCl3) 2840, 1705, 1675, 1410, 1290, 1110, 1010 cm-1 ; 1H NMR (CDCl3) δ 1.42 (t, J=7 Hz, 3, CO2CH2CH3), 2.0 (d, J=0.5 Hz, 3, C=CCH3), 3.95 (s, 3, OCH3), 4.42 (q, J=7 Hz, 2 CO2CH2CH3), 7.3-7.85 (m, 4, C=CH, 3', 5', 6' H), 9.67 (s, 1, CHO); MS calcd for C14H16O4 248.1049, found 248.1058.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[C:50]1[C:54]([CH2:55]O)=[C:53]([CH:57]([CH3:59])[CH3:58])[O:52][N:51]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:55][C:54]2[C:50]([C:44]3[C:43]([Cl:42])=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:49])=[N:51][O:52][C:53]=2[CH:57]([CH3:59])[CH3:58])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3Cl)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3Cl)ccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
A mixture of methyl 6-(2-chloro-4-hydroxyphenyl)-1-naphthalenecarboxylate (0.25 g, 0.799 mmol), polymer-bound triphenylphosphine (0.27 g, 0.799 mmol), [3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (0.23 g, 0.799 mmol) and 10 mL of dichloromethane was cooled to 0° C. Diisopropyl azodicarboxylate (0.16 mL, 0.799 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred for 10 minutes at the above temperature and then warmed to room temperature and stirred for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give oil. The crude material was partially purified by flash chromatography over silica gel using 20% EtOAc in hexane to afford 0.36 g of the title compound. 1H NMR (DMSO-d6): 8.75 (d, J=9 Hz, 1H), 8.22 (d, J=8 Hz, 1H), 8.14 (d, J=7 Hz, 1H), 8.0 (s, 1H), 7.53-7.67 (m, 5H), 7.36 (d, J=8.6 Hz, 1H), 7.03-7.04 (m, 1H), 6.84-6.87 (m, 1H), 4.92 (s, 2H), 3.93 (s, 3H), 3.46 (m, 1H), 1.34 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])OC.O[C@H]1C[NH:17][C@H:16]([C:19](O)=O)[CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(N)(C)C>[Cu]I.CS(C)=O>[CH:16]([N:17]1[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:9]1=[O:12])([CH3:19])[CH3:15]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: COC(=O)Nc1ccncc1Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)N
Solvent: CS(C)=O
Product: CC(C)n1c(=O)[nH]c2ccncc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 142 %

Procedure:
A sealed tube was charged with methyl 3-bromopyridin-4-ylcarbamate (1.76 g, 7.6 mmol.), CuI (290 mg, 1.52 mmol.), trans-4-hydroxy-L-proline (400 mg, 3.04 mmol.) and K3PO4 (3.2 g, 15.2 mmol.), evacuated and backfilled with argon. Isopropylamine (674 mg, 11.4 mmol.) and DMSO (15 mL) were added successively. The reaction mixture was stirred at 70° C. for 12 h and then at 130° C. for 12 h. The reaction mixture filtered and the filtrate was concentrated and purified by prep-HPLC to afford 3-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (765 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C@@H:11]([OH:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)C(=O)N[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of cis-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one from Step B (17.1 g, 67.0 mmol) in THF (400 mL) at 0° C. was added NaH (60% dispersion in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate (8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), diluted with H2O (700 mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the alcohol as a mixture of four isomers. Additional purification was achieved by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH-90:10:0.1. The first major peak to elute was a mixture of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 5:1). The second major peak to elute was a mixture of ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 3:1). Further purification of the second major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH-90:10:0.1, to give ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second. Further purification of the first major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH-90:10:0.1, to give ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second, the title compound. MS: m/z=342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Yield: 24 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 24% yield as a white solid: mp 180-183° C.; 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=7.3 Hz, 1H), 8.22 (d, J=5.0 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.64-7.47 (m, 3H), 4.29 (m, 1H), 3.51 (dd, J=7.2, 2.1 Hz, 1H), 3.05 (m, 2H), 2.91 (m, 2H), 2.80 (dd, J=10.2, 4.0 Hz, 1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.78-1.60 (m, 3H); MS (APCI) m/z 382 [M+H]+
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[N:23]([CH2:26][CH2:27][CH3:28])=[C:24]=[O:25]>ClCCl>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([NH:15][C:24]([NH:23][CH2:26][CH2:27][CH3:28])=[O:25])[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cc(N)ccn2)CC1
Reactant: CCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccnc(N2CCN(CC)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
A mixture of 20.6 mg (0.1 mmol) 2-(4-ethyl-piperazin-1-yl)-pyridin-4-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml dichloromethane was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 7.2 mg (25%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH3:13][C:14]([CH3:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14](=[O:15])[CH3:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To the solution of 4-chlorobenzaldehyde (8.43 g, 60 mmol) in acetone(60 ml) and ethanol (6 ml) was added under stirring 10% NaOH aqueous solution(48 ml) and water(240 ml), the reaction solution was stirred at 25° C. for 8 hr. The precipitated solid was collected by filtration and washed with water, dried to give the title compound 10.5 g as a white solid, mp 56-57° C., yield: 96.9%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N:12]=[C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)[C:16](=[O:27])[C:15](=[C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[S:29]2)[S:14]1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N:12]=[C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[C:16](=[O:27])[C:15](=[C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[S:29]2)[S:14]1)[CH3:2]
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1cccc(O)c1
Temperature: -78 °C
Yield: 26.5 %

Procedure:
To a N2-purged flask was added the product of Example 114 (60 mg, 0.11 mmol) and anhydrous DCM (5 mL). The solution was cooled to −78° C. prior to the addition of a 1.0M solution of BBr3 in DCM (0.50 mL). The solution was allowed to warm to ambient temperature with stirring. After 7 h the solution was quenched by addition of MeOH (10 mL) and then concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (15 mg, 26%). 1H-NMR (CDCl3): δ 7.40 (1H, d), 7.35 (1H, t), 7.29 (1H, dd), 7.13-7.25 (3H, m), 6.95-7.01 (3H, m), 6.76 (1H, dd), 6.49 (1H, d), 5.08 (2H, s), 3.56 (3H, s), 3.02 (2H, q), 1.05 (3H, t); MS(ESI): 514 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: CC(C)Oc1cc(F)ccc1B(O)O
Product: CC(C)Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 5 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [4-fluoro-2-(propan-2-yloxy)phenyl]boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]3[C:23]4[N:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40]Cl)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[I-].[K+]>CC#N>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40][N:13]([C@H:10]1[CH2:9][CH2:8][C@@H:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: c1cnc2c(c1)CCCC2N[C@H]1CC[C@@H](N2CCOCC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)[C@H]1CC[C@@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
The above amine (69.0 mg, 0.22 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (70.0 mg, 0.26 mmol), N,N-diisopropylethylamine (50 μL, 0.28 mmol), and potassium iodide (3.7 mg, 0.02 mmol) in CH3CN (1.5 mL) were stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, NH4OH/MeOH/CH2Cl2, 1:1:98 then 1:2:97) afforded the desired compound (56.8 mg, 47%) as a pale yellow solid. 1H NMR (CDCl3) δ 1.30-1.34 (m, 2H), 1.45-1.66 (m, 11H), 1.88-2.01 (m, 4H), 2.05-2.16 (m, 4H), 2.40 (br m, 4H), 2.54 (t, 1H, J=4.4 Hz), 2.59 (t, 1H, J=3.9 Hz), 2.68-2.73 (m, 1H), 3.04-3.11 (m, 1H), 3.61-3.71 (m, 4H), 4.29 (dd, 1H, J=8.7, 5.7 Hz), 4.43 (s, 2H), 6.829 (dd, 1H, J=7.5, 4.8 Hz), 7.07 (d, 1H, J=6.9 Hz), 7.22-7.28 (m, 2H), 7.61-7.70 (m, 1H), 7.73-7.79 (m, 1H), 8.32 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:15][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:14])[CH3:1])/[N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)=CC(=O)NC(=S)N1CCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A mixture of 3-methyl-N-(pyrrolidine-1-carbonothioyl)but-2-enamide (230 mg, 1.08 mmol, Eq: 1.00), sodium carbonate (121 mg, 1.14 mmol, Eq: 1.05) and iodomethane (769 mg, 339 μl, 5.42 mmol, Eq: 5) in tetrahydrofuran (7 ml) was stirred for 18 hours at 70° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 50-100% as eluent affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (119 mg/48.5%) as a light yellow liquid. MS: m/e=227.1 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH2:20][OH:21])[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH:20]=[O:21])[C:15]#[N:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.3 g (1.03 mmol) of 3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxymethylbenzonitrile was dissolved in 3 ml of dichloromethane (dehydrated). 0.36 g (4.1 mmol) of activated manganese dioxide was added to the obtained solution in the presence of argon, and they were stirred at room temperature overnight. The reaction solution was filtered through Celite to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCCCCOC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCCCCN2CCNCC2)c2ccccc2)cc1
Yield: 93 %

Procedure:
Using 5-(dipenylmethoxy)pentyl chloride and piperazine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound.