Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[C:8]([CH:20]([C:22]2[CH:27]=[C:26]([S:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:30])[OH:21])=[CH:7][N:6]=1>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[C:8]([C:20]([C:22]2[CH:27]=[C:26]([S:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:30])=[O:21])=[CH:7][N:6]=1
Reactant: CSc1ccc(C)c(C(O)c2cnc(Oc3ccc(F)cc3F)nc2Oc2ccc(F)cc2F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CSc1ccc(C)c(C(=O)c2cnc(Oc3ccc(F)cc3F)nc2Oc2ccc(F)cc2F)c1
Yield: 84.8 %

Procedure:
[2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-(2-methyl-5-methylsulfanyl-phenyl)-methanol (2.15 g, 4.281 mmol) was dissolved in 40 mL methylene chloride together with 10.0 g of MnO2, and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from methylene chloride/hexanes to yield 1.816 g of [2,4-Bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-(2-methyl-5-methylsulfanyl-phenyl)-methanone, MS (M+H)=501.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14](=[O:15])[NH:13][C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].CI>C(#N)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:14](=[O:15])[N:13]([CH3:22])[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[O:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[O:4]
Reactant: COC(=O)c1c(OC(=O)C(C)C)c2nccnc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(OC(=O)C(C)C)c2nccnc2n(C)c1=O
Temperature: 100 °C
Yield: 94.5 %

Procedure:
To a suspension of 8-isobutyryloxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (0.422 g) (Example 7.2) in acetonitrile (12 ml) was added potassium carbonate (0.401 g) followed by methyl iodide (0.30 ml). The reaction mixture was heated to 100° C. for 10 minutes in a microwave, and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and water. The phases were separated. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:2 to 1:1) to give 8-isobutyryloxy-5-methyl-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as an orange oil (0.418 g). 1H-NMR (400 MHz, CDCl3): 1.36 (d, 6H), 2.95 (sept, 1H), 3.79 (s, 3H), 3.94 (s, 3H), 8.49 (d, 1H), 8.59 (d, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[C:11]1([CH2:17][CH2:18][CH2:19][NH:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:24](/[S:21]([NH:20][CH2:19][CH2:18][CH2:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:23])=[O:22])\[C:25]#[N:26])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)NCCCc1ccccc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and (3-phenyl-n-propyl)aminosulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[(3-phenyl-n-propyl)aminosulfonyl]acrylonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:45][C:46]([NH2:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([NH:49][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[CH:23][CH:24]=1)([CH3:48])([CH3:47])[CH3:45]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.11 mmol) of the compound from Example 28A was introduced in 1 ml of DMF and admixed with 18 mg (0.14 mmol) of HOBt and with 28 mg (0.15 mmol) of EDC. After 10 minutes of stirring at RT, 13 μl (0.12 mmol) of 2-methylpropan-2-amine were added and the mixture was stirred at room temperature for 16 h. Subsequently the reaction solution was admixed with about 3 ml of water and extracted with twice 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography [Method 8]. This gave 31 mg (55% of theory) of the target compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:21])([CH2:12][CH2:13][O:14]C1CCCCO1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([NH:8][C:9]([CH3:21])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(CO)(CCO)NCc1ccccc1

Procedure:
The crude 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (12D, 80.1 g, 0.273 mol) was dissolved in 3N NCl (128 mL). After 5 min the mixture was washed with Et2O (200 mL). The aqueous solution was concentrated by rotary evaporation to give a thick oil which was cooled and basified with excess 50% NaOH. The oily amine which formed was extracted with Et2O (3×200 mL). The Et2O extracts were combined and concentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g (94%) of 2-benzylamino-2-methyl-1,4-butanediol as a pale yellow oil (bp 168°-170°/0.35 mm) (C,H,N).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[O-]S([O-])(=O)=O.[Mg+2]>C1CCCCC1>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCCCC1
Product: C1CCC(N2CCCC2)CC1
Yield: 91 %

Procedure:
Cyclohexylpyrrolidine was prepared as described in the procedure below. In a 3-neck reaction flask equipped with a mechanical stirrer and heating mantle, a 2 molar equivalent of pyrrolidine were mixed with 1 molar equivalent of cyclohexanone in dry cyclohexane to make a 1M solution with respect to the cyclohexanone. To the mixture, 2 molar equivalents of anhydrous MgSO4 (as dehydrating agent) were added. The resulting mixture was refluxed for 94 hours. The progress of the reaction was monitored by NMR analysis.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
43 g of carbon tetrabromide was dissolved in 100 ml of dichloromethane, and then 69 g of triphenylphosphine was added to the solution while cooling in an ice bath, followed by stirring at 0° C. for ten minutes. Then, to the resulting solution, a solution of 7.0 g of 4-benzyloxybenzaldehyde dissolved in 100 ml of dichloromethane was added dropwise, followed by stirring at 0° C. for further twenty minutes. 30 ml of a saturated sodium bicarbonate aqueous solution was added slowly to the reaction solution, followed by adding 100 ml of water. The reaction solution was extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ether was added to the residue, and insoluble substance was removed by filtration and the filtrate was evaporated. The residue was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:20) was collected, to afford 6.4 g of the titled compound(a) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:36][CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([C:9]3[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[N:10]=3)[C:5]([F:8])=[N:6][CH:7]=2)[CH2:39][CH2:40]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3F)n2)cc1
Temperature: 130 °C
Yield: 54.1 %

Procedure:
A mixture of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.0 g, 4.17 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific) (1.051 g, 5.00 mmol), Pd2(dba)3 (0.191 g, 0.208 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.199 g, 0.417 mmol) and 2 N Na2CO3 (5.21 mL, 10.42 mmol) in 10 mL of dioxane was heated in a microwave at 130° C. for 30 min. The reaction mixture was partitioned between 10 mL of 0.5 N NaOH and 50 mL of EtOAc. The organic layer was separated and washed with brine, dried and concentrated. The residue was purified on a silica gel column and eluted with 25 to 75% EtOAc in hexanes to give the title compound (1.19 g, 54% yield) as an off white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51-8.47 (m, 2H), 7.24 (t, J=9.2 Hz, 4H), 6.90 (m, 4H), 6.38 (m, 1H), 4.78 (s, 2H), 4.76 (s, 2H), 4.24 (d, J=2.7 Hz, 2H), 3.84 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.51 (m, 2H), 2.47 (s, 3H). m/z (ESI, positive ion) 528.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1)(=[O:34])=[O:33])[CH:26]=[CH:25]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([S:32]([C:27]4[CH:26]=[CH:25][C:24]5[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=5)[CH:28]=4)(=[O:34])=[O:33])[CH2:36][CH:37]3[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:19])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)O)sc2CN1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (30 ml), 6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (WO94/21599) (742 mg), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-ethoxycarbonylpiperazine hydrochloride (WO96/10022) (1.00 g) and benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP®) (1.50 g) were dissolved. Triethylamine (0.40 ml) was added to the resulting solution, followed by stirring overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated aqueous NaCl solution and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane ethyl acetate=4:1), whereby the title compound (505 mg, 30%) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:30][C:31]=1[C:38]([F:41])([F:40])[F:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 100.2 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(4-nitro-3-(trifluoromethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide (1.37 g, 2.31 mmol) and 10% Pd/C (catalytic) in MeOH (23 mL) was stirred under a hydrogen atmosphere (10 psi) for 1 h. The reaction mixture was filtered through celite, evaporated, and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.3 g, quant.) as a white solid. LCMS (m/z, ES+)=562.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 131 (2.8 g, 6.2 mmol), DMAP (150 mg, 1.2 mmol), triethylamine (930 g, 9.2 mol) and tert-butylchlorodimethylsilane (1.1 g, 7.5 mmol) in dichloromethane (40 mL) was stirred for 12 hours at room temperature, then quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (2×40 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by a silica gel column, eluted with 1%-3% methanol in dichloromethane to afford 132 as a white solid (2.6 g, 75%). (ES, m/z) [M+H]+ 569.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.38 (m, 5H), 6.13 (d, J=6.3 Hz, 1H), 4.49 (s, 2H), 4.34-4.36 (m, 1H), 4.06-4.08 (m, 1H), 3.83-390 (m, 1H), 3.59-3.67 (m, 2H), 3.30-3.55 (m, 5H), 1.58 (s, 9H), 0.98 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([NH:28][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)N
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled solution of picolinic acid (3.6 g, 29.2 mmole, Aldrich) and triethylamine (8 mL, 57.4 mmole) in 80 mL of methylene chloride at 0° C. was added pivaloyl chloride (3.8 mL, 30.8 mmole). The mixture was stirred for 1 hour at 0° C., t-butylamine (4.0 mL, 38.1 mmole) was added, and stirring was continued for 1 hour at 0° C. and 1 hour at room temperature. Saturated NaHCO3 (30 mL) was added, the layers were separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic solutions were dried and concentrated, and the residue was chromatographed in silica gel, eluting with 30 to 60% ethyl acetate in hexane, to provide 5.2 g of the title compound as an oil. MS: 179 (M+H)+ ; 1H NMR (CDCl3) δ: 8.52 (m, (1H), 8.18 (dm, J=7.5 Hz, 1H), 8.0 (s, br, 1H), 7.84 (dt, J=7.5, 1.5 Hz, 1H), 7.40 (ddd, J=7.5, 5.0, 1.5 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17](=[O:18])[NH2:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NCCC(N)=O
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NCCC(N)=O)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
In 10 ml of DMF, 1.0 g (4.9 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then 668 mg (5.37 mmol) of β-alanineamide hydrochloride and 1.09 g (10.7 mmol) of triethylamine were added thereto under ice cooling. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.05 g (yield: 79.8%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (0.15 g, 0.75 mmol) and 3-(trifluoromethyl)benzaldehyde (0.12 mL, 0.156 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.24 g, 1.12 mmol) and a few drops of acetic acid, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloroethane and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and chromatographed on silica gel, eluting with 30% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.45 (m, 3H), 4.41 (m, 1H), 3.50 (m, 2H), 3.50 (m, 1H), 2.77 (d, J=12.21 Hz, 2H), 2.11 (t, J=11.70 Hz, 2H), 1.91 (d, J=11.53 Hz, 2H), 1.41 (s, 9H), 1.34 (m, 2H); MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([OH:24])([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO>[CH2:20]([C:19]([C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][C:9]([OH:8])=[CH:18]2)=[CH:13][CH:14]=1)([OH:24])[CH2:22][CH3:23])[CH3:21]
Reactant: [H][H]
Reactant: CCC(O)(CC)c1ccc2ccc(OCc3ccccc3)cc2c1
Solvent: CCO
Product: CCC(O)(CC)c1ccc2ccc(O)cc2c1
Yield: 93.9 %

Procedure:
Treat a mixture of 3-(7-benzyloxynaphthalen-2-yl)pentan-3-ol (1.45 g, 4.53 mmol) and 5% Pd/Al2CO3 (0.044 g) in EtOH (725 mL) with hydrogen at 60 psi for 8 h at RT. Remove the catalyst by filtration and concentrate the filtrate to give the title compound as a yellow oil (0.98 g, 94%). MS (ES) m/e 229 (M−1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[C:12]([F:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[C:12]([F:29])=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 98.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.050 g, 0.09 mmol) prepared in Example 40a, triethylsilane (0.07 mL), trifluoroacetic acid (0.09 mL) and dichloromethane (0.9 mL), to yield the title compound (0.040 g, 86%) as a colorless solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1>C(O)C>[C:1]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)#[N:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 65 °C

Procedure:
In a 500 μl 4-opening flask equipped with a stirring bar, 49.01 g of sodium cyanide was mixed with 70.07 g of water and 50.96 g of ethanol. Then, the temperature of the flask was elevated to 60° C. and the sodium cyanide was completely dissolved. To said solution, 87.50 g of 4-chloromethylstyrene was slowly added and it was reacted for 3 hours while stirring and maintaining the reaction temperature within 60-70° C. When the reaction terminated, said solution was cooled to 40° C., and 100 g of diethylether was added and the diethylether layer was separated. The separated organic layer was extracted with 300 g of water three times, and the water layer was extracted with 50 g of diethylether and was combined with said organic layer. The separated obtained organic layer was dried with magnesium sulfate for one day, and then the organic solvent was removed using an evaporator to obtain the product 4-cyanomethylstyrene. The yield of the product was 80%, and the product was a deep purple color.