Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC[C:4]1[C:12]2[C:7](=[CH:8]C=CC=2)[NH:6][CH:5]=1.C(Cl)Cl.C(Cl)(Cl)Cl.O1[CH2:24][CH2:23][CH2:22]C1>N1C=CC=CC=1.C(N(CC)CC)C.C(OCC)C>[CH:23]([N:6]([CH:7]([CH3:12])[CH3:8])[CH2:5][CH3:4])([CH3:24])[CH3:22]
Reactant: C1CCOC1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(C)C)C(C)C

Procedure:
As shown in reaction Scheme B, the 2-aryltryptamine may be condensed with a carboxylic acid of type (6) using the coupling reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide derivative (7). Alternatively, 2-aryltryptamine (5) can be treated with an active ester or acid chloride of type (8) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0°-25° C. for 30 minutes to 4 hours to give (7). ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:35]=[CH:36][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:28][CH:29]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(OC(F)(F)F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-(trifluoromethoxy)phenacyl bromide*.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1>C1C=CC=CC=1>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)O)c1

Procedure:
A stirred mixture of 0.907 g. of N-decyl-3-(3-aminophenyl)propenamide and 25 ml. of benzene was heated on a steam bath until a solution was obtained. To this solution was then added 0.358 g. of maleic anhydride in one portion. In about 30 seconds a solid precipitated. The mixture was allowed to cool and then the solid was recovered by filtration. The solid was recrystallized from acetic acid, to give 1.1 g. (92% yeild) of the title compound, melting point 187°-188° C. The IR spectrum (KBr disc) showed absorptions at 3279, 2899, 1724, 1653, 1626, 1587 and 1563 cm-1. The NMR spectrum (in DMSO-d6) showed absorptions at 0.91 (m, 3H), 1.24 (s, 16H), 3.18 (m, 2H), 6.50 (m, 4H), 7.42 (m, 4H), 8.11 (m, 2H) and 10.50 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:35])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[N:4][C:5]([Br:35])=[CH:6][N:7]=1
Reactant: Nc1nccnc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-4-(3-aminopyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (389 mg, 1.006 mmol) in acetonitrile (21 mL) was added NBS (171 mg, 0.961 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. After quenched with sat NaHCO3, and stir for 30 min. The reaction mixture was extracted with EtOAc 3 times, the organic was washed by sat NaHCO3, water and brine, dried, filtered off, and concentrated. The crude material was taken to the next step without further purification. LCMS (m/z): 367 (MH+), 0.88 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) was dissolved in ethanol (30 ml), and to the solution, sodium borohydride (0.08 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 1) (0.26 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:56][Si:57]([CH:60](O)[CH3:61])([CH3:59])[CH3:58]>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:61][CH2:60][Si:57]([CH3:59])([CH3:58])[CH3:56])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(O)[Si](C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (222 mg, 0.66 mmol), PPh3 (260 mg, 0.996 mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) at 0° C. was added a solution of trimethylsilyl ethanol (142 μL, 0.996 mmol) in THF (3 mL). The resulting yellow solution was allowed to warm up to room temperature and stirred overnight. The reaction was worked up by concentrating the solution to dryness and addition of ether and hexanes. Triphenylphosphine oxide was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to provide 248 mg of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[C:14](=[C:16]([CH3:28])[C:17]3[N:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[S:20][C:21]=3[CH:22]=2)[N:15]=1)=[O:9]>O1CCOCC1>[CH2:1]([N:3]([N:23]([C:24](=[O:27])[CH3:25])[C:19]1[S:20][C:21]2[C:17](=[C:16]([CH3:28])[C:14]3[N:15]=[C:11]([N:10]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8](=[O:9])[CH3:7])[S:12][C:13]=3[CH:22]=2)[N:18]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1c2nc(NC(=O)CCl)sc2cc2sc(NC(=O)CCl)nc12
Reactant: CCNCC
Solvent: C1COCCO1
Product: CCN(CC)N(C(C)=O)c1nc2c(C)c3nc(N(C(C)=O)N(CC)CC)sc3cc2s1
Reaction time: 3 h

Procedure:
20 gm of diethylamine were added to 11.5 gm of 2,6-bis-(chloroacetyl-amino)-4-methyl-benzo[1,2-d:5,4-d']bisthiazole in 80 ml of dioxane and the mixture was boiled for 3 hours. Then it was evaporated to dryness in vacuo, and the residue (12 gm) was chromatographed on a dry 300 gm-silicagel column with benzene/chloroform (1:1) as the mobile phase. The title compound was obtained first; 9.0 gm (66% of theory), melting point 191°-192° C., were obtained after recrystallization from alcohol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:43]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:43])[NH2:2]
Reactant: O
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (1-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C8, 173 mg) in ethanol (4 mL) and dimethyl sulfoxide (2 mL), 2.0 mol/L aqueous sodium hydroxide (0.45 mL) and 35% aqueous hydrogen peroxide (87 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water (15 mL) was added. The solid matter was taken by filtration, washed successively with water and ethyl acetate, and then dried under reduced pressure to obtain (S)-tert-butyl (1-((3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C7, 102 mg) as white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11](=[O:27])[C:10]=2[CH:28]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CC(O)=O>[CH2:30]([N:16]1[CH2:17][CH2:18][C:13]2([N:12]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:19]2)[CH2:14][CH2:15]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCNCC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(Cc3ccccc3)CC1)O2
Yield: 95 %

Procedure:
(E)-3-{1′-Benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester was obtained by reacting (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (485 mg, 1.13 mmol, Intermediate 6) with benzyl bromide, according to the procedure described in Example 2, Step A, giving a white solid (544 mg, quantitative). The methyl ester (500 mg, 1.03 mmol) was hydrolyzed with HCl 20% and AcOH following the procedure described Example 55, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid as a white solid (500 mg, 95%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (228 mg, 40%). Finally, removal of the THP protecting group (177 mg, 0.312 mmol) following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide (150 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:24])=[O:25])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(C=CS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1c(C(=O)c2cccc(CCS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Reaction time: 96 h
Yield: 45 %

Procedure:
A mixture of 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)-pyrazole (2.1 g, 5.43 mmol) and palladium hydroxide (0.6 g) in methanol (150 ml) was shaken in a Parr apparatus under hydrogen atmosphere at 50 psi. After 4 days, the reaction mixture was filtered through Celite® and the filtrate was concentrated. The residue was purified by flash chromatography (elution gradient: 40-100% ethyl acetate/hexane) to give a crude product which was recrystallized from methanol/ethyl acetate/hexane to give 5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.95 g, mpt. 170-170.4° C.) as a solid.
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:11]([C:9]1[S:8]/[C:7](=[N:15]\[C:22](=[O:23])[C:21]2[CH:25]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[F:26])/[N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc(Cl)ccc1F
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: I
Solvent: c1ccncc1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A mixture of 5-tert-butyl-3-butylthiazol-2(3H)-imine (free base of Example 6A, 500 mg, 2.4 mmol), 5-chloro-2-fluorobenzoic acid (670 mg, 2.8 mmol), EDCI (900 mg, 4.7 mmol), HOBt (635 mg, 4.7 mmol) and DMAP (36 mg, 0.3 mmol) in pyridine (20 mL) was stirred at room temperature for 2 hours. The solvent was removed, the mixture was diluted with water, and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was triturated with EtOAc, to give 537 mg (61%) of the title compound. MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([OH:12])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:38]1([CH2:44][C:45]2[CH:46]=[C:47]([CH:53]=[CH:54][CH:55]=2)[O:48][CH2:49][CH2:50][CH2:51][NH2:52])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[N:38]1([CH2:44][C:45]2[CH:46]=[C:47]([CH:53]=[CH:54][CH:55]=2)[O:48][CH2:49][CH2:50][CH2:51][NH:52][C:10](=[O:12])[CH2:9][S:8][CH2:7][CH2:6][NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COC(=O)NCCSCC(=O)O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
There was dissolved 2.07 g (0.011 mol) of 2-[2-(methoxycarbonylamino)ethylthio]acetic acid in 50 ml of dichloromethane and added 1.68 g (0.011 mol) of HOBt and 2.27 g (0.011 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 2.7 g (0.011 mol) of 3-[3-(piperidinomethyl)phenoxy]propylamine and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 3.69 g of the titled compound as oily matter.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12](F)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[NH2:8])[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:18])([F:20])[F:19])[NH2:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(N)ccc1C(F)(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)Cc1cc(N)ccc1C(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
3-Isobutyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (874 mg, 3 mmol) was dissolved in dimethylsulfoxide (20 ml), followed by portion-wise adding sodium borohydride (340 g, 9 mmol) and stirring at 60° C. for 3 hours. The reaction solution was added with small amount of ice sequentially, followed by dropwise addition of acetic acid. The reaction solution was diluted with ethyl acetate, and washed four times with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain 830 mg of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (73 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (133 mg) and tributylphosphine (130 μL), and the mixture was stirred at room temperature for 60 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (144 mg) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:16]([S:17]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:19])=[O:18])=[CH2:15]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CS(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (683 mg, 6.75 mmol) is added to a solution of piperidine (274 mg, 3.22 mmol) and 2-chloroethanesulfonyl chloride (500 mg, 3.07 mmol) in dichloromethane (8 mL). The reaction is stirred for 2 h at room temperature. The reaction is diluted with ethyl acetate, sat. sodium bicarbonate solution is added. The organic layer is washed with brine and dried with MgSO4. The solvents is removed under vacuum to afford crude 1-(vinylsulfonyl)piperidine which is used directly in the next step without further purification. HPLC-MS calculated for C7H14NO2S (M+H+) 176.0, found 176.0.
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[O:11][C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2ccccc2c1
Solvent: CCO
Product: Nc1ccncc1Oc1ccc2ccccc2c1
Reaction time: 20 h
Yield: 98.4 %

Procedure:
A suspension of 3-(2-naphthyloxy)-4-nitropyridine-N-oxide (8.5 g) in 250 ml ethanol containing 0.5 g platinum oxide was hydrogenated for 20 hours at 60 psi and thereafter filtered through Celite. The filtrate liquid was concentrated to 8.3 g oil. This oil was purified by flash chromatography (silica, ethyl acetate) to give a solid (7 g). This solid was recrystallized from anhydrous ether to give crystals, 4.6 g, mp 117°-118° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][CH2:12][CH3:13])[N:6]([CH3:7])[S:5](=[O:9])(=[O:8])[NH:4][C:3]1=[O:10].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:14]1([S:20][CH2:21][N:4]2[C:3](=[O:10])[C:2]([CH3:1])([CH2:11][CH2:12][CH3:13])[N:6]([CH3:7])[S:5]2(=[O:9])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCSc1ccccc1
Reactant: CCCC1(C)C(=O)NS(=O)(=O)N1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC1(C)C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 75 °C
Yield: 17.7 %

Procedure:
A mixture of 4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.44 g, 28.31 mmol), phenylthiomethyl chloride (5.39 g, 33.97 mmol) and tetrabutylammonium bromide (0. 912 g, 2.83 mmol) suspended in DMF (120 ml) was heated at 75° C. for 23 hours, cooled, and poured into 250 ml of ice/water. The mixture was extracted with ethyl acetate (3×150 ml), and the organic layer was washed with water and brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography (silica gel; 10% ethyl acetate in hexane) to afford 1.65 g (17.7%) of 2-phenylthiomethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =propyl; R2 =CH3 ; R3 =CH3).