Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[N:25]=[C:21]([CH3:20])[S:22][CH:23]=4)[CH:27]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 424.03 g/mol.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:13]=[CH:12]2)C1C=CC=CC=1.C1CCCCC=1.Cl>CCO.[Pd]>[CH3:19][O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:10][C:9]=1[OH:8]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Temperature: 150 °C
Yield: 97 %

Procedure:
To a suspension of 5-(benzyloxy)-6-methoxy-1-(phenylsulfonyl)-1H-indole (Intermediate 14, 6.6 g, 17 mmol) and Pd/C 10 wt. % (2.0 g, 1.9 mmol) in EtOH (30 mL) were cyclohexene (9 mL) and conc. HCl (9 mL) added. The reaction mixture was heated at 150° C. for 5 minutes in a microwave heater. The Pd/C was filtered off and the solvent was removed under reduced pressure to afford the title compound (5.0 g) as a black gum. MS m/z 304 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)=[C:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:19])[C:7]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[S:4][C:5]([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:19])[C:7]=12
Reactant: CSc1sc(-c2cc[nH]n2)c2c1C(=O)N(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(-c2cc[nH]n2)c2c1C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 3-(methylsulfanyl)-4-oxo-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridine-5(4H)-carboxylate (20 mg, 0.055 mmol) in CH2Cl2 (274 μL) at 0° C. was added TFA (274 μL). The solution was stirred at 0° C. for 15 min. The resulting mixture was quenched with saturated aq. NaHCO3 and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-10% MeOH/dichloromethane) afforded the title compound. 1H NMR (400 MHz, ppm, CDCl3) δ 11.66 (s, 1 H); 8.05 (s, 1 H); 7.77 (d, J=2.6 Hz, 1 H); 6.53 (d, J=2.6 Hz, 1 H); 3.58 (t, J=6.5 Hz, 2 H); 3.07 (t, J=6.5 Hz, 2 H); 2.64 (s, 3 H). HRMS (ES+) m/z 266.0414 [(M+H)+; calcd for C11H11N3OS2: 266.0416].
Reaction SMILES: C1C2C3C(=CC=CC=3)C(C=O)=CC=2SC=1.[CH:16]([C:18]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:21]2[S:22][C:23](C(OC)=O)=[CH:24][C:20]=2[CH:19]=1)=[O:17]>C(Cl)Cl.CCCCCC>[S:22]1[CH:23]=[CH:24][C:20]2[CH:19]=[C:18]([CH:16]=[O:17])[C:34]3[C:29]([C:21]1=2)=[CH:30][CH:31]=[CH:32][CH:33]=3
Reactant: COC(=O)c1cc2cc(C=O)c3ccccc3c2s1
Agent: O=Cc1cc2sccc2c2ccccc12
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc2ccsc2c2ccccc12
Yield: 61.9 %

Procedure:
Using the procedure outlined in 7B, methyl naphtho[1,2-b]-thiophene-2-carboxylate (10A) gave a 61.9% yield of naptho[1,2-b]thiophene-5-carbaldehyde, mp 96°-96.5°, (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: [CH2:1]1[N:16]2[C:17]3[C:8]([S:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:18])[CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:2]2[C:3](=[O:18])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:17]=3[N:16]([CH:1]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:9]4)[CH:20]=1
Reactant: O=C1CCN2c3ccccc3Sc3cccc1c32
Reactant: O=Cc1cccnc1
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Sc1ccccc1-2
Yield: 83 %

Procedure:
According to Example 1<step 4>, 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazin-3-one (20 mg) prepared by the procedure described in literature( J. Heterocycl. Chem., 29, 675 (1992)) was reacted with pyridine-3-aldehyde (12 μl) to obtain the title compound (17 mg; 83%). The chemical structure thereof is shown below.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](CO)[CH:6]=[CH:5][N:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([Cl:12])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc(CO)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a magnetically stirred solution of 9 grams (66 mm) of 2-cyano-4-hydroxymethylpyridine [Swan, et al. J. Chem. Soc., 3440 (1963)] contained in 300 mls of benzene is added 15.1 grams (72 mm) of phosphorous pentachloride. After stirring for 1/2 hour, ice and water are added followed by sodium bicarbonate. The organic layer is washed with water and evaporated. The residual oil is crystallized from petroleum ether, to yield 8.5 grams (83%) of 2-cyano-4-pyridyl chloride, m.p. -55°-56°.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:18]1[C:23]([C:24]#[N:25])=[N:22][CH:21]=[CH:20][N:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][C:5]([NH:8][C:20]2[N:19]=[CH:18][C:23]([C:24]#[N:25])=[N:22][CH:21]=2)=[N:6][CH:7]=1
Reactant: N#Cc1nccnc1Br
Reactant: CN1CCC(Nc2cc(N)ncc2Br)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CN1CCC(Nc2cc(Nc3cnc(C#N)cn3)ncc2Br)CC1
Temperature: 90 °C
Yield: 7.4 %

Procedure:
A solution of 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.020 g, 0.070 mmol), 2-bromo-cyanopyrazine (0.013 g, 0.070 mmol), BINAP (0.002 g, 0.005 mmol), sodium tert-butoxide (0.009 g, 0.098 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.003 g, 0.003 mmol) in dioxane (0.5 mL was stirred at r.t. under nitrogen for 10 min before being heated for 6 h at 90° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol/dichloromethane (1/9) to give the title compound as a yellow solid (0.002 g, 7%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[C:33](=[O:38])[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O>C1COCC1>[OH:38][C:33]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:32]2[C:39]([CH3:40])=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]=2[O:35][C:34]1([CH3:37])[CH3:36]
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
n-Butyllithium (hexane solution 1.50 M, 3.40 mL, 5.10 mmol) was added dropwise to solution of 4-bromotoluene (1.10 g, 6.43 mmol) in THF (10 ml) under a stream of argon at −70° C. or less and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (1.00 g, 2.5 mmol) obtained in Reference Example 13 in THF (3 ml) at −70° C. or less and the mixture was allowed to warm to 0° C. After stirring under ice cooling for 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 1.11 g (yield 90%) of the title compound via recrystallization (ethyl acetate-hexane). mp. 145–147° C.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5])C.[NH:15]([C:17]1[N:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[NH2:16].O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]([C:17]2[N:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:16]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1ccccc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 51 %

Procedure:
N-(1-ethoxy-ethylidene)-benzamide 400 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-(3-methyl-5-phenyl-[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide (336 mg, yield: 51%) was obtained as a solid phase.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17]>>[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:16](=[O:17])[CH2:15][C:14]([CH3:20])([CH3:19])[CH3:13])[CH2:11][CH2:12][O:1][CH2:2][CH2:3]1)=[O:17]
Reactant: C1COCCNCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCN(C(=O)CC(C)(C)C)CCOCC1

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)(=[O:29])=[O:28])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: C1COCCN1
Reactant: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(=O)(=O)CCN3CCOCC3)CC2)nc(N2CCOCC2)n1
Yield: 81 %

Procedure:
Reaction of 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole (Example 50) with morpholine as in Example 11 gave 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole in 81% yield. Hydrochloride: mp (MeOH) 255-259° C.; 1H NMR (DMSO-d6) δ10.87 (br s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.72 (t, JHF=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 5.30-5.25 (m, 1H), 4.06-3.95 (m, 2H), 3.98 (s, 3H), 3.86-3.84 (m, 4H), 3.74-3.71 (m, 8H), 3.53-3.49 (m, 6H), 3.37-3.27 (m, 2H), 3.15 (m, 2H), 2.16-2.15 (m, 2H), 2.19-1.87 (m, 2H); Anal. Calcd. for C27H37ClF2N8O6S.0.1H2O: C, 47.9; H, 5.5; N, 16.6; Cl, 5.2. Found: C, 47.9; H, 5.6; N, 16.6; Cl, 5.5%.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(=O)(O)O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[CH:17][CH:16]=1.CN(C)C=O>C(OCC)C>[CH3:5][C:3]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[N:24]=[C:1]([OH:7])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: O=C(O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A mixture solution of ethyl acetoacetate(3.8 ml, 30.3 mmol), 4-fluorophenylguanidine carbonate(5 g, 26.3 mmol), and dimethylformamide(5 ml) was refluxed for 2 hours and cooled to a room temperature. Ethyl ether was added to the reaction mixture and the resulting solid was filtered, washed with ethyl ether, and concentrated under a reduced pressure to give 1.74 g of the titled compound. (Yield 30%)
Reaction SMILES: CN1CCOCC1.[C:8]([S:16][CH2:17][CH2:18][C:19]([N:21]1[C@H:25]([C:26](O)=[O:27])[CH2:24][S:23][C@@H:22]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(=O)OCC(C)C.Cl.[NH2:45][OH:46].[OH-].[Na+]>CO.O1CCCC1>[C:8]([S:16][CH2:17][CH2:18][C:19]([N:21]1[C@H:25]([C:26]([NH:45][OH:46])=[O:27])[CH2:24][S:23][C@@H:22]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)NO)c1ccccc1
Yield: 46.3 %

Procedure:
3.1 g of N--methylmorpholine is added to 180 ml of dry tetrahydrofuran solution of 12.5 g of (2R,4R)--3--(S--benzoyl--3--mercaptopropionyl) --2--(2--hydroxyphenyl)--4--thiazolidine--carboxylic acid. To the reaction mixture, 4.1 g of isobutyl chlorocarbonate is added dropwise while stirring under ice-cooling and further stirred for 30 minutes at the same temperature. To this suspension, 120 ml of methanol solution containing 6.3 g of hydroxylamine hydrochloride and 3.6 g of sodium hydroxide is added dropwise, and stirred for 2 hours by gradually restoring the room temperature. The solvent is removed in vacuo, and N hydrochloric acid is added to the resulting residue. Separated oil is extracted with ethyl acetate, and the organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and the resulting oily residue is purified by silica gel coulumn chromatography to give 6.0 g of the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2)[CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCC1Cc2cc(CNCc3ncc[nH]3)ccc2C1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCC1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (54.8 mg) obtained in Example 127-14 was dissolved in methanol (2.74 ml) and added with 1-methyl-2-imidazole carboxaldehyde (21.9 mg) and sodium cyanoborohydride (16.7 mg). Then, the solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and added with saturated saline solution. The solution was subjected to separation/extraction with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (35.9 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=O)[CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH3:2].CC([S@]([NH2:24])=O)(C)C.[BH4-].[Na+]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[NH2:24][C@@H:9]([C:7]1[CH:6]=[CH:5][C:4]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH2:10][CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1ccc(NS(C)(=O)=O)c(CC)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCc1cc([C@H](N)CC)ccc1NS(C)(=O)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a stirred solution of N-(2-ethyl-4-propionylphenyl)methanesulfonamide (7.8 mmol) in tetrahydrofuran (15 ml) and titanium (IV) ethoxide (15 ml), (R)-(+)-2-methyl-2-propanesulfinamide (7.8 mmol) was added. The mixture was stirred at 80° C. for 16 hours. Upon completion, as determined by LC-MS, the mixture was cooled to room temperature and then to 0° C. before it was added dropwise into a 0° C. solution of sodium borohydride (1.18 g, 31 mmol) in tetrahydrofuran (15 ml). The mixture was stirred at 0° C. for 3 hours and then quenched with methanol. After stirring at room temperature for 2 hours, Celite pad and water were added to the mixture, filtered thorough Celite, and washed with dichloromethane-ethyl acetate-methanol. The filtration was evaporated under the reduced pressure and the given residue was purified by silica gel eluting with dichloromethane-ethyl acetate (1:1) to afford the title compound as yellow oil. It was dissolved in methanol (30 ml) and hydrogen chloride-methanol (30 ml) was added. The solution was stirred at room temperature for 1 hour. After the solvent was removed under the reduced pressure, the product was recrystallized from diethylether-methanol to afford the desired product as hydrogen chloride salt.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH:14]([CH3:16])[CH3:15])[N:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:52])([F:51])[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>ClCCl>[CH2:18]([O:17][N:11]1[C@H:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C@@H:9]([NH:8][S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:51])[F:52])=[CH:36][CH:37]=3)=[CH:46][CH:45]=2)(=[O:49])=[O:48])[C:10]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[C@@H]1C[C@@H](N)C(=O)N1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a solution of (3R,5S)-3-amino-1-(Benzyloxy)-5-isopropyl-2-pyrrolidinone trifluoroacetate (0.072 g, 0.19 mmoles), triethylamine (0.13 mL, 0.93 mmoles) and dry dichloromethane (1.0 mL) was added in small portions 4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonyl chloride (0.063 g, 0.20 mmoles) during two minutes. The mixture was stirred under dry nitrogen at 22° C. for 45 minutes, concentrated by rotary evaporation, re-dissolved in dichloromethane (2 mL), mixed with a silica (1 g), concentrated again and then applied on a silica column. Elution with ethyl acetate/n-heptane (1:4 through 1:1) and concentration of pure fractions gave 0.082 g (83% yield) of the title compound as a white solid. LC-MS (APCI) m/z 533 (M+1). 1H NMR (CDCl3) δ 8.01 (d, J=8 Hz, 2H), 7.72 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H) 7.70 (d, J=8 Hz, 2H), 7.41–7.33 (m, 5H), 5.55 (d, J=4 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 4.93 (d, J=11 Hz, 1H), 3.79 (dt, J1=4 Hz, J2=9 Hz; 1H), 3.37–3.31 (m, 1H), 2.29 (ddd, J1=2 Hz, J2=9 Hz, J3=11 Hz; 1H), 2.09–1.98 (m, 2H), 0.85 (d, J=7 Hz, 3H) and 0.76 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[CH:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:22]([O:21][C:19](=[O:20])[NH:18][CH:14]([C:13](=[O:26])[NH:12][C:10]1[N:9]=[CH:8][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH:11]=1)[CH2:15][CH2:16][CH3:17])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)CO)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a solution of 2-[4-(2-tert-Butoxycarbonylamino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester (9.6 g, 25.2 mmol) in 100 mL of diethyl ether at 0° C. is added 1.0 M lithium aluminum hydride (37.9 mL, 37.9 mmol) in diethylether dropwise over 1 h. The reaction is stirred at 0° C. for 15 min and warmed to rt for 1 h. The reaction is slowly quenched with 200 mL of water and ethyl acetate (200 mL). The reaction is filtered and the aqueous is extracted with ethylacetate, dried, and concentrated. The resultant residue is purified by silica gel chromatography to provide the title compound (5.8 g); MS m/z 355.3 (M+1).
Reaction SMILES: C(NCCC)CC.[NH2:8][S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][C:19](=O)[CH2:18][CH2:17]2)(=[O:11])=[O:10].[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(O)C.[Pt]=O>[NH2:8][S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([NH:32][CH2:31][CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][CH2:17]2)(=[O:11])=[O:10]
Reactant: NCCCc1ccccc1
Reactant: NS(=O)(=O)c1cccc2c1CC(=O)CC2
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCCNCCC
Product: NS(=O)(=O)c1cccc2c1CC(NCCCc1ccccc1)CC2
Yield: 99.3 %

Procedure:
The compound was prepared in a manner similar to the preparation of the dipropylamine above using 8-aminosulfonyl-2-tetralone (1.13 g, 5.0 mmol), 3-phenyl-1-propylamine (0.75 ml, 5.3 mmol), p-toluenesulfonic acid (0.10 g, 0.53 mmol), and platinum oxide (0.30 g) in benzene (20 mls) and ethanol (35 mls) to give a solid (1.71 g). The compound was crystallized from acetonitrile and converted to the hydrochloride salt as above. (m.p. 105°-130° C.).