Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:2]2[C:6]3[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COc1ccc(C2(O)c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 40 %

Procedure:
Using N-(3-hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 258, the title compound was synthesized in the same manner as in Example 271. Yield: 40%. Melting point: 175-176° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)([O-])=O.[CH:25](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:15]1[CH2:14][CH2:13][CH:12]([N:11]2[C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[N:1]=[CH:25]2)[CH2:17][CH2:16]1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c[n+]([O-])ccc2[N+](=O)[O-])CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1cc2ncn(C3CCNCC3)c2cn1
Temperature: 105 °C

Procedure:
To tert-butyl 4-[(4-nitro-1-oxidopyridin-3-yl)amino]piperidine-1-carboxylate (1.6 g) in toluene (3 ml) was added trimethyl orthoformate (3.6 ml) followed by p-toluenesulfonic acid (105 mg) and the resulting mixture was heated to 105° C. for 4 hours. The mixture was cooled and partitioned between ethyl acetate (75 ml) and water (75 ml). The organic layer was washed with brine, dried and evaporated to dryness to give the title compound as a solid. Yield 1.18 g. NMR (CDCl3) 1.5 (s, 9H), 2.1 (m, 2H), 2.25 (m, 2H), 3.0 (m, 2H), 4.4 (m, 3H), 7.7 (dd, 1H), 8.1 (s, 1H), 8.5 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:22])([CH3:21])[CH2:4][CH2:3]1)[O:13][C:12](=[O:16])[CH:11]=[C:10]3[C:17]([F:20])([F:19])[F:18].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:22])([CH3:21])[CH2:4][CH2:3]1)[O:13][CH:12]([OH:16])[CH:11]=[C:10]3[C:17]([F:20])([F:18])[F:19]
Reactant: CC1(C)CCC(C)(C)c2cc3c(C(F)(F)F)cc(=O)oc3cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OC(O)C=C3C(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 6,6,9,9-tetramethyl-4-trifluoromethyl-6,7,8,9-tetrahydro-benzo[g]chromen-2-one (Intermediate 3, 348 mg, 1.07 mmol) in CH2Cl2 (5 mL) at −78° C. was added di-iso-butyl aluminum hydride (DIBAL-H, 1.40 mL, 1.0 M in CH2Cl2) over 10 min. After stirring at −78° C. for 3 h, the reaction was quenched with aqueous NH4Cl, followed by 1M HCl, and the aqueous layer was extracted with Et2O (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexane) to give the title compound as a clear oil (346 mg, 99%) that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH2:10][CH2:11][CH:12](O)[CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[NH:10][CH2:11][CH:12]([CH2:13][CH3:14])[O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(O)CN
Reactant: O=Cc1cccc(Cl)c1
Product: CCC1CNC(c2cccc(Cl)c2)O1

Procedure:
Twenty-five grams of m-chlorobenzaldehyde was combined with 15.8 g of 1-amino-2-butanol and heated on the rotary evaporator for 1 hour to remove water. The yield was 37.9 g, nD30 1.5741.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17](OC)=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].C[N+]1([O-])CCOCC1>O1CCCC1.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:17]=[O:18]
Reactant: COC(=O)c1oc2ccc(N3CCOCC3)cc2c1C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2ccc(N3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution (2 mL) of methyl 3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carboxylate (0.69 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added to an ice-cooled solution (5 mL) of lithium aluminum hydride (0.25 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (0.65 mL), 1N aqueous sodium hydroxide solution (3.2 mL) and water (0.65 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (0.48 g) of [3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl]methanol as a pale-yellow oil. The obtained oil was dissolved in acetonitrile (5 mL), tetrapropylammonium perruthenate (0.07 g) and N-methylmorpholine N-oxide (0.46 g) were added to the solution at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.24 g, 40%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:43])(=[O:42])[NH:37]C(C)(C)C)=[CH:26][C:25]=2[F:44])[C:7](=[O:22])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[Cl:21])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:42])(=[O:43])[NH2:37])=[CH:26][C:25]=2[F:44])[C:7](=[O:22])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[Cl:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 90 %

Procedure:
The title compound was prepared in 90% yield by deprotection of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-[2-chloro-5-(propionylamino)-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) with trifluoroacetic acid in the presence of anisole according to the procedure of Example 28, Step G. The material was obtained as a white solid, mp 135°-137° C.; satisfactory purity by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 586 (M+1)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)=O.[CH2:27]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Product: CCOC(=O)C1=C(c2cccc(OCc3ccccc3)c2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Using 1-tert-butyl 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate and 3-benzyloxyphenylboronic acid, the title compound was obtained in a similar manner to Reference Example 550.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)CC1
Product: CC(C)c1noc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][C@@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])(=[O:31])=[O:30]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of (S)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A, J.; Michnick, J.; Kumar, A. M.; Underiner, G. E. Asymmetric Synthesis of Chiral Secondary Alcohols, U.S. Pat. No. 5,629,423 (May 13, 1997)) (14 g, 50 mmol) and triethylamine (14 ml) was cooled to 0° C. in dichloromethane (200 ml) and methanesulfonyl chloride (5.80 ml. 75 mmol) was added slowly at 0° C. After stirring for an additional 4 hours at 0° C., the reaction was quenched by the addition of water and extracted with dichloromethane (4x 150 ml). The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:20]=[C:21]([CH2:24][O:25]C(C(C)(C)C)=O)[S:22][CH:23]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(-c3csc(COC(=O)C(C)(C)C)n3)cn(CC3CCCCC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2c(-c3csc(CO)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1-(cyclohexyl)methyl-7-methoxy-3-{2-[(tertbutylcarbonyloxy)methyl]thiazol-4-yl}-1H-indole (0.92 g, 2.10 mmol) was dissolved in methanol (20 ml) and 4N sodium hydroxide (5 ml) added. The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue taken up in dichloromethane. Water (10 ml) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the combined organic layers concentrated in vacuo to yield 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]-7-methoxy-1H-indole as a pale orange foam (0.55 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31].C(OCC)(=O)C.O1CCCC1.O>N1C=CC=CC=1>[CH2:30]([NH:32][C:33]([NH:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1)=[O:34])[CH3:31]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CCN=C=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) in pyridine (3 mL) was added ethyl isocyanate (380 μL, 4.8 mmol), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate/tetrahydrofuran and water were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (160 mg, 72%) as a pale-yellow solid.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]1[CH2:13][CH:14]=[CH2:15].[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][CH2:15][CH:14]1[CH2:13][N:3]2[C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:1]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCn1c(=O)[nH]c2ccccc2c1=N
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C2=NC(CBr)CN12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of 3,4-dihydro-4-imino-3-allyl-2(1H) -quinazolinone (10 g, 50 mmol) in tetrahydrofuran (70 mL) was added N-bromosuccinimide (9.0 g, 50 mmol). The mixture was then stirred at room temperature for 25 minutes. The solid was collected by filtration and recrystallized from THF to afford 2-bromomethyl-2,3-dihydro-imidazo[1,2-c]quinazolin-5(6H)-one (11.18 g, 95%), mp 213°-214° C. 1H NMR (300 MHz, DMSO-d6): δ3.67(m, 2H, CH2), 3.74 (q, 1H, CH), 3.94 (t, 1H, CH), 4.57 (m, 1H, =CH), 7.07 (q, 2H, Ar--H), 7.51 (t, 1H, Ar--H), 7.78 (d, 1H, Ar--H), 10.65 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): d 47.80, 64.16, 110.27, 115.13, 122.23, 125.80, 133.59, 139.97, 147.47, 153.98, 206.07. Anal. Calcd for C11H10N3OBr: C, 47.16; H, 3.59; N, 15.00. Found: C, 47.09; H, 3.41; N, 14.90.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: CSc1ccc(N)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: CSc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Yield: 89 %

Procedure:
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.00 g, 6.00 mmol) and 4-(methylthio)aniline afforded (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile as a brown oil (1.55 g, 89%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:40](O)[CH3:41]>S(=O)(=O)(O)O>[CH2:40]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)[CH3:41]
Reactant: CCO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 3.5 h

Procedure:
700 mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid was added. The reaction solution was boiled for 3.5 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 480 mg. MS (ES+): m/e=586.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22].[H-].[Na+].[CH3:34]I>CN(C)C=O.C(OCC)(=O)C>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:34])[C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22]
Reactant: CI
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 1.50 g) was dissolved in N,N-dimethylformamide (6 mL). To this solution, sodium hydride (185 mg, 60% oil suspension) was added and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.4 mL) was then added and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column-chromatography (ethyl acetate:hexane=1:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (1.36 g, 88%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.BrCCCCC1C2C(=CC=CC=2)NC=1.[CH2:29]1[C:34]2[S:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:33]=2[CH2:32][CH2:31][NH:30]1>C(#N)C>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][C:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[S:35][C:34]=3[CH2:29]2)=[CH:7]1
Reactant: ClCCCCc1c[nH]c2ccccc12
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: BrCCCCc1c[nH]c2ccccc12
Solvent: CC#N
Product: c1ccc2c(CCCCN3CCc4c(sc5ccccc45)C3)c[nH]c2c1

Procedure:
A solution of 20.8 g of 3-(4-chlorobutyl)indole [or 25.2 g of 3-(4-bromobutyl)indole] and 18.9 g of 1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine in 100 ml of acetonitrile is stirred at 20° for 12 hours. The usual working up is carried out, and 2-[4-(3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine ("A"), m.p. 113°-115° is obtained.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=O)C1C=CC=CC=1>[Pd].O.C(O)C>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A slurry of palladium on carbon (1.5 g, 10% w/w) in water (3 mL) was added to a solution of tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate (15.28 g, 29.70 mmol) in ethanol (200 mL). The resulting slurry was stirred vigorously under a hydrogen atmosphere (45 psi) at 50° C. for 18 h. Catalyst was then filtered off, rinsing with ethanol (400 mL). Concentration of the filtrate under vacuum afforded tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a colorless oil that crystallized upon standing under vacuum (10.52 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=8 Hz) and 8.08 (d, J=8 Hz) total 1H, 7.90-7.87 (m, ca 1H); 7.87-7.28 (m, 4H); 7.25-7.20 (m, 1H); 6.51 (d, J=9 Hz) and 6.17 (d, J=9 Hz) total 1H; 4.99-4.92 (m, 1H); 3.96 (d, J=4 Hz) and 3.90 (d, J=3 Hz) total 1H, 3.80-3.69 (m, 1H); 2.68-2.64 (m) and 2.53-2.57 (m) total 1H, 1.53-1.23 (m, 18H). ES-LCMS m/z 380 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]=[C:11]=S)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([F:33])([F:32])[F:31])[CH2:26][CH2:25]2)=[CH:17][C:18]([NH:22][CH3:23])=[C:19]([CH:21]=1)[NH2:20].CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:22]([CH3:23])[C:18]3[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([F:32])([F:33])[F:31])[CH2:26][CH2:25]4)[C:15]([Cl:14])=[CH:21][C:19]=3[N:20]=2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1
Reactant: N#Cc1cc(N=C=S)c(Cl)cc1F
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C#N)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 76 using 4-chloro-2-fluoro-5-isothiocyanatobenzonitrile (300 mg; 1.41 mmol), 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (434 mg; 1.41 mmol), DIC (178 mg; 1.41 mmol) and DMF (12 mL).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:34]1([CH2:37][OH:38])[CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:38][CH2:37][CH:34]2[CH2:36][CH2:35]2)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: OCC1CC1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1OCC1CC1

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 393 instead of the compound prepared in Example 215 and cyclopropylmethanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:8][C:7](=[S:9])[C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1.[OH-].[Na+].I[CH3:20]>>[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:20])[C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1
Reactant: CCCc1nc(C)c2c(=S)[nH]c(N)nn12
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc(C)c2c(SC)nc(N)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine-4(3H)-thione, hydrochloride (0.65 g.) in a slight excess of 2N sodium hydroxide was treated with iodomethane (0.4 g.) and the mixture was stirred 2 hours at room temperature. The solid was collected and crystallised from aqueous ethanol and had m.p. 139°-140°. Its hydrochloride melted at 207°-208°.