Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCCOCc4ccccc4)c4ccccc4)ccc3n2C)cc1
Yield: 73 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 73% of theory, C40H46N6O4 (674.9) Rf value: 0.46 (silica gel; dichloromethane/ethanol=9:1) ##EQU135##
Reaction SMILES: Cl.[NH2:2][OH:3].O(C(C)(C)C)[K].[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1>CS(C)=O.O>[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:23])[NH:2][OH:3])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2ccc(Br)o2)cc1
Reactant: NO
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N=C(NO)c1ccc(-c2ccc(Br)o2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled suspension of hydroxylamine hydrochloride (17.25 g, 0.25 mol) in DMSO (150 ml) was added portionwise KO-t-Bu (28.0 g, 0.25 mol) and the mixture was stirred under nitrogen for 30 min. 2-Bromo-5-(4-cyanophenyl)furan (17.37 g, 0.07 mol) was then added and the mixture was stirred overnight at room-temperature. The resulting solution was diluted with excess water to give 2-bromo-5-[4-(N-hydroxyamidino)phenyl]furan as an off-white solid, which was collected and washed with water. Yield: 19.45 g, 99%; mp 162-164° C. 1H NMR (DMSO-d6): 5.84 (broad s, 2H), 6.71 (d, J=3.6 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 9.70 (s, 1H). IR (cm−1): 3475, 3369, 3209 (broad), 1639, 1482, 1341, 1017, 927, 787. The intermediate amidoxime (38.9 g, 0.138 mol) was dissolved in a mixture of DMSO (60 ml) and dioxane (300 ml) and with chilling was treated with a solution of LiOH hydrate (11.61 g, 0.277 mol) in water (60 ml). At room temperature, the resulting suspension was then treated dropwise via an addition funnel with dimethyl sulfate (26.18 g. 0.208 mol) over the course of ˜30 min. Following the addition, the mixture became slightly warm and the solids dissolved. After stirring overnight, the mixture was diluted with excess water and extracted with EtOAc. Purification of the residue by column chromatography on silica gel eluting with 10% EtOAc in hexane gave the slightly impure product, which was further purified by recrystallization from MeOH/water in multiple crops to give an off-white solid, mp 116-117° C. Yield: 28.0 g, 69%. 1H NMR (DMSO-d6, an apparent mixture of stereoisomers): 3.74 (2s, 3H), 6.09 (broad s, 2H), 6.72 (2d, J=3.6 Hz, 1H), 7.09 (2d, J=3.6 Hz, 1H), 7.70 (m, 4H). IR (cm−1): 3459, 3312, 3177, 2957, 2935, 2901, 2818, 1634, 1403, 1051, 910, 842, 785.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][CH:16]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1ccc(C(N)=S)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 10.0 g (30 mmoles) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester and 3.5 g (35 mmoles) of triethylamine in 250 ml of pyridine, hydrogen sulfide gas is introduced until the solution is saturated. The reaction mixture is then stirred at 25° for 18 hours, followed by evaporation of the solvent. The residue is slurried with 50 ml of carbon disulfide for 1 hour and the resulting crystalline solid recovered by filtration to yield 8.7 g (24 mmoles, 80 %) of N-acetyl-α-ethoxycarbonyl-4-thiocarbamoylphenylalanine ethyl ester, m.p. 168°-172°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]1)(=[O:28])=[O:27].[CH:43]1([NH:46][C:47](=[O:65])[C:48]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[C:51]([CH3:63])=[C:50]([F:64])[CH:49]=2)[CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:24])([CH3:25])[CH2:13][N:7]1[CH:6]=[C:5]([S:26]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]2)(=[O:28])=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:52]3[CH:53]=[C:48]([C:47](=[O:65])[NH:46][CH:43]4[CH2:44][CH2:45]4)[CH:49]=[C:50]([F:64])[C:51]=3[CH3:63])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(S(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}-1,4-diazepane-1-carboxylate (Example 46c, 83 mg) in DMF (2 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (39 mg), Pd-118 (2.4 mg) and potassium carbonate (33 mg) under nitrogen. The resulting mixture was stirred at 70° C. for 1 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (3×100 mL), brine (3×100 mL) dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was purified (SiO2 chromatography, elution with 50% ethyl acetate/isohexane) to afford the subtitle compound (0.055 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].O=S(Cl)Cl.[CH2:20](N(CC)CC)C>>[CH3:20][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To 3,5-Dinitro-benzoic acid (Aldrich, 21.2 g, 100 mmol) was added SOCl2. The mixture was refluxed overnight. The excess SOCl2 was removed under reduced pressure. The residue was dissolved in 100 mL of MeOH, cooled in ice bath, and triethylamine (Aldrich, 21 mL, 150 mmol) was added slowly added. After the mixture was stirred at ambient temperature for 3 h, solvent was removed under reduced pressure. The residue was diluted with EtOAc and 1N HCl. The mixture was extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4. Removal of the solvent gave 22.0 g (97%) of product, which was pure enough for the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (t, J=2.1 Hz, 1H), 8.92 (d, J=2.1 Hz, 2H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
(6-Bromopyridin-2-yl)acetonitrile (Example 235, Step 1) (500 mg, 2.54 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LHMDS (1.0 M in THF, 3.05 ml, 3.05 mmol) was added dropwise, and the solution was maintained at −78° C. for 20 minutes. A solution of (2-bromoethoxy)-tert-butyldimethylsilane (600 μL, 2.79 mmol) in THF (5.0 mL) was added dropwise over 5 minutes. The resulting mixture was maintained at −78° C. for 2 hours and warmed to room temperature overnight. The solution was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Silica gel chromatography (0-15% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.FC(F)(F)S(O[Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])(=O)=O>C(Cl)Cl.CCCCCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.25 g, 4.1 mmol) in MeCl2 (17 ml) containing imidazole (2.55 g, 48.7 mmol) was cooled to 0° C. and treated with triisopropylsilyl trifluoromethanesulfonate (7.41 g, 24.2 mmol). The reaction mixture was allowed to warm to RT and stirred for 16 hrs. The reaction mixture was diluted with MeCl2 (20 ml) and n-hexane (40 ml). The resultant suspension was filtered and the filtrate was passed over SiO2. Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.35 g, 86.3%). Mass Spec: C49H83NO12Si(906.29) FAB:928(M+Na), 756, 678, 511, 266.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
2-[(4-{2-[(4′-Fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (351 mg) obtained in Example 34-1 was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (293 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOCC>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(N)CN
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a mixture of 88.2 g (1 mol) of 1,2-diamino-2-methylpropane, 50 ml of triethylamine and 500 ml of diethyl ether was added dropwise to a solution of 27.1 g (0.25 mol) of ethyl chloroformate in 100 mL of ether. The reaction mixture was stirred for 16 hours at 25° C. and filtered. Evaporation of the filtrate to dryness gave 38 g (95%) of product which was identified by NMR and IR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1nc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N

Procedure:
A stirred solution of 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine [prepared by the method of Taylor and Ray--JOC, 52, 3997 (1987)], 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid commercially available or prepared by the method of Thompson and Gaudino--JOC, 49, 5237 (1984)], 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine.
Reaction SMILES: C(O[NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CNOCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=CO
Product: CCCCCC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 199.2 %

Procedure:
To a cold solution of 2-(benzyloxyaminomethyl)heptanoic acid (1.57 g, 5.92 mmol) in HCO2H (29 mL) and dichloromethane (29 mL) was added acetic anhydride (5.9 mL, 62.75 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added to the residue, and the solution was washed with brine, and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound (1.73 g, 100%). 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91–4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+ 294.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:15]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(NC2CCCCC2)cc1F
Yield: 67.9 %

Procedure:
A solution of compound (7) (1.50 g, 7.6 mmol), cyclohexanone (1.57 mL, 15.2 mmol), and NaBH3CN (0.96 g, 15.2 mmol) in methanol (10 mL) and acetic acid (0.2 mL) was allowed to undergo conventional reactions, followed by the same reactions and treatments as those in Example 3. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 1.37 g (65%) of compound (11b) of interest as brown powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: Cc1ccc(C(C)C)cc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mL) dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:16]=[C:17](SC)[NH:18][C:19]([O:21]C(C)(C)C)=[O:20])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][NH2:39]>CC(O)=O>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:38]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[Cl:31])[N:39]=[C:17]([NH:18][C:19](=[O:20])[OH:21])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: NNc1ccccc1Cl
Reactant: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
CH3COOH (50 ml) was added to a mixture of methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate, from Example 569, (1.0 g, 2.08 mmol) and (2-chlorophenyl)hydrazine hydrochloride (0.74 g, 4.16 mmol). The resulting mixture was stirred at 120° C. overnight. The reaction mixture was concentrated and purified by silica gel chromatography (Hexanes: EtOAc, 3:1-1:1) to give 5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamic acid (630 mg, 60%). 1H NMR (DMSO, 400 MHz) δ 10.60 (s, 1H), 7.76 (s, 1H), 7.70-7.68 (m, 1H), 7.63-7.60 (m, 2H), 7.52-7.52 (m, 1H), 7.48-7.46 (m, 1H), 7.18 (s, 1H), 7.10-7.07 (m, 1H), 5.45 (s, 1H), 4.42 (s, 4H)
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH3:12])[CH:11]=1.C(OO)(=O)C.[O-]S([O-])=O.[Na+].[Na+]>O>[CH3:5][C:6]1[CH:7]=[N+:8]([O-:3])[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(=O)O
Reactant: Cc1cncc(C)c1
Agent: CC(=O)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c[n+]([O-])c1
Temperature: 50 °C

Procedure:
98 ml of glacial acetic acid were added dropwise, at 25° C., to 350 g of 3,5-dimethylpyridine. The mixture was heated to 50° C. and 870.3 g of 40% peracetic acid were metered in such that the temperature could be kept at 50° C. by cooling. About 1 hour after the addition of the peracetic acid had ended, the reaction mixture was cooled to 25° C. and 230 g of Na2SO3 in 1 1 of water were added dropwise, with cooling. After the excess peracetic acid had been destroyed (KI-starch test), 1330 ml of water were added, the mixture was rendered alkaline with 730 ml of 50% NaOH and the solution was extracted in several portions with a total of about 4500 ml of chloroform. The combined organic phases were dried with Na2SO4 and the solvent was evaporated off to about 740 ml.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:22]([N:24]([CH2:27]CCl)[CH2:25]C)[CH3:23].CN(CCCl)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][CH2:22][N:24]([CH3:27])[CH3:25])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CCCl
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Agent: CN(C)CCCl
Product: CN(C)CCN1CCN(Cc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3 (b), is alkylated by following the procedure described in Example 3 (c), whereby, in place of the diethylamino ethylchloride, the equimolecular amount of dimethylamino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 190° C./0.01 mm. Hg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]3[N:17]=[CH:18][CH:19]=[CH:20][C:8]=3[N:7]=2)=[CH:2]1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: CN(C)CCCCl
Reactant: c1cnc2c(c1)N=C(c1ccsc1)c1ccccc1N2
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccsc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.