Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([N:8]1[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CC(=O)NC(=O)N1Cc1ccc(Cl)cc1
Yield: 60.3 %

Procedure:
Into a 50 ml round bottomed flask equipped with a calcium chloride drying tube and a magnetic stirrer were placed 5 ml of dry pyridine and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5 dione. The mixture was then stirred and cooled in an ice bath, 0.5 g of methanesulfonyl chloride was added dropwise. After the product had been added the mixture was brought to ambient temperature and stirred for 5 hours. The solvent was then removed in vacuum and the residue was neutralized with dilute hydrochloric acid. The crystals obtained were filtered off and recrystallized from alcohol to yield 0.8 g of 1-methane sulfonyl-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 145°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][Br:15]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(CO)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(CBr)c1
Yield: 230.6 %

Procedure:
By the method of Example 1, Step B, 61.90 grams (0.279 mole) of 2,3-dichloro-5-nitrophenylmethanol and 26.41 grams (0.098 mole) of phosphorus tribromide were reacted in 800 mL of toluene, yielding 64.38 grams of 2,3-dichloro-5-nitrophenylmethyl bromide as a golden oil which solidified upon standing. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][Li]>O1CCCC1>[C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:13])[CH3:14]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Yield: 34.4 %

Procedure:
Quinaldic acid (2.76 grams, 0.017 mole) was dissolved in 100 ml of dried tetrahydrofuran. Then 25 ml of 1.6 M (0.04 mole) of methyl lithium was added using a syringe. Reaction appeared immediate. The solution was stirred and heated under reflux for two hours and then poured into 600 ml of ice water. The ketone (2-acetylquinoline) was extracted with four 25 ml portions of ethyl ether which, after drying, was removed by rotary evaporation to yield ca. 1.0 g (ca. 40%) of 2-acetylquinoline.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1.[OH-].[NH4+:19]>[O-]S([O-])(=O)=O.[Cu+2]>[NH2:19][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1nc(-c2ccccc2F)ncc1Br
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Product: Nc1cnc(-c2ccccc2F)nc1C(=O)O
Temperature: 110 °C
Yield: 53 %

Procedure:
CuSO4 (with 5H2O, 65 mg) was added to a mixture of the above made 5-bromo-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid (770 mg, 2.59 mmol) and 28% aqueous ammonium hydroxide (12 ml). The reaction was heated in a microwave reactor at 110° C. for 30 min. It was cooled to RT and concentrated in vacuo. The residue was diluted with 1N HCl (20 mL) and extracted with EtOAc 3×. Combined organic extracts were dried over sodium sulfate and filtered and concentrated to give 5-amino-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid (320 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:22](=[O:25])[CH2:23]Cl)[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl-].[NH4+].O>CN(C)C(=O)C>[CH3:21][O:20][C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:23][C:22]2=[O:25])[CH2:13][CH2:14]1)=[O:19]
Reactant: COC(=O)[C@H]1CC[C@H](N(CCNC(=O)OC(C)(C)C)C(=O)CCl)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1CC[C@H](N2CCN(C(=O)OC(C)(C)C)CC2=O)CC1
Reaction time: 0.5 h

Procedure:
Methyl trans-4-[{2-[(t-butoxycarbonyl)amino]ethyl}-(chloroacetyl)amino]cyclohexanecarboxylate (560 mg) obtained in Reference Example 71(2) is dissolved in N,N-dimethylacetamide (5 ml), and 60% sodium hydride in oil (119 mg) is added thereto under ice-cooling. The reaction solution is then stirred for 0.5 hours under the same cooling conditions. Saturated aqueous ammonium chloride solution and water are poured to the reaction solution successively under ice-cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give t-butyl 4-[trans-4-(methoxycarbonyl)cyclohexyl]-3-oxopiperazine-1-carboxylate (302 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([C:12]3[N:13]([CH3:25])[CH:14]=[C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:16]=3)[NH:11][C:7]=2[C:6]=1[O:28][CH3:29])=[O:4].Cl>[OH-].[Na+]>[C:21]([O:20][C:18]([NH:17][C:15]1[CH:16]=[C:12]([C:10]2[NH:11][C:7]3[C:6]([O:28][CH3:29])=[C:5]([C:3]([OH:4])=[O:2])[CH:27]=[CH:26][C:8]=3[N:9]=2)[N:13]([CH3:25])[CH:14]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3cc(NC(=O)OC(C)(C)C)cn3C)[nH]c2c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)ccc2nc(-c3cc(NC(=O)OC(C)(C)C)cn3C)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
Methyl ester 16 (51 mg, 0.13 mmol) was dissolved in 1 M NaOH (1:1 dioxane/H2O, 5 mL) and stirred overnight at r.t and an additional 3 h at 50° C. The reaction mixture was cooled to 0° C. and 1N HCl was added dropwise to adjust the pH to 3-4, while a white precipitate was formed. Separation of the product was accomplished by centrifugation and decanting of the supernatant. Lyophilization gave 36 mg (73%) of 17 as a beige solid. Data of 17: 1H NMR (500 MHz, DMSO-d6): δ 1.40 (s, 9H), 3.97 (s, 3H), 4.28 (s, 3H), 6.76 (s, 1H), 6.92 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 9.13 (s, 1H), 12.20 (brs, 1H). 13C NMR (125 MHz, DMSO-d6): δ 27.80, 36.34, 60.78, 78.29, 102.88, 104.47, 114.67, 116.12, 119.79, 123.54, 124.96, 135.00, 139.02, 145.90, 150.62, 152.78, 167.70. UV (H2O): λmax 319. MS (ESI): m/z (rel intensity) 387 (100). HRMS (FAB): calcd for C19H23N4O5, 387.1668; found, 387.1658.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[H][H]>[Pd]>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[NH2:1])[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CCC(CC)Nc1ccccc1N
Yield: 100 %

Procedure:
In a 2 liter Paar hydrogenator is placed 2.5 grams of 10% palladium on carbon catalyst, 800 milliliters of absolute alcohol and 250 grams of o-nitro-N-(1-ethylpropyl)aniline. Hydrogen is introduced and the reduction takes about 21/2 hrs. The reaction is exothermic and the temperature subsides as the reaction goes to completion. The catalyst is removed by filtration and the ethanol evaporated to yield a nearly quantitative yield (214 grams) of product as a dark oil. A pure sample is obtained by vacuum distillation b.p. 2.0 mm Hg=125°-126° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)CBr
Product: COC(=O)CSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2

Procedure:
Use a method similar to the Example 347, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl bromoacetate to give 3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
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]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][S:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>O1CCCC1.O.C(N(CC)CC)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[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([S:48][CH2:47][C:43]5[S:42][CH:46]=[CH:45][N:44]=5)=[CH:50][CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: Nc1ccc(SCc2nccs2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccs4)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (438 mg) in tetrahydrofuran (10 ml) was added one droplet of DMF. Then, thionyl chloride (0.095 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature under nitrogen atmosphere and the mixture was stirred for 1 hour. This solution was added to a solution of 4-[(thiazol-2-ylmethyl)sulfanyl]aniline (265 mg) and triethylamine (3.6 ml) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred overnight at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(thiazol-2-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (424 mg) (Compound 316) as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:19])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>C(C(C)=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:29][CH2:28][CH2:27][Br:26])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)coc12

Procedure:
To a solution of 3-phenyl-6-hydroxy-7-propylbenzofuran (3.54 g, 13.99 mmol) and potassium carbonate (2.08 g, 15.05 mmol) in dry methyl ethyl ketone (50 ml) was added 1,3-dibromopropane (2.84 ml, 27.98 mmol). The reaction mixture refluxed for 5 hours under nitrogen. The mixture was partitioned between isopropyl acetate and pH4 buffer. The organic was dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, 50% methylene chloride in hexane) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14]Br.CN(C)C=O.[N-:22]=[N+:23]=[N-:24].[Na+]>O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][N:22]=[N+:23]=[N-:24]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Reaction time: 8 h
Yield: 95.8 %

Procedure:
2.47 g (8.46 mmol) of 2-(bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is mixed with 8.3 ml of N,N-dimethylformamide and 5.5 ml of water. After 0.82 g (12.66 mmol) of sodium azide is added, the batch is stirred overnight. The reaction mixture is added to water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. Chromatography on a Flashmaster yields 2.06 g (95.8%) of the desired azide.
Reaction SMILES: [NH2:1]C1N=C(C2C(Cl)=CC3COCC4C=3C=2C=CC=4)N=C(SCCC(O)=O)N=1.[Cl-].[NH4+].[NH2:30][C:31]1[N:36]=[C:35]([C:37]2[C:38]([Cl:50])=[CH:39][C:40]3[CH2:41][O:42][CH2:43][C:44]4[C:49]=3[C:48]=2[CH:47]=[CH:46][CH:45]=4)[N:34]=[C:33]([S:51][CH2:52][CH:53]([CH3:57])[C:54]([OH:56])=O)[N:32]=1>>[NH2:30][C:31]1[N:36]=[C:35]([C:37]2[C:38]([Cl:50])=[CH:39][C:40]3[CH2:41][O:42][CH2:43][C:44]4[C:49]=3[C:48]=2[CH:47]=[CH:46][CH:45]=4)[N:34]=[C:33]([S:51][CH2:52][CH:53]([CH3:57])[C:54]([NH2:1])=[O:56])[N:32]=1
Reactant: CC(CSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1)C(=O)O
Reactant: Nc1nc(SCCC(=O)O)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(CSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1)C(N)=O
Yield: 65 %

Procedure:
Proceeding in the same manner as in Step 2 of Example 205 and replacing N-methylamine hydrochloride and 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-propionic acid by ammonium chloride (963 mg, 18 mmol) and 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-2-methyl-propionic acid (1.5 g, 3.6 mmol) respectively, there was obtained 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-2-methyl-propionamide (978 mg, 65%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:7])=[CH:24][CH:25]=1)[CH3:27]
Reactant: Cc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxybenzoyl)-2-(4-tolyl)benzofuran with 2-diethylaminoethyl chloride by the procedure of Example 1 gives the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>C(#N)C>[CH2:26]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and allyl bromide (0.16 ml, 2.0 mmol). Yield: 0.42 g (80%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-226° C. MS m/z (relative intensity, 70 eV) 287 (M+, 70), 286 (90), 260 (bp), 258 (53), 82 (95).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][C@@H:10]([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C@@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][C@H:22]3[CH3:21])=[N:18][C:12]=2[O:11][C@@H:10]([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: C[C@H]1CN(Cc2ccccc2)Cc2ncc(Cl)nc2O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1COCCN1c1cnc2c(n1)O[C@@H](C)CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of (6S)-8-benzyl-3-chloro-6-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (313 mg), (3R)-3-methylmorpholine (164 mg), Pd2(dba)3 (30 mg), XPhos (62 mg) and sodium tert-butoxide (208 mg) in toluene (5 mL) was stirred under an argon atmosphere with heating at 100° C. for 3 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 9→50% ethyl acetate/hexane) to give the title compound (233 mg, 61%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26])=[O:31]
Reactant: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1N
Reactant: Cc1cccc(C(=O)Cl)c1C
Product: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C

Procedure:
By using 5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione, and 2,3-dimethylbenzoyl chloride, the title compound was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13]>ClCCCl.O.C(Cl)Cl.[I-].[Zn+2].[I-]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)S
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g) in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol (9.92 mL) in one portion. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was diluted with water (100 mL) and methylene chloride (100 mL). The organic phase was removed, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 14.4 g of an oil.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[Cl-].[C:17]([O:28][CH3:29])(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-])=[O:23])=[CH:20][CH:19]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:22]([C:21]4[CH:25]=[CH:26][C:18]([C:17]([O:28][CH3:29])=[O:27])=[CH:19][CH:20]=4)=[O:23])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.138 g) in anhydrous benzene (5 ml) and pyridine (2 ml) was added with monomethyl terephthalate chloride (0.177 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.205 g, yield: 82%) as colorless needles (melting point: 217-218° C.).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4]1.[C:12]([NH:19][CH2:20][CH2:21]Br)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)C(C)C)(C)C>CO.C(#N)C>[N:7]1([CH:5]2[CH2:6][N:3]([CH2:21][CH2:20][NH:19][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: C1CCN(C2CNC2)C1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CC(N2CCCC2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
595 mg of 1-(azetidin-3-yl)pyrrolidine dihydrochloride (Example 219A, 2.75 mmol, purity about 92%, 1 equivalent) were reacted in 3 batches. To obtain the free base, the 1-(azetidin-3-yl)pyrrolidine dihydrochloride was passed over a StratoSpheres™ SPE column. To this end, the column was initially moistened with 1 ml of methanol. 1-(Azetidin-3-yl)pyrrolidine dihydrochloride, dissolved in 3 ml of methanol, was then passed over the column and the column was rinsed with 3 ml of methanol. The solution obtained was concentrated (the column retains about 0.9 mmol of salt). The free base was then initially charged in 26.8 ml of acetonitrile, 656 mg of 2-(Boc-amino)ethyl bromide (2.9 mmol, 1.05 equivalents) and 1.45 ml of N,N-diisopropylethylamine (8.25 mmol, 3 equivalents) were added and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 5:1; dichloromethane/methanol 10:1; dichloromethane/methanol 4:1 and dichloromethane/1 N ammonia in methanol 4:1). This gave 463 mg (67% of theory) of the title compound.