Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(-c2ccccc2)c1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a mixture of 1-benzyloxy-2-bromo-4-nitrobenzene (100 mg, 0.33 mmol), Pd(dppf)Cl2.DCM (12 mg, 0.016 mmol), phenylboronic acid (48 mg, 0.39 mmol) and potassium phosphate (207 mg, 0.98 mmol) was added dioxane under an argon atmosphere. The mixture was stirred overnight at 80 C and filtered. The filtrate was concentrated and purified by flash chromatography (5:1 hexanes/ethyl acetate) to give 2-benzyloxy-5-nitro-biphenyl (81 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3]([C:9](=[NH:10])[NH:12][OH:13])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(NO)c1nc(Br)cnc1N
Temperature: 0 °C
Yield: 77 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carbonitrile (1 g, 5.025 mmol) was dissolved in MeOH (20.00 mL) and cooled to 0° C. Hydroxylamine hydrochloride (349.2 mg, 5.025 mmol) and triethylamine (508.5 mg, 700.4 μL, 5.025 mmol) were added and the reaction allowed to warm to ambient temperature. After 2 hours the resultant precipitate was filtered off and dried (898 mg, 77% Yield). MS (ES+) 234.89
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([OH:13])[CH2:12][CH2:11]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([O:13][C:10]1([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:11][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1(CCOC2CCCCO2)CC1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1(CCOC2CCCCO2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol (730 mg, 4.05 mmol) and benzoic acid (590 mg, 4.86 mmol) in 30 mL of CH2Cl2 was added DMAP (98.8 mg, 0.81 mmol, Shanghai Haiqu chemical Ltd.) and EDCI (1.16 g, 6.08 mmol, Shanghai Haiqu chemical Ltd.) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc)) to afford the title compound as colorless oil (690 mg, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[F-].[K+]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Product: O=C(O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 170 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 ml of 2-nitrofluorobenzene (Aldrich), 1.44 g of 4-aminophenyl acetic acid and 0.550 g of KF is stirred at 170° C. for 16 hours in a sealed tube. The mixture obtained is allowed to cool to rt, triturated in CH2Cl2/MeOH (95:5) and filtered. The filtrate obtained is concentrated and the concentrate obtained is purified by silica gel column chromatography. [4-(2-Nitro-phenylamino)-phenyl]-acetic acid is obtained in the form of a solid: ES-MS: 273.0 [M+H]+; single peak at tR=4.44 min (System 1); Rf=0.20 (CH2Cl2/MeOH, 95:5).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[K+].[Cl-].[Na+]>O.CS(C)=O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([S:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1ncccn1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ncccn2)cc1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of 1.12 g (10 mmoles) of 2-mercaptopyrimidine, 1.4 (10 mmoles) of 1-fluoro-4-nitrobenzene, 0.5 of potassium hydroxide and 10 ml of dimethylsulfoxide were heated at 120°-130° C. for 6 hours and then cooled. After pouring into a mixture of ice, water and sodium chloride the mixture was allowed to stand for 30 minutes and then filtered. The solid was washed with water, air dried and chromatographed on silica gel using ethyl acetate/hexane (1:1 by volume) as the eluent. The fractions containing the product were combined and concentrated to give 1 g (43%) of the product as yellow rods, mp 103°-104° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)[C:14](=[O:30])[CH2:13]1)=[O:11])(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:24]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:29])[C:14](=[O:30])[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1CC(=O)N(CC(=O)NC2CC2)c2ccccc2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)N1CC(=O)N(CC(=O)NC2CC2)c2ccccc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of [3-(1-cyclopropylcarbamoylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (40 mg, 0.07 mmol) in DCM (2 mL), was added trifluoroacetic acid (0.2 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 2-{4-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-N-cyclopropyl-acetamide (32 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(C)n(-c2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
Part D: To a magnetically stirred solution of methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (8.0 gram, 0.035 mol) in THF (100 ml) was added a solution of LiOH (1.68 gram) in water (100 ml). The resulting mixture was heated at 70° C. for 16 hours, allowed to attain room temperature and acidified with 2 molar equivalents of a 1N HCl solution. The formed precipitate was collected to give crude 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (7.0 gram, 93% yield). 1H-NMR (400 MHz, DMSO-d6): 2.31 (s, 3H), 2.43 (s, 3H), 7.56-7.61 (m, 2H), 7.66-7.71 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A solution of ethyl 4-bromobenzoylacetate (14.8 g, 0.05 mol) and 9-hydroxyxanthene (10.9 g, 0.06 mol) in ethanol-acetic acid (1:1, 150 ml) was stirred as described in Example 3 (ii) and a white solid collected. The filtrate was stirred a further 3 days and a second crop collected to give ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[K+].[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27]C([O-])=O.[Cl-].[Mg+2].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6](=[O:8])[CH2:27][C:26]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1ccccc1C=CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)/C=C/c1ccccc1C
Reaction time: 1 h

Procedure:
To a solution of 2-methylcinnamic acid (50.71 g, 312.7 mmol) in tetrahydrofuran (500 ml) was added 1,1′-carbonyldiimidazole (55.8 g, 344 mmol) at room temperature, and the mixture was stirred as it was for 1 hr. To the mixture were added monoethyl malonate monopotassium salt (58.5 g, 344 mmol) and magnesium chloride (16.4 g, 172 mmol) at room temperature, and the mixture was stirred at 60° C. overnight. The reaction solution was diluted with ethyl acetate and water and acidified with conc. hydrochloric acid. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to give the objective substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C(O[C:17](=O)[N:18]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=1)[CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[NH:23][CH:22]=1)(C)(C)C.[OH-].[Na+].C(O)(=O)C(O)=O>O.C1COCC1>[CH2:31]([O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:20][CH2:19][N:18]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=1)[CH3:17])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CCc1c[nH]c2ccc(OCc3ccccc3)cc12)Cc1cccc(Oc2ccccc2)c1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1c[nH]c2ccc(OCc3ccccc3)cc12)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Combine 1.0 M solution of LiAlH4-THF (13.4 mL, 13.4 mmol) and (3-phenoxy-benzyl)-(2-(5-benzyloxy-1H-indol-3-yl)-ethyl)-carbamic acid tert-butyl ester (1.83 g, 3.34 mmol) and slowly add 15 mL dry THF. After addition, heat the reaction mixture to reflux. After 4.5 h, cool down to room temperature. Quench the reaction by adding water (1.5 mL) cautiously, followed by 10% NaOH. Filter off the suspension and wash repeatedly with ether. Dry the organic solution over Na2SO4 and concentrate the solvent in vacuo. Purification by silica gel chromatography using CH2Cl2/MeOH as eluent to give the free base: 1H NMR (300 MHz, CDCl3) 2.35 (s, 3H), 2.69–2.74 (m, 2H), 2.91–2.96 9 m, 2H), 3.65 (s, 2H), 5.07 (s, 2H), 6.90–7.53 (m, 18H), 7.80 (s, 1H). This compound reacted further with oxalic acid to form the salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Sn].Cl.C(=O)([O-])[O-].[K+].[K+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(C(=O)C(O)c2cccc(Cl)c2)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CN(C)c1ccc(C(=O)Cc2cccc(Cl)c2)cc1

Procedure:
A mixture of 9.08 g, of 2-(3-chlorophenyl)-2-hydroxy-1-[4-(dimethylamino)phenyl]ethanone, 3 equivalents of mossy tin, a spatula tip of copper (II) sulfate, 20 ml of concentrated HCl, and 60 ml of 95% ethanol was stirred at reflux 3 hours. The mixture was basified with potassium carbonate solution and filtered. The cake was washed with ethyl acetate and the filtrate separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (10:1 hexane-ethyl acetate) and then recrystallized from ethyl acetate-hexane to give 3.8 g of 2-(3-chlorophenyl)-1-[4-(dimethylamino)phenyl]ethanone, m.p. 126°-128° C.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(C)nc3)CCC2)CCN(C)C1
Temperature: 90 °C
Yield: 25.1 %

Procedure:
5-(2-Bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (127 mg, 0.58 mmol) and K2CO3 (120 mg, 0.87 mmol) were mixed in 1,2-dimethoxyethane (4 mL) and water (2 mL). The reaction mixture was purged with nitrogen, Pd(PPh3)4 (17 mg, 0.0147 mmol) was added and the reaction mixture was heated at 90° C. for 45 min. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 26 mg of 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (dd, 1H), 7.61 (d, 1H), 7.31 (s, 1H), 6.95-7.10 (m, 2H), 4.7 (d, 1H), 4.38 (d, 1H), 3.8 (m, 1H), 3.55 (m, 1H), 2.82-3.2 (m, 9H), 2.61 (s, 3H), 2.4 (s, 3H), 2.3 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH:6][C:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
L-Phenylalanine methyl ester hydrochloride (77.0 mmol) and 5-chloro-1 H-indole-2-carboxylic acid (77 mmol) were coupled according to procedure A (0-25° C.) and the product purified by chromatography on silica gel in 10 and 20% ethyl acetate-hexanes giving the title substance as an off-white solid (22.12 g, 81%): mp 156-157° C.; HPLC (60/40) 9.5 minutes (98%); PBMS 357/359 (MH+, 100%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)N.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=O)[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C:16]3[C:8]4[CH:7]=[CH:6][CH:5]=[N:4][C:3]=4[NH:1][C:17]=3[C:18]([CH3:21])([CH3:22])[C:19]=2[CH:20]=1
Reactant: NNc1ccccn1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3ncccc3c1C2
Temperature: 190 °C
Reaction time: 48 h

Procedure:
2-Hydrazinopyridine (1.3 g, 11.8 mmol) and 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.4 g, 11.8 mmol) were dissolved in NMP (60 mL), and stirred at 190° C. for 48 hr. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the target compound (white solid, 101 mg, 3%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:16]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH:21]([C:26](OC)=[O:27])[CH2:20]1)(=[O:18])[CH3:17].[O-]CC.[Na+].O>C(O)C>[OH:27][C:26]1[C:21]2[CH2:20][N:19]([C:16](=[O:18])[CH3:17])[CH2:24][CH2:23][C:22]=2[N:14]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:11][CH:10]=2)[N:15]=1
Reactant: COC(=O)C1CN(C(C)=O)CCC1=O
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Yield: 61.8 %

Procedure:
1-(4-(Oxazol-5-yl)phenyl)guanidine (2.7 g, 13.35 mmol), methyl 1-acetyl-4-oxopiperidin-3-carboxylate (2.66 g, 13.35 mmol) and sodium ethoxide (0.946 g, 13.35 mmol) in ethanol (15 mL) were heated in a microwave reactor at 100° C. for 15 minutes. The reaction mixture was allowed to reach room temperature and water was added. The solid obtained was filtered, washed with water and dried in a vaccum oven yielding 1-(4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (2.90 g, 61.8%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=[O:9])[CH2:4][CH2:5][CH3:6].C=O.C[CH2:17][O:18]CC>CO.O>[CH2:3]([C:7]([CH2:17][OH:18])([CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCC(C=O)CCCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(C=O)(CO)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of 1 N sodium hydroxide (150 mL) was added dropwise to a solution of 209 g of dibutylacetaldehyde (supplied from Aldrich) and 127 g of an aqueous solution of 35% formalin (supplied from Wako Pure Chemical Industries) in 1500 mL of methanol under ice cooling, and stirred at room temperature overnight. Then 2 L of ether and 2 L of water were added to the reaction solution, and the mixture was separated into two liquid phases. The organic layer was dried on sodium sulfate anhydrate and concentrated, to yield 248 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25](O)=[O:26])=[CH:18][C:17]=4[CH:28]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:51][C:52]1[CH:67]=[CH:66][C:55]([CH2:56][N:57]([CH2:59][CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH3:58])=[CH:54][CH:53]=1>CN(C=O)C.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:64]([O:63][C:61]([CH2:60][CH2:59][N:57]([CH2:56][C:55]1[CH:66]=[CH:67][C:52]([NH:51][C:25]([C:19]2[CH2:20][CH2:21][S:22](=[O:24])(=[O:23])[C:16]3[CH:17]=[CH:28][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:12][CH:11]=4)=[CH:14][C:15]=3[CH:18]=2)=[O:26])=[CH:53][CH:54]=1)[CH3:58])=[O:62])[CH3:65]
Reactant: CCOC(=O)CCN(C)Cc1ccc(N)cc1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (101 mg) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (144 mg), and the mixture was stirred for 2 hours. To the mixture were added a solution of ethyl 3-[N-(4-aminobenzyl)-N-methylamino]propionate (133 mg) and triethylamine (0.1 ml) in DMF (5 ml) and a piece of 4-dimethylaminopyridine, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:9) and recrystallized from ethyl acetate/hexane to give yellow crystals of N-[4-[N-(2-ethoxycarbonylethyl)-N-methylaminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 24) (133.6 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:3][CH2:4][CH3:5].Cl.[NH:17]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:18]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:19][CH2:20][C:21](=O)[OH:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:17]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@H:18]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:19][CH2:20][C:21]([NH:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:3][CH2:4][CH3:5])=[O:22]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCC[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The resulting H-Nva-OBzl.HCl was dissolved in methylene chloride (60 mL) and the resulting reaction solution was maintained at 0° C. To the reaction solution, Z-Glu-OBzl (N-α-carbobenzoxy-L-glutamic acid α-benzyl ester, 3.24 g, 8.72 mM), triethylamine (1.34 mL, 1.1 eq., 9.59 mM), HOBt.H2O (1-hydroxybenzotriazole hydrate, 1.47 g, 1.1 eq., 9.59 mM) and WSC.HCl (1.84 g, 1.1 eq., 9.59 mM) were added. The temperature of the reaction solution was gradually increased and stirred at room temperature overnight (16 hours). Then the reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the resulting residue, and the organic phase was then washed once with water (80 mL), twice with a 5% aqueous solution of citric acid (80 mL), once with a saturated common salt solution (80 mL), twice with a 5% aqueous solution of sodium hydrogen carbonate (80 mL), and once with a saturated common salt solution (80 mL). Then, the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed through filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate and n-hexane, the crystals thus obtained were collected through filtration and dried under reduced pressure to give crystals of Z-Glu(Nva-OBzl)-OBzl (4.05 g).