Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)c2cncn2C)ccc1N
Temperature: 25 °C

Procedure:
A mixture of (1-methyl-1H-imidazol-5-yl)(3-methyl-4-nitrophenyl)methanone (3.3 g, 13.456 mmol, Intermediate 40: step b) and tin(II)chloride dihydrate (15.6 g, 67.282 mmol) in EtOH (80 mL) was stirred at reflux for 1 hour, cooled to room temperature overnight and evaporated in vacuo to remove most of the EtOH. The residue was poured into a 3M aqueous NaOH/ice solution rinsing with EtOAc. The mixture was stirred at room temperature for 15 minutes and layers were separated. The aqueous layer was again extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to provide crude product. The tan solid title compound was precipitated from Et2O, collected by filtration and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@@H:4]([NH:14][C:15]([C:17]1[N:18]=[C:19]([CH2:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH:21]=2)=[O:16])[CH2:5][C:6]1[S:7][C:8]([CH:11]=[CH:12][CH3:13])=[CH:9][CH:10]=1>[Pd]>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([C:15]([NH:14][C@@H:4]([CH2:5][C:6]4[S:7][C:8]([CH2:11][CH2:12][CH3:13])=[CH:9][CH:10]=4)[C:3]([OH:44])=[O:2])=[O:16])[N:18]=[C:19]3[CH2:38][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)([CH3:36])([CH3:35])[CH3:37].[CH3:1][O:2][C:3](=[O:44])[C@@H:4]([NH:14][C:15]([C:17]1[N:18]=[C:19]([CH2:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:32][CH:33]=1)[CH:21]=2)=[O:16])[CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH3:13])=[CH:9][CH:10]=1
Reactant: CC=Cc1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)OC)s1
Agent: [Pd]
Product: CCCc1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)O)s1
Product: CCCc1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)OC)s1

Procedure:
The title compound was prepared by treatment of 2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propenylthiophen-2-yl)-propionic acid methyl ester (prepared in Example 23) with Pd/C and H2 (1 atm) by the general procedure N to afford 2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propylthiophen-2-yl)-propionic acid methyl ester. The ester was hydrolyzed by the general procedure C to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=[C:5]([CH:13]=[CH2:14])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=[C:5]([CH:13]2[CH2:14][O:23]2)[CH:4]=1
Reactant: C=Cc1cc2c(c(OC)c1)C(=O)OC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C2CO2)cc2c1C(=O)OC2
Reaction time: 12 h

Procedure:
To a solution of 7-methoxy-5-vinyl-2-benzofuran-1(3H)-one in DCM (5 mL) was added meta-chloro perbenzoic acid (0.18 g, 1.05 mmol) at 0° C. and stirred for 12 h. TLC indicated completion of the reaction; the mixture was diluted with saturated sodium bicarbonate solution and extracted with DCM (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting epoxide was purified by silica gel column chromatography (hexanes/EtOAc=1/1) to give 7-methoxy-5-oxiran-2-yl-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=207.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CO>[BrH:14].[N:1]1([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: BrCCNCCBr
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2ccc(N3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A mixture of 23 g of 7-amino-3,4-dihydrocarbostyril, 48 g of bis(β-bromoethyl)amine hydrobromide and 200 ml of methanol was refluxed with stirring for 8 hours. After cooling to room temperature, 7.52 g of sodium carbonate was added to the mixture followed by refluxing while stirring for additional 8 hours. After distilling off methanol under reduced pressure, isopropanol was added to the residue. After cooling, crystals which precipitated were collected by filtration and recrystallized from ethanol 3 times to give 15 g of 7-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide, m.p. 174°-177° C., colorless granules.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[S:34]([Cl:37])(=[O:36])=[O:35].ClC1C=CC=CC=1S(NC1C=C(N2CCN(C(OC(C)(C)C)=O)CC2)C2OC=CC=2C=1)(=O)=O>CC#N>[ClH:37].[CH2:21]([N:20]([CH2:23][CH3:24])[C:18](=[O:19])[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:34]([C:28]3[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=3[O:26][CH3:25])(=[O:36])=[O:35])[CH:3]=2)[CH2:12][CH2:13]1)[CH3:22]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: CCN(CC)C(=O)CN1CCN(c2cc(N)cc3ccoc23)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Solvent: CC#N
Product: CCN(CC)C(=O)CN1CCN(c2cc(NS(=O)(=O)c3cc(C)ccc3OC)cc3ccoc23)CC1
Product: Cl

Procedure:
2-[4-(5-Amino-1-benzofuran-7-yl)piperazin-1-yl]-N,N-diethylacetamide (0.095 g, 0.29 mmol; Intermediate 23) was reacted with 2-methoxy-5-methylphenylsulfonyl chloride according to the procedure of Intermediate 19. Yield: 0.05 g (33%) after preparative HPLC (System F; 10-50% MeCN). HPLC purity 93%, RT=1.87 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.0 Hz, 3H) 1.16 (t, J=7.0 Hz, 3H) 2.20 (s, 3H) 3.08-3.45 (m, 7H) 3.58-3.73 (m, 4H) 3.87 (s, 3H) 4.40 (s, 2H) 6.61 (d, J=1.8 Hz, 1H) 6.85 (d, J=2.0 Hz, 1H) 6.93 (d, J=1.8 Hz, 1H) 7.04 (d, J=8.5 Hz, 1H) 7.32 (dd, J=8.8, 2.0 Hz, 1H) 7.52 (d, J=1.8 Hz, 1H) 7.89 (d, J=2.3 Hz, 1H) 9.75 (s, 1H) 10.07 (s, 1H) MS (ESI+) m/z 515.4 (M+H)+.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[CH2:9][O:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[CH2:9][O:10][C:11]1[C:12]2[N:13]([C:17]([CH2:3][N:4]([CH3:1])[CH3:5])=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C=O
Reactant: CNC
Reactant: Cc1cn2cccc(OCc3ccccc3Cl)c2n1
Solvent: CC(=O)O
Product: Cc1nc2c(OCc3ccccc3Cl)cccn2c1CN(C)C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of 37% aqueous formaldehyde (2.38 g) in acetic acid (38 ml) was added dropwise 50% aqueous dimethylamine (2.63 g) with ice-cooling over a period of 10 minutes and the mixture was stirred for an additional 10 minutes. The mixture was heated at 50°-55° C. for 2 hours after an addition of 8-(2-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (7.6 g) thereto and then evaporated in vacuo. The residue was basified with aqueous sodium hydroxide and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residual solid was recrystallized from a mixture of diethyl ether and n-hexane to give 8-(2-chlorobenzyloxy)-3-dimethylaminomethyl-2-methylimidazo[1,2-a]pyridine (7.85 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19]>C(Cl)Cl.O1CCOCC1>[CH2:18]([O:20][CH:21]([N:12]1[C:13]([NH2:14])=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11]1)[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Temperature: 75 °C
Yield: 80.3 %

Procedure:
A solution of N-(4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (17.6 g, 78 mmol), ethoxyethene (11.2 mL, 117 mmol) and HO in 1,4-dioxane (1 mL, 4 mmol) in CH2Cl2 (520 mL) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in ethanol (260 mL) and 25% aq. NaOH solution (260 mL) and the reaction mixture was heated to 75° C. for 4 h and cooled to room temperature. The ethanol was partly concentrated in vacuo and the resulting solid collected by filtration, washed with water and minimum cold ethanol and dried in vacuo to provide the title compound as a solid (16 g).
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH2:41])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>N1C=CC=CC=1>[CH3:46][S:47]([NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45])(=[O:49])=[O:48]
Reactant: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(N)c(OC)c5)cn4)CC3)nc2)cc(OC)c1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(NS(C)(=O)=O)c(OC)c5)cn4)CC3)nc2)cc(OC)c1NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a solution of 1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine tetrahydrochloride (40.0 mg, 0.0570 mmol), which was synthesized in Example 34, in pyridine (1.0 mL) was added methanesulfonyl chloride (30.0 mg, 0.260 mmol). The reaction mixture was stirred for 15 minutes, and concentrated under reduced pressure. A solution of the residue in methanol-chloroform (1:10) was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a pale brown crystalline powder (melting point: 235.0-239.0° C.) (28.0 mg, yield: 68%).
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C([O-])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(O)(=O)C=CC1C=CC=CC=1>>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:1])[CH3:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])C=Cc1ccccc1
Agent: O=C(O)C=Cc1ccccc1
Agent: [Na+]
Product: CC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
10 Liters of medium were prepared in a 14 L fermenter and were sterilized at 121° C. for 30 minutes. After sterilization, 100 g of sterile 50% dextrose solution and 100 ml of 48 hours grown inoculum were added. Periodically, after 24 hours of incubation, aliquouts of sterile 10% sodium cinnamate solution, pH 7.0 were added to maintain an approximate concentration of 5 g/L cinnamic acid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Fc1ccc(CCl)c(Cl)c1
Solvent: CCO
Product: Cl
Product: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c(Cl)c1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-chloro-4-fluorobenzyl chloride (281 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 249 mg of the product 229. 1H NMR (DMSO-d6) δ 11.35 (s, 2H), 8.00-7.80 (m, 1H), 7.75-7.60 (m, 1H), 7.55-7.35 (m, 1H), 7.20-7.00 (m, 6H), 7.00-6.85 (m, 4H), 5.80 (s, 2H), 4.90 (s, 2H); MS: m/z 397 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[NH:7][CH:8]1[CH2:10][CH2:9]1.[C:16]([O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)([CH3:19])([CH3:18])[CH3:17].N12CCCN=C1CCCCC2>O.C(OCC)(=O)C>[CH:8]1([NH:7][C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([F:15])=[C:2]([N:23]3[CH:24]=[CH:25][CH:26]=[C:22]3[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH:11]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccn1-c1cc(NC2CC2)c([N+](=O)[O-])cc1F
Yield: 13 %

Procedure:
5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (460 mg, 2 mmol) is heated to 80° for 40 hours with L-proline tert-butyl ester (342 mg, 2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (304 mg, 2 mmol). The reaction mixture is then dissolved in a water/ethyl acetate mixture (1:1, 100 ml). The ethyl acetate phase is washed with 10 percent sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (eluent: hexane/ethyl acetate 8:2). The product is crystallized from ether/n-hexane. There are obtained 94 mg (13%) of tert-butyl rac-1-[5-(cyclopropylamino)-2-fluoro-4-nitro-phenyl]pyrrole-2-carboxylate with a m.p. of 142°-143°.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][S:7]([CH2:10][CH3:11])(=[O:9])=[O:8])(=[O:5])=[O:4])[CH3:2].[CH:12]([O-])([O-])OCC.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[CH2:10]([S:7]([C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:12][NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=1)(=[O:9])=[O:8])[CH3:11]
Reactant: CCOC([O-])[O-]
Reactant: CCS(=O)(=O)CS(=O)(=O)CC
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: CCS(=O)(=O)C(=CNc1ccc(Cl)cc1)S(=O)(=O)CC
Yield: 43.2 %

Procedure:
Ten grams (0.05 mole) of bis(ethylsulfonyl)methane, prepared by the procedure described in Cronyl "Sulfones. I. Methods for the Preparation of Certain Alkanes, Alkenes, Acids and Lactones with Bis-(ethylsulfonyl)-methane" in J. Am. Chem. Soc., vol. 74, page 1225 (see p. 1228), published 1952, was mixed with 7.4 grams (0.05 mole) of ethyl orthoformate and 6.4 grams (0.05 mole) of p-chloroaniline and the mixture was heated at 95°-145°C. (pot) during which time about 7 milliliters of ethanol distilled off. The reaction mixture was then further heated at 150°-160°C. for 1 hour and then cooled. The solid reaction product was then washed with cold ethanol, and recrystallized from ethanol to give 7.3 grams of 2,2-bis(ethylsulfonyl)vinyl-4-chloroaniline, melting point 173°-175°C. having the structural formula ##SPC5##
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=2)[C:22](Cl)=[O:23])[CH:12]=[CH:13][CH:14]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=1[CH3:40]>ClCCl.C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=3[CH3:40])=[O:23])[CH:25]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (74 ul, 0.53 mmol, 1.5 eq) was added to a suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoylchloride (105 mgs, 0.36 mmol) and ethyl (4-amino-3-methylphenyl)acetate (103 mg, 0.53 mmol, 1.5 eq) in dichloromethane (5 ml). The mixture was stirred at room temperature overnight. The mixture was then diluted with acetonitrile and purified by SCX cartridge (5 g) eluting with acetonitrile. Fractions containing product were combined and evaporated to give the title compound as a yellow gum, 174 mg. MS (ES+) m/z 452 [M+H]+ (C26H2635ClNO4).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH2:51]1>CN(C=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:50]5[CH2:53][CH:52]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH2:51]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: C1CN(C2CNC2)CCO1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)N2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (500 mg, 1.19 mmol), 2-chloro-1-methylpyridinium iodide (729 mg, 2.86 mmol) and DIPEA (500 μL, 2.87 mmol) in DMF (10 mL) was added 4-azetidin-3-ylmorpholine (288 mg, 2.0 mmol) and the resulting mixture allowed to stir at r.t for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc which was washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-5%) affording 799 as a cream solid (290 mg, 45%). LCMS (method G): RT 5.90 min, [M+H]+ 544.5. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.67-7.67 (1 H, m), 7.28-7.20 (2 H, m), 4.73-4.72 (1 H, m), 4.70-4.00 (4 H, brd s), 4.53-4.51 (1 H, m), 4.29-4.21 (1 H, m), 4.18-4.08 (4 H, m), 3.87 (4 H, t, J=4.67 Hz), 3.78 (4 H, t, J=4.60 Hz), 3.30-3.30 (1 H, m), 2.88-2.88 (1 H, m), 2.47-2.45 (4 H, m), 1.35-1.34 (2 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([CH:26]=O)[CH:23]=[N:24][CH:25]=2)=[CH:16][CH:15]=1.[H][H]>C1COCC1.[Pd]>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]([CH2:26][NH:1][CH2:2][C@H:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[O:4]3)[CH:23]=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: NC[C@H]1CCc2ccccc2O1
Reactant: O=Cc1cncc(-c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Fc1ccc(-c2cncc(CNC[C@H]3CCc4ccccc4O3)c2)cc1
Yield: 100 %

Procedure:
5.07 g of (R)-2-aminomethylchroman and 5.00 g of 5-(4-fluorophenyl)-pyridine-3-carbaldehyde are dissolved in 38 ml of THF, and 6 g of 5% palladium on activated carbon are added with stirring. The mixture is hydrogenated at room temperature under atmospheric pressure with stirring. When the take-up of hydrogen is complete, the catalyst is filtered off, giving 8.66 g of (R)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman by removal of the solvent by distillation (68% yield).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[OH:30][C:31]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:32]=1[C:33](O)=[O:34]>>[OH:30][C:31]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:32]=1[C:33]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:34]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(O)ccc1O
Agent: Cl
Product: CN(C(=O)c1cc(O)ccc1O)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2,5-dihydroxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2,5-dihydroxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18])[C:9](O)=[O:10]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)Cc1ccc(C(=O)O)cc1Br
Product: CCC(C)Cc1ccc(C(=O)Cl)cc1Br
Yield: 98.1 %

Procedure:
Thionyl chloride (118 g) was added to the 3-bromo-4-(2'-methylbutyl)benzoic acid (100 g, 0.37 mol) followed by refluxing the mixture for 2 hours and distilling off excess thionyl chloride under reduced pressure to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid chloride (105.1 g).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[NH2:6][C:7]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[CH:9][N:8]=1>>[CH2:2]([C:1]1[NH:13][C:12]2[C:7]([N:6]=1)=[N:8][CH:9]=[CH:10][C:11]=2[CH3:14])[CH3:3]
Reactant: Cc1ccnc(N)c1N
Reactant: CCC(=O)O
Product: CCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
A mixture of propionic acid (0.89 ml, 12 mmols), 2,3-diamino-4-picoline (1.23 g, 10 mmol) and polyphosphoric acid (40 g) was heated to 100° C. for 6 hours. Work-up of the reaction and purification of the crude product according to the procedure described in Step 1 of Example 9 gave the desired compound (1.46 g, 90%) as a tan colored solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.I[CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:17]
Reactant: CCI
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), iodoethane (31 uL, 0.39 mmol, Sigma-Aldrich, Cat. No. 17780), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water. The product was extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 34 mg of the product which was directly used in the next step reaction without further purification.