Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:35][NH:34][CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CNC2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl 3-(N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl}-piperidyl)-2-oxoethyl]-carbamoyl)azetidinecarboxylate (Step a) (309 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min]provided the title compound (TFA salt) as a white foam (205 mg). MS (ESI, pos. ion) m/z: 519 (M+1); (ESI, neg. ion) m/z: 517 (M−1). Calc'd for C25H31ClN4O4S: 518.18. Anal. Calcd for C25H11ClN4O4S 1.4C2HF3O2: C, 49.20; H, 4.81; N, 8.26. Found: C, 49.31; H, 4.91; N, 8.25.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.[Cl-].[Na+]>CO.O>[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC1c1ccc(C(C)(C)C)s1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(C2CC2C(=O)O)s1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Ethyl 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylate (4.49 g, 0.018 mol) was dissolved in methanol (45 ml) and a solution of potassium hydroxide (1.99 g, 0.036 mol) in water (45 ml) added dropwise at room temperature. The solution was refluxed for 3 hours, cooled to room temperature and carefully neutralised with 2M HCl. Saturated sodium chloride was added, the aqueous solution extracted with ethyl acetate (4×50 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylic acid (3.79 g, 94%).
Reaction SMILES: C1(COC([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]2=[O:27])=O)C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].C1COCC1>[NH2:11][C@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[C:13]1=[O:27]
Reactant: O=C(N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a 30° C. mixture of 1-[((3S)-3-[(phenylmethoxy)carbonyl]amino-hexahydro-2-oxo-1H-azepin-1-yl)acetyl]pyrrolidine (20 g, 54 mmol), ethanol (100 mL), THF (100 mL) and wet 10% Pd/C (4 g) was added ammonium formate (5.1 g, 81 mmol) over 45 min. After stirring for 3 h, the reaction was cooled to room temperature and filtered. The filtrate was concentrated, taken up in TBME (150 mL) and filtered again. The filtrate was concentrated in vacuo to provide 12.3 g (95%) of (S)-1-[(3-amino-hexahydro-2-oxo-1H-azepin-1-yl)acetyl]pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[CH2:32]([CH:34]([NH2:37])[CH2:35][CH3:36])[CH3:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:37][CH:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[O:13]
Reactant: CCC(N)CC
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)NC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and 1-ethylpropylamine (66 mg, 0.7586 mmol) were dissolved in methylene chloride (5 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (146 mg, 0.7616 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]-1-ethylpropylamine (63 mg, 0.1280 mmol, 54%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:12][C@H:11]2[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[NH:5]1)([OH:3])=[O:2].[C:13]([C@@H:18]([NH:22][C@H:23]([C:25](O)=[O:26])[CH3:24])[CH2:19][CH2:20][CH3:21])([O:15][CH2:16][CH3:17])=[O:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Na+].[Cl-]>C(#N)C.C(N(CC)CC)C>[CH2:16]([O:15][C:13]([C@@H:18]([NH:22][C@@H:23]([CH3:24])[C:25]([O:2][C:1]([CH:4]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[NH:5]1)=[O:3])=[O:26])[CH2:19][CH2:20][CH3:21])=[O:14])[CH3:17]
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)OC(=O)C1CC2CCCCC2N1)C(=O)OCC

Procedure:
Mixture of 855 mg of benzyl ester of (2S,3aS,7aS)-2-carboxyperhydro indole, 651 mg of N-((S)-1-carbethoxybutyl)-(S)-alanine and 1137 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 0.84 ml of triethylamine was stirred in 20 ml of acetonitrile for 30 minutes. 50 ml of saturated NaCl was added and product was extracted twice with 35 ml of EtOAc. Combined extracts were washed with 70 ml of water/1 ml of conc. HCl and than with 130 ml of waters dried with Na2SO4 and evaporated at 40° C. in vacuum. 1210 mg (87.7%) of benzyl (2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahydroindole-2-carboxylate (benzyl ester of perindopril) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (25 gm.) was suspended in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (22.8 gm).
Reaction SMILES: [Li+].[F:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=O.Cl.Cl.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[F:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH3:22])=[O:7]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C([O-])c1ccc(OCc2ccccn2)cc1F
Agent: Cl
Agent: [Li+]
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A from 2-Fluoro-4-(pyridin-2-ylmethoxy)-benzoic acid lithium salt and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine dihydrochloride salt. MS (ES+) 398.3
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.Cl[C:12]1[N:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17](=[O:23])[C@@H:16]([CH2:24][CH3:25])[N:15]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]=2[N:13]=1>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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]>[CH:26]1([N:15]2[C:14]3[N:13]=[C:12]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[N:21]=[CH:20][C:19]=3[N:18]([CH3:22])[C:17](=[O:23])[C@H:16]2[CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: c1cscn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3nccs3)nc2N1C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (5 eq) in dry THF, BuLi (5 eq) was added dropwise at −78° C. and this was stirred at −78° C. for 30 min. ZnCl2 (1M in ether, 5 eq) was added and stirred at 0° C. for 30 min, then Intermediate B (1 eq) and Pd(dppf)Cl2 (0.1 eq) were added. The reaction was heated to 70° C. for 16 h; then the mixture was diluted with EtOAc, washed with brine and concentrated. The residue was purified by silica gel flash chromatography to give the title compound. LCMS (0.05% TFA): 344.1 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.04 (bs, 1H), 7.99 (bs, 1H), 7.76 (bs, 1H), 4.41 (m, 2H), 3.42 (s, 3H), 2.16 (m, 2H), 2.09˜1.72 (m, 8H), 0.88 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]2([NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([C:25]([N:9]2[C:7](=[O:8])[C:4]3([CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]3)[NH:12][C:10]2=[O:11])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: O=C1NC(=O)C2(CCCCC2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC2(CCCCC2)C(=O)N1C(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
5,5-Pentamethylenehydantoin (2.00 g) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (60%, in oil) (0.49 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthoyl chloride (2.33 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the white solid. Further recrystallization with IPE and ethyl acetate afforded 1.87 g of white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:29][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc4ccccc4c3)c2c1

Procedure:
A mixed solution of 2.2 g of the above-mentioned 2-tert-butyl-9-(naphthalene-2-yl)anthracene, 3.7 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under nitrogen gas stream at room temperature for 1 hour. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(naphthalene-2-yl)anthracene.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(O)C.O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 68.8 %

Procedure:
147 g of the crude diethyl 2-methyl-2-(4-nitrophenyl)-malonate was dissolved in 600 ml of ethanol, and to this was added a solution of 42.4 g (0.846 mole) of 93% sodium hydroxide in 400 ml of water and the solution was reacted at 50° C. for 3 hours. After that, to the reaction mixture was added 1 l of water and the formed oily substance and an aqueous layer were separated. The aqueous layer was acidified with conc. hydrochloric acid and was extracted with 700 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering out magnesium sulfate, ethyl acetate was distilled off to give 66.8 g of crude 2-(4-nitrophenyl)propionic acid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC([S:24]([Cl:27])(=[O:26])=[O:25])=CC=1.N1C=CC=CC=1>ClCCl>[CH3:1][CH2:2][CH2:3][CH:4]([S:24]([Cl:27])(=[O:26])=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCC(O)CCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(CCC)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hexadecanol (12.29 g 0.051 mol) and p-Toluenesulfonyl chloride (12 g 0.063 mol) were dissolved Pyridine (100 ml) and stirred overnight at room temperature. Dichloromethane (400 ml) was added. Dichloromethane solution was then washed well with water, H2SO4 (3%), water, NaHCO3 (3%) and water, dried with anhydrous magnesium sulphate (10 g). After evaporation of the solvent 20 g of crude 4-Hexadecanesulfonyl chloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cccc(C2=Nc3cccnc3Nc3ccccc32)c1
Reaction time: 8 h

Procedure:
A mixture of 14 g (0.0433 mole) of [2-[(3-amino-2-pyridinyl)amino]phenyl](3-chlorophenyl)-methanone and 0.3 g of para toluene sulfonic acid in 500 ml of toluene were heated at reflux overnight using a Dean-Stark trap to collect water. At the end of the reflux time, some of the toluene (ca 250 ml) was distilled off and the hot solution was filtered. Pet. ether (30°-60° C.) was added to the cloud point. The solution was refrigerated overnight and filtered to give, after air drying, 10 g (76%) gold colored crystals. A portion was recrystallized from isopropyl alcohol-isopropyl ether, m.p. 160°-160.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].CC(OC([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=2)[C:48](O)=[O:49])[CH2:40][CH2:39]1)=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)=[CH:4][C:3]=1[CH2:2][NH:1][C:48](=[O:49])[C:47]1[CH:51]=[CH:52][CH:53]=[C:45]([CH2:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CNC(=O)c4cccc(CC5CCNCC5)c4)c3)c2)CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-4′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (0.108 g, 0.261 mmol) in DMF (2.5 mL) was added the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (0.083 g, 0.261 mmol), HATU (0.110 g, 0.290 mmol), and diisopropylethylamine (0.10 mL, 0.574 mmol). The reaction was allowed to stir at room temperature for 2 days. The reaction was diluted with EtOAc (75 mL), washed with 1N HCl (2×20 mL), then saturated NaHCO3 (3×20 mL), then brine (2×20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was taken up in MeOH (4 mL) and HCl (4N in 1,2-dioxane, 2.5 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction was concentrated under vacuum, and the residue was taken up in 1 DMSO/1 MeOH and purified via MDAP (10-90% CH3CN/H2O/(0.1% TFA)). The desired fractions were isolated, and then taken up in DCM (8 mL) and 1N NaOH (8 mL) and allowed to stir for 1 hour. The DCM was isolated using a phase separator and then concentrated under vacuum to give the title compound (84.6 mg, 67.1%). El-MS m/z 515(M−H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=O.Cl.[NH2:25]N.O.CCOC(C)=O>C(O)C>[NH:25]1[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCCC(c2ccn[nH]2)C1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of (E)-benzyl 3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate (19 g, 54.05 mmol, 1.00 equiv, 90%) in ethanol (100 mL). To this was added conc.HCl (3 mL, 36%) drop wise and allowed to stir for 10 minutes. Then, to the resulting mixture was added NH2NH2.H2O (60 mL, 80%) and refluxed overnight. The progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the resulting mixture was concentrated on a rotary evaporator and diluted with H2O (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). Combined organic layers were dried over anhydrous magnesium sulfate, filtered off and concentrated on a rotary evaporator affording a residue that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (2:3) to give benzyl 3-(1H-pyrazol-5-yl)piperidine-1-carboxylate as colorless oil (13 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:32]=O)=[C:26]3[C:31]=2[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:32]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[C:26]3[C:31]=2[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1[nH]c(C(=O)NCCCN2CCCC2)c2c1CCCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]c(C(=O)NCCCN2CCCC2)c2c1CCCC2
Yield: 21.9 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (120 mg) to give 43 mg (22%) of the title compound as a tan-orange solid.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([OH:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:22][C:16]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: COC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1(O)CNC1
Reaction time: 3 h

Procedure:
A reactor was charged with methyl 1-benzhydryl-3-hydroxyazetidine-3-carboxylate (1.6 g, 5.4 mmol), 10% Pd/C (0.300 g, 2.8 mmol), and glacial acetic acid (0.300 mL, 5.2 mmol) in MeOH (30 mL). The mixture was allowed to stir for 3 h under 50 psig of H2. The crude was filtered through Celite and rinsed with MeOH. After evaporation, the solid was rinsed with Et2O to give methyl 3-hydroxyazetidine-3-carboxylate as the acetic acid salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.74 (d, J=9.1 Hz, 2H), 3.69 (s, 3H), 3.44 (d, J=8.9 Hz, 2H), 1.88 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a colorless oil, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(O)cc3)c2CC1)C(F)(F)F
Temperature: 25 °C
Yield: 55.1 %

Procedure:
Dissolve 7-chloro-6-(4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.667 g) in DCM (40 mL). Add a 1M solution of boron tribromide in DCM (10 mL) at 0° C. Stir the reaction for 12 h and gradually raise to room temperature. Quench the reaction with saturated aqueous NaHCO3 and extract with DCM three times. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to give the title compound as an oil (888 mg). MS (ES+) m/z: 399 (M+1)+.