Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)cccc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-(morpholin-4-yl)benzaldehyde (1.34 g, 5.92 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol, 0.910 equiv), 1,2-dichloroethane (30 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (3.42 g, 16.1 mmol, 2.72 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with 1,2-dichloroethane (20 mL). The resulting mixture was washed with H2O (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/2) to yield 1.80 g (77% yield) of tert-butyl 4-[[2-chloro-6-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].[C:13](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:13])[C:7]=12
Reactant: CC(=O)O
Reactant: Clc1nccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of Mel (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1(M+H) (found).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C@H:56]2[C@@H:51]([CH2:52][CH2:53][CH2:54][CH2:55]2)[CH2:50][CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][CH2:50][C@@H:51]5[C@H:56]([CH2:55][CH2:54][CH2:53][CH2:52]5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC[C@H]3CCCC[C@@H]3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with trans-decahydroisoquinoline (TCI-US) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH:19]=O.[BH4-].[Na+]>C(OCC)C.CO>[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH2:19][NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)C#CC=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C#CC=CCNCc1cccc2ccccc12

Procedure:
A mixture of 1-naphthalenemethanamine (1.34 g, 8.51 mmol) and 6,6-dimethyl-2-hepten-4-ynal (1.16 g, 8.51 mmol) in 20 ml of dry ethyl ether was stirred over 4A sieves overnight. Sieve material was then removed by centrifugation, washed once with ethyl ether and the combined ether fractions concentrated to afford the crude condensed product. About 8.08 mmol of this material was stirred with sodium borohydride (343 mg, 9.06 mmol) in 20 ml of methanol at room temperature for 3.75 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate and methylene chloride, the aqueous layer extracted twice with methylene chloride, and the combined organic solution washed with water and dried over magnesium sulfate. Removal of the solvent afforded N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine as a mixture of the E and Z isomers. Flash chromatography of this product on silica gel (5 cm column, eluting with 0.2% triethylamine in chloroform) afforded 0.74 g of the pure (E)-N-6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)(=O)[CH3:2].[NH2:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O>C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:26][C:24]1[CH:25]=[C:18]2[C:19]([CH:20]=[CH:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]4[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=4[CH:16]=3)=[N:17]2)=[CH:22][CH:23]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Temperature: 200 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 5-acetyl-2-methoxycarbonylbenzofuran (0.57 g), 2-amino-4-chlorobenzaldehyde (0.40 g) and p-toluenesulfonic acid monohydrate (0.04 mg) was stirred at 200° C. for 3 hours. After being cooled, the resulting mixture was dissolved in chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrated under reduced pressure to give 7-chloro-2-(2-methoxycarbonylbenzofuran-5-yl)quinoline (0.32 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[OH:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[O:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(O)c2ccco2)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccco2)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
The alcohol (3.2 g) was stirred with manganese (IV) oxide (10 g) in CH2Cl2 (100 ml) at RT for 3 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The residual dark oil was subjected to chromatography (SiO2) to give (3-cyclopentyloxy-4-methoxyphenyl)-(2-furyl)ketone (1.9 g); vmax (neat) 1620cm-1. n-Butyllithium (1.6M solution in hexanes; 4.2 ml, 6.64 mmol) was added to a solution of a 4-methylpyridine (0.62 g, 0.65 ml, 6.64 mmol) in THF (25 ml) at -70° C. After 0.5 h, a solution of the crude ketone (1.9 g, ca 6.6 mmol) in THF (5 ml) was added, stirred for 1 h at -70° C., then at RT fix 0.25 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The extract was dried (MgSO4), concentrated in vacuo, and the residual red oil subjected to chromatography (SiO2 ; EtOAc/hexane, 3:2) to afford the title compound (1.23 g, 49%) as a pale yellow oil; δH (CDCl3) 1.5-1.9 (8H, br m, (CH2)4), 2.84 (1H, br s, OH), 3.30 (1H, d, J 13.2 Hz, CHAHB pyridine), 3,59 (1H, d, J 13.2 Hz, CHAHB pyridine), 3.82 (3H, s, OMe), 4.65 (1H, br m OCH), 6.24 (1H-[, dd, J 3.3, 0.7Hz, furan H3), 6.35 (1H, dd, J 3.3, 1.8Hz, furan H4), 6.75-6.85 (3H, m, C6H3), 6.85 (2H, dd, J 4.5, 1.6Hz, pyridine H3,H5), 7.43 (1H, dd, J 1.8, 0.7Hz, furan H5), and 8.33 (2H, dd, J 4.5, 1.6Hz, pyridine H2, H6); m/z (ESI) 402 (M+ +23, 20%), 380 (M+ +1, 35), 287 (100), 95 (28), and 94 (97).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(F)nc1I
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(F)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (56 mg), and 4-dimethylaminopyridine (31 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (2 mg, yield 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 91 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-chlorobenzofuran, mp. 99°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:27][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(N)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and was added ammonium hydroxide (2.0 mL, excess), and HOBt (645 mg, 4.78 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (0.990 g, 99% yield) MS (ESI+) m/z=251 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[S:9][C:10]=1[C:11]([C:13]#[C:14][CH2:15][O:16][CH3:17])=[O:12].[H][H]>C(O)C.[C].[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[S:9][C:10]=1[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12]
Reactant: COCC#CC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCCC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Yield: 99.9 %

Procedure:
Compound 414 (92.3 mg, 0.255 mmol) was dissolved in ethanol (5 mL), and 10% palladium-carbon (15.8 mg) was added thereto, followed by stirring in an atmosphere of hydrogen at room temperature for 1.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the entitled Compound 415 (93.3 mg, 100%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (35%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]2[C:16](=[O:18])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=1
Reactant: CCCCN
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 5 °C

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 550 g of anhydride. To a solution of the anhydride in 600 ml of toluene was added 219 g of n-butylamine diluted with an equal weight of toluene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot toluene solution was cooled to 5°C to give 280 g of crude 4-chloro-N-butyl phthalimide. Recrystallization from 1000 ml ethanol afforded 240 g of 99% pure imide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:19]([Cl:30])=[CH:18][N:17]=1>>[Cl:30][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4O)n3)cc2CC1
Yield: 35 %

Procedure:
Analagous to Example 318b, trans-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-cyclopropyl-benzamide was prepared from 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol in 35% yield as a foam. LCMS (m/e) 416 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.35 (s, 1H), 7.23 (m, 1H), 7.05 (m, 1H), 6.82 (s, 1H), 5.16 (m, 1H), 3.90 (m, 1H), 3.48 (m, 1H), 2.7-3.2 (m, 10H), 2.14 (m, 2H), 1.78 (m, 2H), 1.2-1.5 (m, 8H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][NH:12][C:13]([C:15]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([F:34])[C:18]2[N:19]=[CH:20][N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14])C)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[OH:40][C:38]([C:37]([F:42])([F:41])[F:36])=[O:39].[CH3:6][NH:7][CH2:9][CH2:10][O:11][NH:12][C:13]([C:15]1[C:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[Cl:33])=[C:23]([F:34])[C:18]2[N:19]=[CH:20][N:21]([CH3:22])[C:17]=2[CH:16]=1)=[O:14]
Reactant: CN(CCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
Prepared from (2-{[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethyl)-methyl-carbamic acid tert-butyl ester 29ww by trifluoroacetic acid deprotection in methylene chloride. MS APCI (+) m/z 470, 472 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.74 (s, 1H), 7.51 (d, 1H), 7.19 (dd, 1H), 6.39 (dd, 1H), 4.11 (m, 2H), 3.97 (s, 3H), 3.12 (m, 2H), 2.72 (s, 3H); 19F NMR (376 MHz, CD3OD) −77.41 (s, 3F), −134.79 (s, 1F).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][O:23][CH3:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a mechanically stirring solution of (R)-tert-butoxycarbonylamino-(4-hydoxy-phenyl)-acetic acid (37.41 g, 140 mmol) (pepared according to the procedure of Salituro, G. M.; Townsend, C. A. J. Am. Chem. Soc. 1990, 112, 760) in N,N-dimethylformamide (750 mL) cooled in a dry ice/acetone bath was added sodium hydride (60% suspension in mineral oil) (12.32 g, 308 mmol) in small portions. The mixture was stirred while cooling in a dry ice/acetone bath for 30 minutes, then a solution of bromoethyl methyl ether (19.73 mL, 210 mmol) in N,N-dimethylformamide (200 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and acidified using concentrated aqueous hydrochloric acid to pH=1. The resulting mixture was extracted with ethyl acetate (3×), the organic extracts were combined, washed with water, brine and dried over sodium sulfate. Evaporation of the solvents gave (R)-tert-butoxycarbonylamino-{4-[2-(methoxy)-ethoxy]-phenyl}-acetic acid as a white solid (35.7 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]1[CH2:18]OS(C)(=O)=O.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@@H:7]1[CH2:18][NH:31][CH3:30]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)[C@H]1COS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CCN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2R,3S)-tert-butyl 3-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 and once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 147% mass balance; the material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](O)=O)=[CH:6][CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:50]=[C:51]([CH:59]=[CH:60][C:61]=1[NH:62][CH2:63][CH:64]1[CH2:66][CH2:65]1)[C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53]>>[CH:64]1([CH2:63][N:62]2[C:61]3[CH:60]=[CH:59][C:51]([C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53])=[CH:50][C:49]=3[N:48]=[C:12]2[CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)[CH2:65][CH2:66]1
Reactant: CCN(CC)C(=O)c1ccc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(CCc2nc3cc(C(=O)N(CC)CC)ccc3n2CC2CC2)cc1
Yield: 57 %

Procedure:
Following general procedure 13B, 3-(4-ethoxyphenyl)propanoic acid (0.0409 g, 0.211 mmol), HATU (0.0801 g, 0.211 mmol), DIPEA (0.050 mL, 0.29 mmol), and 3-amino-4-[(cyclopropylmethyl)amino]-N,N-diethylbenzamide (0.0500 g, 0.191 mmol) were combined. The crude product was purified by column chromatography (19:1 CH2Cl2:MeOH) to provide the title compound (0.0457 g, 57%). 1H-NMR (CD3OD): δ 7.64 (s, 1H), 7.55 (d, 8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 3.97 (d, J=7.2 Hz, 2H), 3.95 (q, J=6.8 Hz, 2H), 3.57 (br s; 2H), 3.34 (br s, 2H), 3.23-3.07 (m, 4H), 1.34 (t, J=6.4 Hz, 3H), 1.36–1.02 (overlapping 2×br s and m, 7H), 0.55–0.46 (m, 2H), 0.40–0.32 (m, 2H). 13C-NMR (CD3OD): δ 174.08, 159.08, 157.72, 142.60, 136.95, 133.70, 132.03, 130.46, 121.97, 117.21, 115.59, 111.83, 64.41, 48.69, 45.15, 40.98, 34.38, 30.54, 15.18, 14.43, 13.12, 12.15, 4.54. MS (ESI) (M+H)+=420. The HCl salt was prepared using HCl in Et2O. A white solid was obtained after lyophilization. Anal. Calcd for C26H33N3O2.1.0HCl.0.8H2O: C, 66.38; H, 7.63; N, 8.93. Found: C, 66.35; H, 7.60; N, 8.81.