Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.O>[CH3:17][S:18]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (23 g, 0.099 mol) and TEA (42 mL 0.298 mol) in dry dichloromethane (400 mL) maintained at 0° C. under nitrogen atmosphere, was added methanesulfonylchloride (12.6 g, 0.109 mol) over a period of 20 min. The reaction mixture was stirred at room temperature for 6 h and diluted with water. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtrated and concentrated. The crude product was recrystallized from petrol ether:EtOAc (9:1) to afford the title compound as a solid (27 g, 87% yield). TLC: Rf=0.75 (Chloroform:MeOH; 9:1). 1H NMR (CDCl3, 300 MHz) δ: 2.82 (3H, s), 3.32 (4H, m), 3.79 (4H, m), 6.68) (1H, d, J=9 Hz), 7.68 (1H, d, J=9 Hz), 8.42 (1H, s).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[N:33]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of the product from Example 1C (50 mg, 0.102 mmol) and aniline (0.2 ml, 2.19 mmol) were stirred at rt for 48 h. The mixture was partitioned between 1N aq. HCl and ethyl acetate, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in hexanes. The title compound was obtained as a yellow solid (19 mg, 48%).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45]Br)=[O:42])([CH3:39])([CH3:38])[CH3:37].[Na+].[I-]>CN(C=O)C.C1COCC1>[O:29]=[C:21]1[N:22]([CH2:45][CH2:44][NH:43][C:41](=[O:42])[O:40][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]1[CH:17]1[CH2:18][CH2:19][N:14]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:15][CH2:16]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a stirred mixture of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (100 mg, 0.257 mmol, this was prepared as Example 17) and THF (2 ml) was added t-BuOK (35 mg, 0.308 mmol) at 0° C. Then N-(t-butoxycarbonyl)-2-bromoethylamine (86 mg. 0.385 mmol, this was reported by E. Vedejs et al. J. Org. Chem. 1988, 33, 2226-2232). NaI (8 mg, 0.0513 mmol), and DMF (0.5 ml) were added to the reaction mixture. After 8 h stirring at 60° C., the reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2. washed with water, dried (Na2SO4). and filtered. The filtrate was concentrated and the residue was purified by preparative TLC (MeOH/CH2Cl2: 1/10) to give 98 mg (71.6%) of amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])C1C=CC=CC=1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: Nc1ccccc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)Nc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and aniline (10.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-phenylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (35.4 mg).
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].[CH3:47][C@@H:48]([CH2:51][CH3:52])[CH2:49][NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:50][CH2:49][C@@H:48]([CH3:47])[CH2:51][CH3:52])=[O:42])[CH2:38][CH2:39]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)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC[C@H](C)CN
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
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC[C@@H](C)CC)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 (S)-(−)-2-methylbutylamine (Alfa) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.COCCO.C(OCC)C.C(Cl)Cl>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C[C@@H](O)C(F)(F)F)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](O)C(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
(R)-3-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (82 mg, 0.30 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (95 mg, 0.28 mmol), and 4.00 M of Hydrogen chloride in 1,4-Dioxane (0.20 mL) were combined in 2-Methoxyethanol (2.5 mL) and heated at 120° C. After two hours, the mixture was cooled to room temperature, then diluted with 10 mL ethyl ether. A mixture of solids and gum formed, which was intractable, so the mixture was further diluted with 10 mL DCM and Macroporous carbonate resin (3.16 mmol/g loading; 0.75 g, 2.37 mmol) was added, stirred for 4 h then filtered and concentrated in vacuo to afford an oil, which was chromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM). The product elutes with 5% MeOH, to give N-((1R,2R)-2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (145 mg, 90%) as an off white foam. LCMS (m/e) 577 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.29 (m, 1H), 7.05 (d, 1H, J=7.8 Hz), 6.88 (s, 1H), 5.42 (d, 1H, J=7.5 Hz), 5.41 (br s, 1H), 4.05 (m, 1H), 3.85 (m, 1H), 3.74 (t, 1H, J=4.5 Hz), 3.50 (t, 1H, J=4.5 Hz), 3.22 (m, 1H), 2.8-3.0 (m, 7H), 2.79 (s, 3H), 2.5-2.8 (m, 3H), 2.21 (m, 1H), 1.83 (m, 1H), 1.36 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[C:9]([F:18])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)(C)(C)C>[OH-].[Na+]>[CH3:1][O:5][C:6](=[O:19])[CH2:7][C:8]1[C:9]([F:18])=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncccc2c1F
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc2ncccc2c1F

Procedure:
(5-Fluoro-quinolin-6-yl)-acetic acid tert-butyl ester (5 g, 19 mmol) in 25 ml of aq. NaOH (4N) was heated to reflux for 4 h. The mixture was washed with ethyl acetate and the aqueous layer was acidified to pH 5 with conc. HCl. The resulting precipitate was collected and washed with water and dried in vacuo to return (5-fluoro-quinolin-6-yl)-acetic acid. To this solid was added conc.H2SO4 (1.2 ml) and MeOH (20 ml) and the solution heated to reflux for 6 h. After cooling the solvent was removed in vacuo and the residue purified by flash column chromatography to return the title compound (2.0 g 48%).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.Cl.[CH2:15]([NH2:17])[CH3:16].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:15]([NH:17][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[S:1])[O:3][C:4]=2[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCN
Reactant: O=C(O)c1ccc2[nH]c(=S)oc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Example 92B, 424 mg, 2.17 mmol), ethanamine hydrochloride (266 mg, 3.26 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (991 mg, 2.61 mmol) were combined in tetrahydrofuran (5 mL). Triethylamine (1.4 mL, 977 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of hydrochloric acid, and absorbed on silica gel. The crude mixture was purified with silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%). The chromatographed material was triturated with dichloromethane to afford the title compound. MS (ESI−) m/z 220.9 (M−H)−.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C@H:10]([OH:16])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:12]1[C:11]2([CH2:14][CH2:15][NH:8][CH2:9][C@H:10]2[OH:16])[CH2:13]1
Reactant: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CNCCC12CC2

Procedure:
100 mg (S)-6-benzyl-6-aza-spiro[2.5]octan-4-ol were dissolved in 1 ml methanol and hydrogenated over palladium on barium sulfate. After de-benzylation (IPC by GC), the catalyst was filtered and the filtrate was concentrated under reduced pressure to provide the title compound. The amino alcohol was treated with di-tert-butyl-dicarbonate in methanol in the presence of triethylamine. The crude tert-butoxycarbonyl-protected amine product was analyzed by chiral GC (BGB-176; 30 m×0.25 mm; 80° C. to 210° C. in 43 min) and proved to be identical with intermediate 2b.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[C:14]([I:15])=[CH:13][C:12]([CH2:16][CH:17]([NH2:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[I:22])[CH:2]=1.[ClH:23].[CH3:24]O>>[ClH:23].[CH3:24][O:19][C:18](=[O:20])[C@H:17]([CH2:16][C:12]1[CH:11]=[C:10]([I:22])[C:9]([O:8][C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][CH:2]=2)=[C:14]([I:15])[CH:13]=1)[NH2:21]
Reactant: CO
Reactant: NC(Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Reaction time: 16 h
Yield: 95 %

Procedure:
Five g (9.52 mmoles) of L-3,5-diiodothyronine (Sigma Chemical Company, St. Louis, Mo. 63178, Catalog No. D0629) was suspended in 50 ml of methanol (MCB, Norwood, Ohio 45212, Catalog No. MX0488-1). Dry hydrogen chloride was bubbled through the resulting suspension until the methanol was saturated with hydrogen chloride. The mixture warmed as the 3,5-diiodothyronine dissolved, resulting in a yellowish-green solution. The reaction mixture was allowed to stand for 16 hours at ambient temperature in a closed vessel. Dry hydrogen chloride was again passed through the reaction mixture. The reaction mixture was allowed to stand for an additional six hours in a closed vessel. The methanol was allowed to evaporate from the reaction mixture in a fume hood at ambient temperature, leaving 5.2 g (95% yield) of white, crystalline powder, 3,5-diiodothyronine methyl ester hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])[C:11]([OH:13])=O)=[O:6].ClCl.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1.Cl.[CH2:64]([O:71][NH2:72])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]1=[O:27])[C:11]([NH:72][O:71][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:13])=[O:6]
Reactant: NOCc1ccccc1
Reactant: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)O)CCN(CCc2ccccc2)C1=O
Agent: Cl
Agent: ClCl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A cold (0° C.) solution of α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetic acid (427 mg, 0.908 mmol) in 2:1 CH2 Cl2 /DMF (6 mL) is treated with HOBT (147 mg, 1.09 mmol), EDC (209 mg, 1.09 mmol), and 4-methylmorpholine (120 μL, 1.09 mmol). The ice bath is removed, and after 1 hour, a second portion of 4-methylmorpholine (150 μL, 1.36 mmol) and O-benzylhydroxylamine HCl (217 mg, 1.36 mmol) are added. The solution is stirred overnight at room temperature under N2. The solution is diluted with EtOAc (25 mL) and washed with 1N HCl (10 mL), 1N NaOH (10 mL), H2O (2×10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 530 mg of a yellow solid. The solid is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 373 mg (71%) of the title compound as a white, amorphous solid:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][O:33][C:34]([CH:36]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][NH:37]1)=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClCCl.O.CN(C)C=O>[CH3:32][O:33][C:34]([CH:36]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][N:37]1[CH2:18][CH2:17][CH2:16][N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:35]
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1Cc2ccccc2CN1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2CN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1.05 g, 0.0041 mol, prepared similarly as described in example 2) in dichloromethane (40 ml) at 0° C., triethylamine (1.28 g, 0.013 mol) was added, followed by methanesulfonyl chloride (0.9 ml, 0.012 mol). After stirring for 30 minutes at 0° C., water (50 ml) was added and the phases were separated. The organic layer was washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (12 ml), and 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (1.13 g, 0.0050 mol), N,N-dimethyl-formamide (5 ml), potassium carbonate (1.32 g, 0.0096 mol) and potassium iodide (0.30 g, 0.0018 mol) were added. The reaction mixture was heated at 82° C. for 12 h. N,N-Dimethylformamide (5 ml) was added and heating was continued for further 16 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography on silica gel (80 g) using a gradient of heptane and ethyl acetate (10:0→10:3), affording 1.4 g (76%) of 2-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester as an oil.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[C:54](Cl)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:54]([N:26]1[C@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[CH3:21])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:53])=[O:24])[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27]1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester di hydrochloride was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and benzoyl chloride (3 eq) added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (17 mg). LCMS (m/z): 781.
Reaction SMILES: N#N.[H-].[Na+].[CH3:5][C:6]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH:13]=[CH:12][C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[C:9]=3[C:8]=2[CH:7]=1.S(OCC)(O[CH2:27][CH3:28])(=O)=O.C(O)C(O)C(O)C(O)C(O)C=O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl.O>[CH2:27]([N:15]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[C:9]=2[C:8]2[CH:7]=[C:6]([CH3:5])[CH:18]=[CH:17][C:16]1=2)[CH3:28]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc2[nH]c3ccc4ccccc4c3c2c1
Agent: N#N
Agent: O=CC(O)C(O)C(O)C(O)CO
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccc(C)cc2c2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, rubber septum and N2 inlet line was added a 50% oil dispersion of NaH (7.47 g, 0.155 mol). The oil was removed by washing the dispersion with hexane (3×φmL). Dry THF (100 mL) was added to the flask by cannula to cover the NaH. A solution of 10-methyl-7H-benzo[c]carbazole (Cambridge Chemicals, Inc., 30.0 g, 0.113 mol) in THF (250 mL) was added to the flask by cannula. The mixture was stirred for 30 min at RT. Diethyl sulfate (Aldrich, 24.1 g, 0.156 mol, 20.4 mL) was then added to the flask by syringe and the resulting mixture stirred overnight at RT. H2O (20 mL) was added to the flask to destroy excess NaH. The mixture was then extracted with CH2Cl2 (3×1 L). The organic layers were combined and washed sequentially with H2O (3×500 mL), saturated NaCl solution (3×500 mL), dried (Na2SO4) and concentrated to give a 38.7 g of a crude oil. This material was passed through a plug of Magnesol® using CH2Cl2 as the eluting solvent. The appropriate fractions were combined and the solvent removed to give after drying 34.1 g of a crude oil. This material was recrystallized from CH3OH to give 28.3 g (84.0) of 7-ethyl-10-methyl-7H-benzo[c]carbazole, mp 69°-74°, (C,H,N).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]=[C:13]1[NH:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13](=[O:12])[NH:17]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C1NC(CO)CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
p-Toluenesulfonyl chloride (1.01 g, 0.0053 mole) was added to a stirred solution of 2-oxo-1,3-oxazolidin-4-methanol (0.619 g, 0.0053 mole) and 4-dimethylaminopyridine (1.30 g, 0.0106 mole) in 60 ml. methylene chloride at 0° C. under an atmosphere of nitrogen. After 1 hour at 0° C., 0.121 g. more p-toluenesulfonyl chloride was added and the reaction mixture was stirred at 0° C. for 30 min. and at 25° C. for 1 hour. The reaction solution was then washed with two 50 ml. portions of 1N aqueous hydrochloric acid solution, 50 ml. water, 50 ml. saturated aqueous sodium bicarbonate solution and 50 ml. saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to a white solid of the title compound (1.22 g, 85% yield). NMR (CDCl3): 2.45 (s, 3H); 3.87-4.54 (c, 5H); 6.18 (b, 1H); 7.3 (d, 2H); and 7.73 (d, 2H)ppm.