Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)=[C:8]([CH3:19])[C:7]=2[CH:20]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:19])[C:7]=2[CH:20]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(=O)c3ccccc3)c(C)c2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(c2ccccc2)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a mixture of (5-methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methanone (2.03 g) synthesized above, methyl 4-aminobenzoate (1.27 g), triethylamine (8.50 mL) and methylene chloride (30 mL) was added titanium (IV) chloride (1.00 mL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (2.18 mL) and sodium cyanoborohydride (955 mg), and the mixture was stirred at room temperature for 2.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title object compound (2.36 g, 77%) as a brown solid.
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:3]([F:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1ncc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1ncc(Cl)cc1-c1ccc(Cl)cc1
Yield: 95.7 %

Procedure:
A mixture of 3-bromo-5-chloro-2-fluoro-pyridine, (CAN 884494-87-5; 2.0 g, 9.50 mmol), 4-chlorophenylboronic acid (CAN 1679-18-1; 1.5 g, 9.50 mmol); tetrakis(triphenylphoshine)-palladium (0.55 g, 0.48 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (50 mL) and THF (50 mL) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with ethyl acetate, phases were separated and the water phase was extracted with ethyl acetate. The organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography (on silica gel with a gradient of heptane to heptane:ethyl acetate=9:1 to yield the title product (2.2 g, 95%) as white solid; MS (ESI): 241.0 (M)+.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6]I)[S:2][CH2:3][CH3:4].[C:9]([O:13][C:14]([N:16]([CH2:21][CH2:22][CH2:23][N:24]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.C(Cl)Cl>[C:1](=[O:8])([O:5][CH2:6][O:20][C:18](=[O:19])[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:22][CH2:23][N:24]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCSC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CN(CCCN(CCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
S-Ethyl O-iodomethyl carbonothioate (423 mg, 1.72 mmol) was added to a stirring mixture of 31 (1.13 g, 1.71 mmol), NaHCO3 (298 mg, 3.55 mmol) and tetrabutylammonium hydrogensulfate (588 mg, 1.73 mmol) in CH2Cl2/H2O (1:1, 17 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) and the aqueous layer was discarded. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaCl, dried over Na2SO4 then concentrated under reduced pressure. The residue was resuspended in Et2O, filtered and again concentrated under reduced pressure. The crude material was purified by silica gel chromatography (25%-60% EtOAc in hexanes over 10 column volumes) to give the colourless liquid 32 (1.23 g, 92%): 1H NMR (400 MHz, CDCl3): δ 1.32 (t, J=7.3, 3H), 1.41-1.47 (m, 40H), 1.61-1.75 (m, 4H), 2.89 (q, J=7.3, 2H), 3.10-3.31 (m, 12H), 3.92 (s, 4/7 of 2H, rotamer A), 4.01 (s, 3/7 of 2H, rotomer B), 5.84 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 81 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:15]Br.O>C(O)(=O)C>[NH2:1][C:2]1[C:9]([Br:15])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1ccc(N)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cnc(N)c(Br)c1
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To a solution of 6-aminonicotinonitrile (3.6 g, 300 mmol) in glacial acetic acid (50 mL) at RT was added sodium acetate (30 mmol). To the resulting well stirred mixture was added bromine (2.58 mL, 30 mmol) dropwise. After 5 min, a precipitate started to form and the mixture became very thick. Acetic acid (10 mL) was added and the mixture was stirred vigorously for 1 h, poured into cold water (100 mL). The mixture was filtered; the solid was washed with water and dried in vacuo to afford 6-amino-5-bromonicotinonitrile (4.25 g) as a solid. LC/MS; (M+H)+=199. Additional solid precipitated from the filtrate after some time which upon filtration and drying gave less pure compound (1.21 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Product: O=C(CCCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 41 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 7-bromoheptylbenzene, the title compound (25 mg, 41%) was obtained as a white solid, using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.38 (m, 6H), 1.63 (quintet, J=7.3 Hz, 2H), 1.80 (quintet, J=7.0 Hz, 2H), 2.61 (dd, J=7.9, 7.6 Hz, 2H), 3.21 (t, J=7.5 Hz, 2H), 7.16-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.54 (ddd, J=7.6, 4.7, 0.9 Hz, 1H), 7.94 (td, J=7.8,1.8 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.9, 29.0, 29.1, 31.4, 35.7, 35.9, 40.1, 124.0, 125.6, 126.7, 128.2, 128.4, 137.3, 142.6, 142.7, 150.8, 161.2, 165.1, 187.2; MALDI-FTMS m/z 350.1859 (C21H23N3O2+H+ requires 350.1863).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH3:9][Si](Cl)(C)C>CO.C(Cl)Cl>[CH3:9][O:7][C:1](=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: C/C=C/C=C/C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Solvent: ClCCl
Product: CC=CC=CC(=O)OC
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of sorbic acid (1.12 g, 10 mmol) in dry methanol (50 mL) was added dropwise a solution of trimethylsilyl chloride (2M, 12 mL) in CH2Cl2. After stirring for 16 hours, the mixture was concentrated under reduced pressure to give a pale yellow oil that was purified by flash chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (1.23 g, 99%) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:29][O:30][CH2:31][CH2:32][N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1
Reactant: COCCBr
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: COCCN1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and bromoethyl methyl ether in the same manner as in Example 32.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]=[CH2:13])[C:7]#[N:8])([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:7]#[N:8]
Reactant: C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C#N)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
The compound (1.90 g, 10.9 mmol) obtained in step A was dissolved in ethanol (100 ml). Then, 10% palladium carbon (containing water) (1.93 g) was added, and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure to give the title compound (1.56 g, yield 98%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:19]
Reactant: Oc1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1cc2ccccc2c(-c2ccccc2)n1
Yield: 39.1 %

Procedure:
The procedure is as in Example 47, starting with 1-phenyl-3-isoquinolinol (4.4 g), N,N-diethyl-2-chloroacetamide (3.3 g), sodium carbonate (4.25 g) and cuprous iodide (1 g) in 2-butanone (90 cc). After chromatography on silica gel with a chloroform/methanol (98:2 by volume) mixture as eluant and crystallization of the product in isopropyl ether, N,N-diethyl-(1-phenyl-3-isoquinolyl)oxyacetamide (2.6 g), m.p. 105° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:29][C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH2:30][CH3:31])[CH2:20][CH3:21])=[CH:28][CH:27]=2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)c1ccc(N=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1
Yield: 83 %

Procedure:
To a refluxing, stirred suspension of 63.3 g (0.3 mole) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 800 ml ethanol was added over 15 min a solution containing 54 g (0.33 mole) of N,N-diethyl-p-phenylenediamine in 50 ml ethanol. The resulting solution was stirred and refluxed for 1 hr, then stored at 0°. The solid was collected, washed with 200 ml cold ethanol, and air dried to give 89 g (83%) of the product m.p. 117°-122°.
Reaction SMILES: [O:1]=[C:2]1[CH:8](C(OC)=O)[CH2:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[CH2:4][CH:3]1C(OC)=O.[OH-].[K+]>C(O)C>[O:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)C1Cc2ccccc2CC(C(=O)OC)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCc2ccccc2CC1
Temperature: 85 °C
Yield: 57 %

Procedure:
The crude dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate was dissolved in 200 mL of ethanol (EtOH) and then 100 mL of 2 N KOH. The resulting mixture was refluxed at 85° C. for 17 h. After cooling to ambient temperature, the volatiles were evaporated. To the residue was added 120 mL of 2N HCl at 0° C., the crude product was extracted by EtOAc (200 mL×2). The combined extracts were washed with brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography on silica gel (hexanes/EtOAc 8:1) to afford 6.6 g (57%) of 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene as a white solid: mp 40-41° C.; 1H NMR (300 MHz, CDCl3) δ: 7.21 (m, 4H), 2.94-2.90 (m, 4H), 2.63-2.60 (m, 4H); LC-MS: 161 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][NH:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:37]([CH2:38][CH2:39][OH:40])[CH3:36])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNCCO
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1
Product: CN(CCO)c1cc(-c2ccc(F)cc2)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A mixture of 0.10 g (0.20 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.45 g (6.0 mmol) 2-(methylamino)ethanol was stirred 6 h at 140° C. After cooling to room temperature the reaction mixture was partitioned between water and tert-butyl methyl ether and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride and water, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 87 mg (78%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1)[CH3:34]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:33][CH3:34])=[CH:41][CH:40]=2)[CH2:47][CH2:46]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: CCOc1ccc(N2CCNCC2)cc1
Product: CCOc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.4 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-ethoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.7 mg, 2.4%) as light yellow oil. MS m/e=535.5 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)[CH2:16][C:17](O)=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.C([N:40]=C=NC(C)C)(C)C.[Br-].[NH4+].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)[CH2:16][C:17]([NH2:40])=[O:18])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC(C)N=C=NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin-7-yl)phenyl)propanoic acid (0.152 mmol) in dichloromethane (1 mL) was treated with 4-(dimethylamino)pyridine (8.19 μmol), N,N′-diisopropylcarbodiimide (0.183 mmol), and ammonium bromide (0.229 mmol). The reaction mixture was sealed and was allowed to stir at room temperature overnight. Minimal conversion of starting material occurred, so additional 4-(dimethylamino)pyridine (8.19 μmol) was added and the reaction was stirred 3 hours at room temperature, at which point the mixture was diluted with acetonitrile (1 mL), and the reaction vessel was sealed and was stirred at 40° C. overnight. Minor conversion had occurred, so N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.183 mmol), 4-(dimethylamino)pyridine (0.457 mmol) and an additional portion of ammonium bromide (0.229 mmol) were added. The reaction mixture was sealed and allowed to stir at room temperature overnight. At this point the reaction was concentrated to dryness under a nitrogen stream. The crude material was purified by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA). The fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v ammonium hydroxide solution. This was concentrated to a minimal volume in vacuo and was then extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, filtered and concentration in vacuo to afford the racemate of the title compound. Resolution of the racemate using chiral HPLC (Chiralpak AS-H, 9:1 acetonitrile:methanol) followed by concentration in vacuo and lyophilization from water with 5% acetonitrile yielded the title compound as a white solid in >99% ee (23% yield). MS(ES)+ m/e 485.4 [M+H]+. αD=−20 deg (c=0.01, 9:1 acetonitrile:methanol).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18]([NH:9][C@@H:10]([CH:11]([CH3:13])[CH3:12])[C:14]([OH:16])=[O:15])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 102.9 %

Procedure:
Na2CO3 (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H2O, 33 mmol) solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) was added dropwise over 15 min, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25 hr. The reaction mixture was washed with ether (50 mL, 3×), and the aqueous phase was cooled with ice-water bath and acidified with concentrated HCl to a pH region of 1-2, and extracted with CH2Cl2 (50 mL, 3×). The organic phase was dried (MgSO4) and evaporated in vacuo to afford Cap-51 as a white solid (6 g). 1H NMR for the dominant rotamer (DMSO-d6, δ=2.5 ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84 (dd, J=8.4, 6.0, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Calcd. for [M+H]+ C2H14NO4: 176.0923. found 176.0922.
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.S(Cl)(Cl)=O.[NH3:20]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:20])=[O:12])=[N:9][CH:10]=1
Reactant: N
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 50 °C

Procedure:
20 g of 5-(3,4-dibromobutyl)picolinic acid was added to 15 ml of thionyl chloride and resulting solution was kept to warm at 50°C for one-half hour. Reaction mixture was evaporated in reduced pressure and resulting oily residue was dissolved in chloroform 100 ml. Through the solution dry ammonia gas was passed for five minutes with cooling. White precipitate was removed by filtration and washed with chloroform. Filtrate and washings are combined and evaporated in reduced pressure. Resulting solid was crystallized from benzene to give 10.2 g of the pure product as platelets.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.N([O-])=O.[Na+]>C(O)(=O)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[CH2:9][CH2:8][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccccc1C=Cc1ccccc1N
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2c1CCc1ccccc1-2
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a stirred solution of ethyl 2-[2-(2-aminophenyl)ethenyl]-benzoate (13.5 grams, 0.05 mole) in warm glacial acetic acid (75 ml) was added a solution of concentrated hydrochloric acid (12 ml) in water (10 ml). The mixture was cooled to 0°, and during a 20 minute period a solution of sodium nitrite (3.7 grams, 0.054 mole) in water (30 ml) was added. The resultant mixture was stirred at 0°-5° for three hours. During a 90 minute period the mixturre was added to a refluxing solution of copper sulfate (35 grams, 0.14 mole) in water (500 ml). After complete addition, glacial acetic acid (40 ml) was added and the mixture refluxed for one hour. The mixture was cooled to room temperature and extracted with three 200 ml portions of methylene chloride. The extracts were combined, washed with water, and evaporated under reduced pressure to give a brown oil. Distillation of the oil under reduced pressure gave ethyl 9,10-dihydrophenanthrene-1-carboxylate (5.5 grams, bp 145°-165°/0.25 mm) as a yellow oil.