Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12](=O)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[N:11]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: O=C(CBr)c1cccc(-n2cncn2)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(-n4cncn4)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1,2,4-triazol-1-yl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1,2,4-triazol-1-yl)-2-pyridyl]thiazole.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].[H-].[Na+].Cl[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>CS(C)=O>[CH3:6][NH:5][CH2:4][CH2:3][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:1][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: CNCCC(O)c1ccccc1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCCC(Oc1ccc2ccccc2n1)c1ccccc1

Procedure:
Following the method of Example 4, reaction of 3-hydroxy-N-methyl-3-phenylpropylamine, sodium hydride and 2-chloroquinoline in DMSO gives the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:42][CH:43]1[CH2:45][CH2:44]1>C(#N)C>[CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][N:31]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Reactant: BrCC1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCN(CC3CC3)CC2)cc1
Reaction time: 8 h
Yield: 81341 %

Procedure:
To a solution of COMPOUND 27 (250 mg; 0.56 mmol) in acetonitrile (8 mL) was added triethylamine (92.7 μL; 0.67 mmol). The solution was cooled to 0° C. than bromomethylcyclopropane (53.5 μL; 0.56 mmol) was added. Reaction mixture was stirred overnight then was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 72 (229 g; 82% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.34-0.40 (m, 2H), 0.65-0.71 (m, 2H), 0.99-1.04 (m, 3H), 1.14 (t, J=6.83 Hz, 3H), 1.30-1.35 (m, 6H), 1.61-1.64 (m, 1H), 1.75-1.78 (m, 2H), 1.85-1.90 (m, 2H), 2.46-2.54 (br s, 1H), 2.95-3.03 (br s, 6H), 3.10-3.18 (br s, 2H), 3.37-3.44 (br s, 5H), 3.54-3.60 (br s, 2H), 7.27-2.31 (m, 3H), 7.50-7.53 (m, 3H), 7.64-7.68 (m, 2H). Found: C, 59.91; H, 8.10; N, 10.28. C32H46N4O×3.2HCl×1.1H2O has C, 60.13; H, 8.10; N, 8.76%. [α]D16=+12.4 deg [c 0.51, MeOH].
Reaction SMILES: O[CH2:2][C:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:5])[CH3:4].[CH3:17][C:18]1[CH:25]=[C:24]([C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[C:3]([CH3:5])([CH3:4])[CH2:2][N:28]1[CH:29]=[CH:30][C:26]([C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH3:17])[CH:25]=2)=[N:27]1
Reactant: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccn(CC(C)(C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Temperature: 25 °C
Yield: 16.3 %

Procedure:
2-(1-hydroxy-2-methylpropan-2-yl)isoindoline-1,3-dione (1.10 g; 5 mmol) and 2-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.366 g; 2.0 mmol) were dissolved in 5 ml of THF under nitrogen atmosphere. Triphenylphosphine (1.05 g; 4.0 mmol) and DIAD (0.79 ml; 4.0 mmol) were added and the reaction stirred at RT over the weekend. Additional triphenylphosphine (0.525 g; 2.0 mmol) and DIAD (0.39 ml; 2.0 mmol) were added and the mixture was stirred at RT for 2 days and then refluxed for 2 hours. Solvent was evaporated, 50 ml of water was added and the mixture was washed with 3×50 ml of DCM, dried over Na2SO4, filtered and evaporated to dryness. The crude mixture was purified twice by CombiFlash (column: silica, eluent 0-100% EtOAc in heptane) to obtain 125 mg (16%) of the title product. 1H-NMR (400 MHz; CDCl3): δ 1.56 (s, 6H), 2.60 (s, 3H), 4.2-4.38 (m, 2H), 6.50 (d, 1H), 7.33-7.87 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([S:9][C:11]2[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(S)c1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cc(F)cc(F)c2)c1
Reaction time: 16 h

Procedure:
In an open flask, cuprous oxide (0.6 g., 4 mmoles) and 3,5-difluorothiophenol (0.76 g., 4 mmoles) were combined with 25 ml. of dimethylformamide and heated in an oil bath maintained at 150°-160° C. for 2 hours. 5-Bromofuran-3-carboxylic acid was added, the flask was equipped with a reflux condenser, and heating at 150°-155° C. was continued for 16 hours. The reaction mixture was cooled, filtered, the filtrate diluted with 150 ml. of water and product extracted into two 30 ml. portions of ethyl acetate. The combined ethyl acetate extracts were back-washed with water, evaporated to an oil, the oil taken up in ether, product extracted into 12 ml. of 1 N sodium hydroxide, the basic extract acidified with conc. hydrochloric acid and the product extracted back into fresh ether and evaporated to yield crude product as an oil. The oil was chromatographed on approximately 100 ml. of silica gel with hexane/5% acetic acid as eluant, clean fractions (Rf 0.2 on thin layer chromatography with the same eluant) were combined, concentrated to dryness, and crystallized by trituration with hexane to yield purified 5-(3,5-difluorophenylthio)furan-3-carboxylic acid (127 mg., m.p. 128°-130° C., m/e 256).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Na].Cl[C:7]1[N:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:8]=1>O>[CH:2]([O:4][C:7]1[N:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:8]=1)([CH3:3])[CH3:1]
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Reactant: CC(C)O
Agent: [Na]
Solvent: O
Product: COc1cc(Nc2nc(OC(C)C)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 66 %

Procedure:
To 2-propanol (321 mg, 5.34 mmol) was added metallic sodium (9 mg, 0.39 mmol). The resulting alcoholate-solution was treated with (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.27 mmol) and the resulting mixture refluxed for 3 hours. Water was added and the product extracted with ethyl acetate. The crude material was purified by chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent to give the title compound as a colorless solid (71 mg, 67%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[I:11]I>C(O)C.O>[I:11][C:6]1[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([OH:10])=[CH:8][CH:7]=1
Reactant: CCCc1ncccc1O
Reactant: II
Solvent: O
Solvent: CCO
Product: CCCc1nc(I)ccc1O
Reaction time: 2 h
Yield: 60.1 %

Procedure:
2-Propylpyridin-3-ol (2.42 g, 17.7 mmol) was dissolved in ethanol (40 mL) and water (10 mL). Iodine (4.71 g, 18.6 mmol) was added thereto under ice-cold conditions, and stirred for 2 hours. Then, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, ethanol was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 6-iodo-2-propylpyridin-3-ol (2.80 g, yield 60%) was obtained as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:45]>>[C:1]1([S:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:45])=[O:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC=CCC=CCC=CCC=CCCCCC(CCCCCCCCCCCO)S(=O)(=O)c1ccccc1
Reactant: CC(C)=O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCC(=O)O)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Jone's reagent was added dropwise to a stirred solution of 17Z,20Z,23Z,26Z)-12-(phenylsulfonyl)dotriaconta-17,20,23,26-tetraen-1-ol (1 M solution in THF, 0.764 mL, 0.764 mmol) dissolved in acetone (5 mL) till the completion of reaction (TLC monitoring). The reaction was quenched with methanol (2 mL) and stirred for 30 min. The solvent was then removed and the crude was purified by silica gel column chromatography using 30% ethyl acetate/hexane to furnish the title compound as a clear oil (0.0643, 84%). 1H NMR (CDCl3): δ7.88 (d, 2H, J=7.2 Hz), 7.60 (m, 3H), 5.36 (m, 8H), 2.79 (m, 7H), 2.27 (t, 2H, J=6.8 Hz), 2.07 (m, 4H), 1.68 (m, 2H), 1.37-1.20 (m, 28H), 1.04 (t, 3H, J=6.8 Hz). m/z (APCI) 613.45 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([OH:44])[CH:38]=2)[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:44][C:39]2[CH:38]=[C:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[CH:42]=[C:41]([I:43])[CH:40]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: Oc1cc(I)cc(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 98.7 %

Procedure:
A similar procedure as described in Example 12, step 7 was used, starting from 4-[3-(6-bromo-hexyl)-2-(ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.67 g, 3.54 mmol) and 3′-fluoro-5-iodo-biphenyl-3-ol (1.01 g, 3.22 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (2.24 g, 99%) as a light yellow oil: ES(+)-HRMS m/e calculated for C35H42FIO6 (M+Na)+ 727.1902, found 727.1902.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C([OH:37])(C)(C)C>O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]([NH2:23])=[O:37])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC(C)(C)O
Solvent: O
Product: Cc1nc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridine-2-carbonitrile (47.2 mg, 0.100 mmol) in tert-butyl alcohol (2 mL) potassium hydroxide (22.4 mg, 0.400 mmol). The reaction mixture was stirred at 80° C. for 5 min. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give a title compound as a colorless amorphous (16.6 mg, 0.0399 mmol, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)nc2)CC1
Yield: 122.4 %

Procedure:
By repeating procedures described in Example B, 4-(6-nitro-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (490 mg, 1.52 mmol) is hydrogenated over Pd—C on an H-cube (Thales) (instead of under an atmosphere of hydrogen) to give 4-(6-amino-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (544 mg, 98%). MS (ESI) m/z 293 (M+H)+
Reaction SMILES: [C:1](OC(OCC)OCC)(=O)C.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:25]([NH2:30])[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:1]=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reactant: CCOC(OCC)OC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc3c(c2)ncc2ncn(CCOc4ccccc4)c23)cc1
Yield: 101.1 %

Procedure:
Under a nitrogen atmosphere, diethoxymethyl acetate (3.0 mL, 18 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (3.0 g, 7.8 mmol) in toluene (30 mL), and the reaction was heated at reflux for three hours. The reaction mixture was concentrated under reduced pressure until a small volume of solvent remained. Hexanes were added, and the resulting mixture was cooled for 20 minutes in a refrigerator. A precipitate formed which was isolated by filtration, washed with hexanes, and dried overnight under reduced pressure to provide 3.12 g of 7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccccn2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The solid obtained from flash chromatography was further purified by reverse phase HPLC on a Polar reverse phase column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as a pale solid, m/z 342 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:33]=[O:34])C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:33]=[O:34])=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc(Br)c(Br)n1COCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1nc(Br)c(C=O)n1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of 1-[(Benzyloxy)methyl]-4,5-dibromo-2-ethylimidazole (28.0 g, 75.0 mmol, Part A of example 544) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere and then added dropwise 1.6 M n-BuLi in hexane (51.75 mL, 82.5 mmol, Aldrich) over 30 mins. The mixture was stirred at −78° C. for 30 mins and then added DMF (16.5 g, 225 mmol, Aldrich) dropwise over 15 mins. The mixture was stirred at −78° C. for 30 mins. A small portion of the reaction mixture was quenched with satd. NH4Cl at −78° C. TLC (30:70 EtOAc/hexane) revealed both starting material and product showed almost identical Rf values (0.71 & 0.70) along with another minor spot at Rf=0.15. However, mass spectrum (CI—NH3) revealed absence of starting material and formation of product (m/z=325, M+2H). The reaction mixture was quenched with satd. ammonium chloride (20 mL) at −78° C. and brought to room temp. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine and dried with anhydrous MgSO4. The solvent was evaporated under reduced pressure to afford crude yellow oil. The crude was purified by flah column chromatography on a silica gel using dichloromethane as eluent to afford 22.6 g (93%) of colorless oil. HRMS calcd. for C14H16N2O2Br: 323.0395. Found: 323.0394 (M+H).
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].CS[C:16]#[N:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:5][C:6]1[C:7]([CH3:13])=[CH:8][C:9]([OH:12])=[C:10]([CH:11]=1)[C:16]#[N:17]
Reactant: Cc1cc(O)ccc1F
Reactant: CSC#N
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(O)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a IM solution of boron trichloride in dichloromethane (48 ml, 48 mmol) was added, in sequence, a solution of 4-fluoro-3-methylphenol (4.44 ml, 40 mmol) in dichloromethane (40 ml), methyl thiocyanate (3.3 ml, 48 mmol) and anhydrous aluminium chloride (5.4 g, 40 mmol) at 0° C. with stirring. The reaction mixture was heated under reflux for 3 h, and stirred at room temperature overnight. The solvent was evaporated, replaced by dichloroethane and added to ice and 4N sodium hydroxide (132 ml). The mixture was heated at reflux for 0.5 h with stirring, cooled to room temperature, the organic layer separated, and the aqueous layer further washed with dichloroethane. The aqueous layer was acidified with 2M hydrochloric acid and the solid that had precipitated collected by filtration, and washed well with water. The solid was dissolved in ethyl acetate, dried over magnesium sulphate, evaporated and the residue triturated with isohexane with ice cooling to give 3.5 g (58%) of the sub title compound as a colourless solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38]CC3C=CC=CC=3)=[C:22]([C:24](=[O:37])[NH:25][CH2:26][C:27](=[O:36])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:23]=[C:12]21)C1C=CC=CC=1.Cl>CO.[Pd]>[NH2:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([OH:38])=[C:22]([C:24]([NH:25][CH2:26][C:27](=[O:36])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[O:37])[N:23]=[C:12]21
Reactant: O=C(CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1)Cc1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(O)c1=O
Reaction time: 2 h
Yield: 83 %

Procedure:
To a mixture of benzyl(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 13 (540 mg, 0.845 mmol) in MeOH (8 mL) was added 1N HCl (0.930 mL, 0.930 mmol) followed by 10% Pd/C (90 mg, 0.085 mmol) and the mixture stirred under a hydrogen atmosphere for 2 h. The mixture was then filtered and thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo and dried under high vacuum overnight to afford the title compound (318 mg, 0.705 mmol, 83% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.07 (1H, br. s.), 9.61 (1H, t, J=5.95 Hz), 7.24-7.30 (2H, m), 7.13-7.20 (2H, m), 4.33 (2H, d, J=6.10 Hz), 4.00 (2H, d, J=3.66 Hz), 3.92 (2H, s), 2.46 (1H, br. s.), 2.01-2.13 (4H, m), 1.79-1.88 (2H, m), 1.68-1.77 (2H, m). LCMS (M+H)=415.15.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:23]1([C@H:33]([N:35]([CH2:43][C@@H:44]2[C@@H:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:47][NH:46][CH2:45]2)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:55]([O:64][CH3:65])(=[O:63])[CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O-])=[O:61]>ClCCl.C(N(CC)CC)C>[C:38]([O:37][C:36]([N:35]([CH2:43][C@@:44]1([C:60](=[O:61])[CH2:59][CH2:58][CH2:57][CH2:56][C:55]([O:64][CH3:65])=[O:63])[C@H:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:47][NH:46][CH2:45]1)[C@@H:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:34])=[O:42])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)[C@@]1(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)CNC[C@H]1c1ccccc1
Reaction time: 72 h
Yield: 94.4 %

Procedure:
At room temperature, 144 mg of WSC hydrochloride, 101 mg of HOBt, 215 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 0.08 ml of triethylamine were added in that order to a mixture of 80 mg of monomethyl adipate and 5 ml of dichloromethane and stirred for 3 days, and then the reaction was quenched by adding water, and this was extracted with chloroform and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 270 mg of methyl 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-3-yl)-6-oxohexanoate as a colorless amorphous substance. FP: 573.