Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:26]=[CH:27][CH:28]=[N:29][C:5]1=2.O.NN>C(O)C>[NH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:26]=[CH:27][CH:28]=[N:29][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: COCN1c2cc(CN3C(=O)c4ccccc4C3=O)ccc2Sc2nccnc21
Agent: NN
Solvent: O
Solvent: CCO
Product: COCN1c2cc(CN)ccc2Sc2nccnc21
Temperature: 60 °C
Yield: 100.9 %

Procedure:
To a solution of 1.3 g of N-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimide in 20 ml of ethanol was added 5 ml of hydrazine monohydrate and the resulting mixture was heated to 60° C. for 10 minutes. After distilling off the solvent under reduced pressure, the residue was distributed into a 5% aqueous solution of sodium hydroxide and ethyl acetate. The organic layer was extracted and the extract was dried over potassium carbonate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 890 mg of the title compound as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Br:8][CH2:9][CH:10]=[CH2:11].C(#N)CCC>>[Br-:8].[CH2:11]([N+:6]1[C:5]([CH3:7])=[CH:4][S:3][C:2]=1[CH3:1])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Cc1csc(C)n1
Solvent: CCCC#N
Product: C=CC[n+]1c(C)csc1C
Product: [Br-]
Yield: 33 %

Procedure:
2,4-Dimethylthiazole (6.04 g, 0.05 mole), 3-bromopropene (6.6 g, 0.055 mole) and butyronitrile (25 ml) were combined and refluxed for 2 hours. Upon cooling a brown oil solidified into a wet ivory powder (8.15 g) which was collected by filtration. The powder was dissolved in methanol, combined with aqueous potassium bromide to make the bromide salt, treated with decolorizing charcoal and filtered while hot. The filtrate was poured into ethyl ether to force the bromide salt out of solution as an oil. The ethyl ether was decanted and the oil which remained was chilled in a dry ice/acetone bath, filtered and dried at 60° to yield 3.86 g (33%) of the title compound as a solid; m.p. 130° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH2:8][OH:9])[CH2:3]1.[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH3:1][N+:2]1([CH3:10])[CH2:7][CH2:6][CH:5]=[C:4]([CH2:8][OH:9])[CH2:3]1
Reactant: CN1CCC=C(CO)C1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[N+]1(C)CCC=C(CO)C1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 179.4 %

Procedure:
The procedures of Reference Example 10 were repeated using 2.8 g of 1-methyl-1,2,5,6-tetrahydro-3-pyridinemethanol and 4.1 g of methyl p-toluenesulfonate to give 6.19 g of the desired compound as a white crystalline product.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]#[N:49])=[N:44][CH:45]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:27][CH2:28][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])[CH2:30][CH2:31]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)=[CH:42][CH:41]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)nc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogen carbonate (0.53 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C. for 30 min, 2-[5-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)pyridin-2-yl]benzonitrile (0.17 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.082 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.098 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:20]1(CBr)C[CH2:21]1>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: BrCC1CC1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 50 °C
Yield: 66.6 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-hydroxyisoquinoline (1.0 g, 5.06 mmol) in acetonitrile (10 ml) was added K2CO3 (2 g, 15.18 mmol) followed by cyclopropylmethylbromide (1.36 g, 10.12 mmol) at room temperature. The reaction mixture was heated to 50° C. for 2 hr. Solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-ethoxyisoquinoline (0.7 g, 55%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.38-8.34 (q, J=8 Hz, 1H), 7.89-7.86 (d, J=12 Hz, 1H), 7.81 (s, 1H), 7.65 (t, J=10 Hz, 1H), 4.11-4.09 (d, J=8 Hz, 2H), 1.43-1.37 (m, 1H), 0.72-0.67 (m, 2H), 0.46-0.39 (m, 2H); MS: MS m/z 252.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][CH:5]([N:8]([C@H:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[C:9](=[O:16])[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[CH3:12])[CH2:4][CH2:3]1.[C:23]([N:27]1[CH2:31][C@@H:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C@H:29]([C:39](O)=[O:40])[CH2:28]1)([CH3:26])([CH3:25])[CH3:24]>>[ClH:38].[C:23]([N:27]1[CH2:31][C@@H:30]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[C@H:29]([C:39]([N:19]2[CH2:20][CH2:21][C@H:17]([N:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH2:4]3)[C:9](=[O:16])[C:10]([CH3:14])([CH3:15])[C:11](=[O:13])[CH3:12])[CH2:18]2)=[O:40])[CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CC(=O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCNC1
Product: CC(=O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(Cl)cc2)C1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Step F, G of Example A1, using N-(4,4-dimethylcyclohexyl)-2,2-dimethyl-3-oxo-N-[(3S)-pyrrolidine-3-yl]butaneamide (50 mg, 0.11 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (56 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[NH:4][C@@H:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:24](O)(=O)C.C(N)=N>C(OCCO)C>[N:4]1([C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[N:1]=[CH:24]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1N)c1ccccc1
Agent: N=CN
Solvent: CCOCCO
Product: CC(C)(C)OC(=O)C[C@H](c1ccccc1)n1cnc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (3R)-3-(2-aminoanilino)-3-phenylpropanoate (78 mg, 250 μmol) in 2-ethoxyethanol (2 mL), was added formamidine acetate (41 mg, 394 μmol). The solution was heated at 80° C. for 1.75 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.30 min, MH+ 323].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:26]=3)[CH2:21][CH2:20]2)=[O:14])[CH2:10][CH2:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4Cl)CC3)CC2)c1

Procedure:
Example 41 was prepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.35 (s, 1H), 7.28–7.19 (m, 3H), 6.92 (d, 1H, J=7.6 Hz), 5.69–5.62 (m, 1H), 3.26 (q, 2H, J=6.7 Hz), 2.89–2.82 (m, 2H), 2.54 (quintet, 1H, J=6.7 Hz), 2.47–2.37 (m, 1H), 2.32–2.26 (m, 3H), 1.97–1.88 (m, 2H), 1.79–1.69 (m, 4H), 1.66–1.56 (m, 4H), 1.24 (d, 6H, J=6.7 Hz), 1.05–1.01 (m, 1H); ESMS m/e: 516.2 (M+H)+; Anal. Calc. for C28H35Cl2N3O2.0.048 CHCl3: C, 64.51; H, 6.76; N, 8.05. Found: C, 64.51; H, 6.60; N, 8.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](NC(=O)c1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of (S)-2-(5-chloro-2-nitro-benzoylamino)-butyric acid-tert-butyl ester (5.72 g,) in ethanol (250 ml) at ambient temperature was added tin(II)chloride bis-hydrate (18.8 g). The mixture was stirred at ambient for 16 hours. The volume was reduced to approximately 50 ml under reduced pressure, and reaction mixture was then diluted with 1M NaOH until the precipitate formed re-dissolved (400 ml). The aqueous was then extracted with diethyl ether (3×100 ml). The organic extracts were combined and washed with brine, dried (MgSO4), and concentrated to give the sub-titled compound as a yellow solid (4.60 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.4 (1H, s), 7.2 (1H, d), 6.6 (2H, m), 5.5 (2H, m), 4.6 (1H, m), 2.0 (1H, m), 1.85 (1H, m), 1.5 (9H, s), 0.95 (3H, t) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([OH:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:29]([F:36])([F:35])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH:29]([F:36])[F:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a solution of 0.30 g of 5-(3,5-dichlorophenyl)-3-(3-hydroxy-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of acetonitrile and 3 mL of water, 0.218 g of ethyl bromodifluoroacetate and 0.293 g of potassium carbonate were added, and stirred at 80° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of water was added in the residue, and extracted with ethyl acetate (20 mL×1). The organic phase was washed with water, and then dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude aimed product as yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([O-])=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]N>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:15]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: NCc1cccc(Cl)c1
Product: Clc1ccc(-c2cn(Cc3cccc(Cl)c3)c3c2CNCC3)cc1

Procedure:
The title compound (212.8 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 μL of 3-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene, replacing SiO2 with crushed 4 Å molecular sieves. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.28 (m, 6H), 7.18-7.15 (m, 2H), 7.12-7.09 (m, 1H), 5.16 (s, 2H), 4.36 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH:38]1([S:41]([NH:44][C:45](=O)[O:46]CC)(=[O:43])=[O:42])[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O.O>[CH:38]1([S:41]([NH:44][C:45](=[O:46])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: CCOC(=O)NS(=O)(=O)C1CC1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 20.3 %

Procedure:
To a solution of the amine 126 (500 mg, 0.953 mmol) in DME (4 ml) was added the carbamate 374 (460 mg, 2.5 eq, 2.383 mmol) and the reaction mixture was heated to 120° C. for 1 day. The mixture was cooled to RT, diluted with EtOAc and water and the organic phase was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc to 50% Acetone in EtOAc) afforded 375 as a brown oil (130 mg, 55%). MS (m/z)=672.5 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20](O)=[O:21])[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12]1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:72]([O:76][C:77](=[O:81])[CH:78]([NH2:80])[CH3:79])([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[C:72]([O:76][C:77](=[O:81])[CH:78]([NH:80][C:20]([CH:15]1[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12][CH:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[S:17][C:16]1([CH3:18])[CH3:19])=[O:21])[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)O)C(C)(C)S2)c(OC)c1
Reactant: CC(N)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)NC(C)C(=O)OC(C)(C)C)C(C)(C)S2)c(OC)c1
Yield: 46.7 %

Procedure:
7-(2,4-Dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylic acid (0.03 g), prepared as in Example 2, was dissolved in DMF (2 mL) and 2-amino-propionic acid tert-butyl ester (0.012 g), N-methylmorpholine (0.2 ml) and PyBOP (0.034 g) were added to the solution at room temperature. The mixture was stirred while the progress of the reaction was followed by analytical HPLC and when complete (16 hours) the solvent was removed in vacuo. Purification of product by preparative HPLC (RPC18 column, 2-70% acetonitrile/water containing 0.1% HCl) provided 2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl }-amino)-propionic acid tert-butyl ester (18 mg) as an off-white powder. LCMS: M+ 575.0.
Reaction SMILES: [CH3:1][C:2]([CH3:41])([O:4][C:5]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:13]([CH2:33][S:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[N:12]=1)=[O:10])=[O:6])[CH3:3].[CH3:42][I:43]>CN(C)C=O>[I-:43].[CH3:3][C:2]([CH3:41])([O:4][C:5]([NH:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([CH2:33][S:34][C:35]2[CH:36]=[CH:37][N+:38]([CH3:42])=[CH:39][CH:40]=2)[C:14]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=1)=[O:10])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CSc2ccncc2)n1
Reactant: CI
Solvent: CN(C)C=O
Product: C[n+]1ccc(SCc2nc(C(=O)NNC(=O)OC(C)(C)C)cc(OCc3ccccc3)c2OCc2ccccc2)cc1
Product: [I-]

Procedure:
2.7 g of the compound of Example 20a and 1.3 g methyliodide were stirred in 30 ml dimethylformamide for 48 hours. Complete reaction by DC after that time. The dimethylformamide was distilled off and the residue stirred with ether yielding 3.3 g of the title compound, yellow solid. M.P.=192°-193° C. (dec).
Reaction SMILES: [C:1](O)(=O)C.C=O.[CH:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.C(NCCCC)CCC>[CH2:1]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[O:14]
Reactant: CC(=O)O
Reactant: CCCCCCC=O
Agent: C=O
Solvent: CCCCNCCCC
Solvent: O
Product: C=C(C=O)CCCCC
Temperature: 50 °C
Yield: 848.9 %

Procedure:
A 3-L three-neck flask fitted with an overhead stirrer and a condenser was charged with di-n-butylamine (33 g) and acetic acid (31 g). Formaldehyde solution in water (500 mL, 33%) was added and the resulting solution was heated to 50° C. with stirring. Heptanal (500 g) was fed in over about 1.5 hours. A slight exotherm was noticed during the feed. GC analysis showed the consumption of heptanal and the production of 2-methylene heptanal, and a conversion rate of about 95% after the feed was completed. The reaction was cooled to room temperature and the reaction mixture was poured into a separatory funnel and washed once with HCl solution (5%). The organic layer was then washed once with saturated sodium carbonate to provide crude 2-methylene heptanal (553 g), which was loaded into a 2-L stainless steel pressure reactor along with dicyclopentadiene (343 g). The pressure reactor was sealed and heated to 170° C. with stirring for two hours. The reaction was then cooled to room temperature. The resulting crude product was purified by distillation to yield 2-pentylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (217 g).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[NH2:18][C:19]([CH2:24][CH3:25])([CH2:22][OH:23])[CH2:20][OH:21]>CO.CCOCC>[ClH:1].[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([CH2:16][NH:18][C:19]([CH2:24][CH3:25])([CH2:22][OH:23])[CH2:20][OH:21])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: CCC(N)(CO)CO
Solvent: CO
Solvent: CCOCC
Product: CCC(CO)(CO)NCc1c2ccccc2c(Cl)c2ccccc12
Product: Cl

Procedure:
Using the reductive amination outlined in 1, 10-chloro-9-anthraldehyde (Aldrich) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-(((10-chloro-9-anthracenyl)methyl)amino)-2-ethyl-1,3-propanediol hydrochloride, mp 252°-254° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 27.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added at 10°-15° C. Successively 11.1 g (0.105 mole) of sodium carbonate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 75.3 g of water was added and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 29.9 g (69.9% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[NH2:12].[N:24]([Si](C)(C)C)=[N+:25]=[N-]>CCOC(C)=O>[N:12]([C:11]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([F:8])[CH:10]=1)=[N+:24]=[N-:25]
Reactant: Nc1ccc(C(=O)N2CCOCC2)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)c(F)c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Tert-butyl nitrite (0.16 mL; 1.34 mmol; 1.5 eq.) was added to a solution of 3-fluoro-4-(morpholin-4-ylcarbonyl)aniline (200 mg; 0.89 mmol; 1.0 eq.) in AcOEt (6 mL) maintained at −10° C. The reaction mixture was stirred at −10° C. for 10 minutes before the addition of azidotrimethylsilane (0.14 mL; 1.07 mmol; 1.2 eq.). Reaction mixture was stirred at RT for 2 hours and concentrated under reduced pressure to give the title compound as a pale orange oil (220 mg, 99%). 1H NMR (300 MHz, DMSO-d6): δ: 7.45 (t, J=8.0 Hz, 1H), 7.15 (dd, J=11.0 Hz, 2.1 Hz, 1H), 7.06 (dd, J=8.0 Hz, 2.1 Hz, 1H), 3.64-3.63 (m, 4H), 3.52 (t, J=4.6 Hz, 2H), 3.23 (t, J=4.6 Hz, 2H). MS (ES+): 2521.1; Rt 1.02 min (purity=92%).