Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (bromomethyl)cyclohexane (0.70 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with 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 solid (0.38 g, 30%).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)Cl>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CCc1ccc(O)cc1
Solvent: ClCCl
Product: CCc1ccc(O)c(Br)c1
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Bromine (11.6 mL, 0.23 mol) was added slowly to a cooled 0° C. of 4-ethylphenol (25 g, 0.21 mol) dissolved in CH2Cl2 (125 mL). After the addition was complete the reaction mixture was stirred for 5 mins and then quenched with 1N NaOH. The reaction mixture was diluted with H2O and the layers separated. The organic layer was concentrated to an orange oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (42 g, 98%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 2.58 (q, J=7.5 Hz, 2H), 5.36 (s, 1H), 6.93 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.28 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([NH:27][C:28]([NH:1][C@H:2]([C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH:20][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 30 mg (0.1 mmol) of (2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane in 1 ml of dichloromethane was treated with 25 μl (0.22 mmol) of t-butylisocyanate. The resulting solution was stirred at ambient temperature, diluted with dichloromethane, washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography using a gradient of 1-3% methanol in chloroform provided 49 mg (98% ) of the desired compound (Rf 0.4, 10% methanol in chloroform) as a white solid, m.p. 193°-196° C. Mass spectrum: (M+H)+ =499.
Reaction SMILES: ClC1C=C(SC2C3C(=CC(C)=CC=3)[NH:12]C=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.C(Cl)(=O)C(Cl)=O.N>>[Cl:32][C:30]1[CH:29]=[C:28]([S:33][C:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[NH:36][C:35]=2[CH2:44][CH2:45][CH2:46][C:47]([NH2:12])=[O:49])[CH:27]=[C:26]([Cl:25])[CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCCC(=O)O)[nH]c2c1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCCC(N)=O)[nH]c2c1
Yield: 17 %

Procedure:
Following the method used to prepare 24a, the use of 50 (135 mg, 0.34 mmol) and oxalyl chloride (43 μL, 0.51 mmol) followed by reacting the intermediate acid chloride with aqueous ammonia (2 mL) provided 23 mg (17%) of product 24c as a pale yellow solid, mp 163-164° C. 1H NMR (300 MHz, CDCl3) δ 1.92-2.01 (q, J=7 Hz, 2H), 2.25 (t, J=7 Hz, 2H), 2.46 (s, 3H), 2.96 (t, J=7 Hz, 2H), 5.42 (brs, 2H), 6.84 (d, J=2 Hz, 2H), 6.96-7.00 (m, 2H), 7.21 (s, 1H), 7.38 (d, J=8 Hz, 1H), 9.34 (brs, 1H). LC-MS (CI): m/z 393.0, 395.0 [(M+H)+ C19H18Cl2N2OS requires 392.05]. Purity (100%). Calcd for C19H18Cl2N2OS: C, 58.02; H, 4.61; N, 7.12; S, 8.15; Cl, 18.03. Found: C, 58.06; H, 4.79; N, 6.88; S, 7.90; Cl, 17.75. The low yield for amide preparation in this case was due to the significant formation of a six membered lactam via cyclization of the intermediate acid chloride.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH2:13]OS(C)(=O)=O)=[CH:11][C:10]([Br:19])=[CH:9][N:8]=1)(=O)=O.[CH3:20][Si:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28][C:27]1=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[Br:19][C:10]1[CH:11]=[C:12]2[CH2:13][C:28]3([C:29]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:20])[CH3:37])[C:27]3=[O:35])[CH2:6][C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: CS(=O)(=O)OCc1cc(Br)cnc1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(Br)cnc3C2)c2cccnc21
Reaction time: 20 h

Procedure:
(5-Bromopyridine-2,3-diyl)dimethanediyl dimethanesulfonate (17.0 g, 45.4 mmol) was added to a mixture of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902, 14.0 g, 53.0 mmol) and cesium carbonate (49.0 g, 150 mmol) in EtOH (500 mL) ambient temperature, and the resulting mixture was stirred for 20 h. The reaction mixture was concentrated then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of heptane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=448.1 (M+1).
Reaction SMILES: [C:1]1([Se:7][C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[NH2:15][C:11]1[CH:10]=[CH:9][C:8]([Se:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][C:12]=1[NH2:13]
Reactant: Nc1cc([Se]c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Product: Nc1ccc([Se]c2ccccc2)cc1N
Reaction time: 2 h

Procedure:
A solution of stannous chloride dihydrate (50 g.) in concentrated hydrochloric acid (100 ml.) was stirred and heated at 60°-70° C. while 5-phenylseleno-2-nitroaniline (14.6 g.) was added in portions. The mixture was stirred at that temperature for 2 hours, and was then cooled and filtered. The solid product was stirred with concentrated sodium hydroxide solution and extracted with ether. The ether extract was separated and dried, and the solvent was evaporated to give the required starting material, 1,2-diamino-4-phenylselenobenzene as a yellow oil which slowly crystallised.
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:3]\[C:4]([OH:6])=[O:5].C(O)(=O)CCC(O)=[O:17]>>[C:4]([OH:6])(=[O:5])[CH2:3][C:2]([CH2:1][C:10]([OH:12])=[O:11])([C:7]([OH:9])=[O:8])[OH:17]
Reactant: O=C(O)/C=C(\CC(=O)O)C(=O)O
Reactant: O=C(O)CCC(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Yield: 37.6 %

Procedure:
Trans-aconitic acid, 10.7 g (0.06 mole), is dissolved in 300 ml of water. An excess of strontium oxide, 12.5 g (0.121 mole) mole is added. This brings the pH to 12.4 and produces a mixture of the strontium salt of trans-aconitic acid and free strontium hydroxide. The resulting mixture is then stirred and heated for 3 hours in a Parr pressure reactor at a temperature of 200° C. The reaction mixture is then cooled and mixed with 121 g of 10% sulfuric acid solution. After stirring the mixture for about 10 minutes, it is filtered to remove precipitated SrSO4. The filtrate is then evaporated in vacuo to give a residue which is purified further by digesting with 100 ml acetone and refiltering to remove insolubles. The acetone filtrade is then evaporated to give an 8.8 g residue containing 54.3% (37.6% yield) of citric acid, 9.6% trans-aconitic acid, 4% succinic acid and the balance, mainly water.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:28](=[O:29])[CH2:27][C:22]2[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.7, 10.8, 13.9, 18.9, 28.8, 36.1, 43.0, 53.0, 62.9, 102.5, 102.7, 103.3, 104.5, 112.3, 112.4, 112.5, 112.6, 132.9, 138.0, 138.9, 161.9, 164.3, 164.5, 169.2, 169.5; MS 407.23 m/z (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O.[CH2:34]1COCC1.O>>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:34])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: C1CCOC1
Agent: [Li]O
Solvent: O
Product: Cc1cnc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoate (Compound 15a) and 8.5 mg (0.20 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. PMR (d6-DMSO): δ 1.29 (6H, s), 2.42 (2H, d, J=4.6 Hz), 6.68 (1H, t, J=4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J=8.2 Hz), 7.77 (1H, d, J=3.3 Hz), 7.93 (2H, d, J=8.2 Hz), 7.98 (1H, d, J=3.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:14])[CH:3]=1.[C:15](Cl)(=O)C(Cl)=O.C[Mg+].[Br-]>C(Cl)Cl.CN(C=O)C.C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](=[O:8])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 4-chloro-2-fluoro-5-nitrobenzoic acid (16.0 g, 72.9 mmol) in anhydrous CH2Cl2 (400 mL) was added oxalyl chloride (9.57 mL, 109 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature until gas evolution ceased. The mixture was concentrated and dried in vacuo. In a separate, heat-dried reaction flask a mixture of ZnBr2 (24.6 g, 109 mmol) in anhydrous THF (300 mL) at −78° C. was added a solution of CH3MgBr (29.1 mL, 3.0 M in Et2O, 87 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 minutes, and then the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled to −78° C. and a solution of the acid chloride in anhydrous THF (100 mL) was added dropwise, followed by Pd(PPh3)4 (1.68 g, 1.46 mmol). The resulting mixture was allowed to stir at −78° C. for 10 minutes, and was then allowed to warm to ambient temperature and stirred for an additional 16 hours. The mixture was quenched by adding aq. 1 M HCl, diluted with H2O (100 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 5% EtOAc in hexanes) to afford the title compound (11.79 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl.N1C=CC=CC=1>[CH3:38][S:39]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)(=[O:41])=[O:40]
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(NS(C)(=O)=O)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of N2-[5-(5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (2 mL) and pyridine (0.5 mL) was added methanesulfonyl chloride (7.62 μl, 0.098 mmol) and mixture was stirred for 18 h. The residue 5-3a was used without further purification. MS APCI: [M+H]+ m/z=615.1.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:19])([CH3:14])[CH3:13]
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)NC1CCCC1N1CCCC1

Procedure:
The title compound, light brown oil, MS: m/e=385.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-isopropoxy-4-trifluoromethyl-benzoic acid (intermediate AF).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Br:40])[CH:39]=1)[C:34](O)=[O:35]>>[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Br:40])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:35]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc(Br)cc(Br)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dibromobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dibromobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 626 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[I:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(c1ccc(I)cc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (25 mg, 0.05 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product (16 mg, 80%); LCMS; 100% ESI+Calcd: 407.3. found m/z: 408.5 (M+1). 1H NMR (500 NM, DMSO-d6); δ 1.71-1.80 (m, 1H), 1.82-2.06 (m, 2H), 2.10-2.20. (m, 1H), 3.16-3.30 (m, 2H), 3.90-4.00 (m, 1H), 4.23-4.27 (m, 1H), 4.38 (dd, J1=10.0 Hz, J2=2.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H):
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[N:22]=1)[CH:6]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])OCC)[CH2:2][CH3:3]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[C:5]1[CH:6]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16](=[O:18])[N:22]2[C:21]=1[CH:26]=[CH:25][CH:24]=[C:23]2[C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=1[CH3:35])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCCN(CCC)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Diethyl [2-(dipropylamino)-1-ethoxy-2-(6-mesitylpyridin-2-yl)ethyl]malonate (0.65 g, 1.35 mmol), was dissolved in 5 mL of Dowtherm A (1:2 biphenyl:phenyl ether). The solution was placed in a pre-heated oil bath at 220° C. The reaction stirred at this temperature for 20 minutes. The solution was cooled and flash chromatographed (15%-35% ethyl acetate/hexanes) to give 0.28 g (48% yield) of an orange solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:20]#[N:21]>>[NH2:2][C:3]1[C:4]([C:20]#[N:21])=[CH:5][C:6]([CH:11]([OH:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CCC(C)(C)NCC(=O)c1cc(C#N)c(N)c(C#N)c1
Agent: Cl
Product: CCC(C)(C)NCC(O)c1cc(C#N)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 231°-233° C. (decomp.), was prepared from 4'-amino-3',5'-dicyano-2-tert.pentylamino-acetophenone analogous to Example 48.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:22]#[N:23])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]#CBr>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2([C:22]#[N:23])[CH2:6][CH2:7][N:2]([C:1]#[N:30])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccc(Cl)cc2)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(Cl)cc2)CC1

Procedure:
A solution of 14.9 g of 1-methyl-4-cyano-4-[2-(4-chlorophenylthio)phenyl]piperidine, Example 1, in 75 ml of chloroform is added dropwise to a rapidly stirring mixture of 30.4 g of potassium carbonate and 7.6 g of cyanogen bromide in 80 ml of chloroform. After total addition, the reaction mixture is refluxed for 16 hours and then successively, filtered, washed thrice with 150 ml portions of water, washed once with 50 ml saturated sodium chloride solution and dried. The residue is dissolved in chloroform and the chloroform solution is chromatographed (silica gel F60, ether as eluant). The purified material is recrystallized from acetone to give 4-[2-(4-chlorophenylthio)phenyl]-1,4-dicyanopiperidine.
Reaction SMILES: [C:1]([O:4][C:5]([C:7]([F:10])([F:9])[F:8])=[CH2:6])(=[O:3])[CH3:2].[Cl:11][SiH:12]([Cl:14])[Cl:13].CCCCCCC>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH:5]([C:7]([F:10])([F:9])[F:8])[CH2:6][Si:12]([Cl:14])([Cl:13])[Cl:11])(=[O:3])[CH3:2]
Reactant: C=C(OC(C)=O)C(F)(F)F
Reactant: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: CC(=O)OC(C[Si](Cl)(Cl)Cl)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Trifluoromethyl)ethenyl acetate (Aldrich, 188.0 grams, 1.22 mole), trichlorosilane (80.6 grams, 0.60 mole), and 200 ml heptane were placed in a round bottom flask equipped with a water condenser and nitrogen inlet. Platinum(O)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylene (10 ml) was added to this solution and heated to reflux for 18 hours. Afterwards, the solution was cooled to room temperature and additional portions of trichlorosilane (80.6 grams, 0.60 mole) and platinum complex (5 ml) were added and heated to reflux for 48 hours. Proton NMR of the solution indicated about 75% conversion. A third portion of trichlorosilane (67.7 grams, 0.50 mole) and platinum complex (5 ml) were then added and the solution heated to reflux for 48 hours. Solvents were distilled off at atmospheric pressure and the residue was fractionally distilled under reduced pressure. 2-Acetoxy-3,3,3-trifluoropropyltrichlorosilane (251.7 grams) (1.A) was collected between 100–125° C. at 20 mm pressure as a clear liquid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:13]1[CH2:14][O:15]1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1I
Agent: [H-]
Agent: [Na+]
Product: Ic1ccccc1OCC1CO1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a round bottom flask under N2 was added 4.56 g (0.095 mole) of 50% NaH in oil. The NaH was washed twice with hexane, then 220 ml of DMF was added. Aliquots of 20.0 g (0.091 mole) of o-iodophenol were added over 15 minutes then 30.0 ml (0.450 mole) of epichlorohydrin was added and the solution heated to 70° C. After two hours the reaction was evaporated in vacuo, taken into CHCl3, washed with 10% NaOH, water, and brine and dried with MgSO4. The solvent was evaporated in vacuo to give 24.93 g of crude product. Distillation at 110°-114° C., 0.05 mm Hg gave 20.0 g (80.0%) of [(2-iodophenoxy)methyl]-oxirane.