Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:19][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1
Reactant: NC1CCc2ccccc21
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1nc(Cl)cc(NC2CCc3ccccc32)n1
Temperature: 160 °C
Yield: 86.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (500 mg, 3.09 mmol), 2,3-dihydro-1H-inden-1-amine (500 mg, 3.78 mmol) and triethylamine (2 mL) in NMP (3 mL) was heated to 160° C. for 2 hours in a BiotageInitiator® microwave synthesizer. The reaction mixture was evaporated and purified by SiO2 chromatography eluting with 1:3 petroleum ether/THF to afford the title compound (700 mg) as a yellow solid. LC-MS (ES) m/z=261 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].[Br:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10]
Reactant: BrCCCBr
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1

Procedure:
A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K2CO2 (2.9 g, 20.3mmol), 1,3-dibromopropane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed. The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again. Purification was carried out by flash chromatography on silica gel (45 g, SiO2; eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.9 g) was recrystallized twice from isopropyl ether to give analytically pure 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of p-chlorophenyl isocyanate (15.3 g, 0.10 mol) in toluene (50 ml) is metered at room temperature into a solution of methyl anthranilate (15.1 g, 0.10 mol) in toluene (100 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (1.4 ml, 1.0 g, 0.010 mol) is metered in and the mixture is stirred at 90° C. for a further 3 hours. After cooling, the product is filtered off with suction and washed with 3×20 ml of toluene and dried. 21.0 g of 3-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione (yield: 77.0% of theory) of melting point 288° to 290° C. are obtained. According to thin-layer chromatography, the product is contaminated with the intermediate ethyl N-(4-chlorophenylcarbamoyl)anthranilate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][C@H:16]1[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:13])=[O:12].FC(F)(F)C(O)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][C@H:16]1[C:27]([OH:29])=[O:28])(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NS(=O)(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2.5 h
Yield: 41.2 %

Procedure:
The tert-butyl ester of example 58 (320 mg, 0.686 mmol) was dissolved trifluoroacetic acid (2 ml) and stirred for 2.5 h after which time the reaction was concentrated in vacuo. The resulting material was recrystallized from CH2Cl2 /CH3OH to give 116 mg (41%) of the title compound as a white solid. Anal. calcd. for C21H18N2O5S.1/4H2O: C,60.79; H,4.49; N,6.75. Found: C,60.94; H,4.45; N,6.71. MS calc for C21H18N2O5S 410, found 410. DSC=221.0°-224.1° C. at 109.2 J/g.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:17].C[Li].C([Li])(C)(C)C.[CH:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[O:32])([CH3:27])[CH3:26]>C1CCCCC1.CCOCC.CCCCC.CCOCC.C1CCCCC1.O>[OH:32][CH:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=1)[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(C)c1Br
Reactant: COc1ccc(C=O)cc1C(C)C
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
970 mg (3.23 mmol) of tert-butyl 4-bromo-3,5-dimethylphenylcarbamate (Example IV) are dissolved in 3 ml of cyclohexane and 3 ml of ether, cooled to −78° C., and added dropwise to 2.53 ml of 1.6 M methyllithium in ether at −78° C. After stirring at this temperature for 10 minutes, 3.8 ml of 1.7 M tert-butyllithium in pentane are added dropwise. The mixture is stirred at −78° C. for 1 hour and, after addition of 518 mg (2.9 mmol) of 3-isopropyl-4-methoxybenzaldehyde dissolved in 1 ml of ether/cyclohexane (1/1), stirred at −78° C. for 30 min and at room temperature for one hour. It is diluted with water and ether, the organic phase is washed with 10% strength citric acid solution, sodium bicarbonate solution and water and dried over sodium sulphate, and the solvent is removed in vacuo. Purification by chromatography (cyclohexane/ethyl acetate=9:1) affords 0.76 g (53%) of tert-butyl 4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](/[N:21]=[N+]=[N-])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]2[C:11]([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:21]2)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Nc1ccc(/C=C(/N=[N+]=[N-])C(=O)OCC)cc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1ccc2cc(C(=O)OCC)[nH]c2c1
Temperature: 80 °C
Yield: 38.2 %

Procedure:
385 mg (1.217 mmol) of ethyl (2E)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-azidoprop-2-enoate was dissolved in 25 mL toluene (˜0.05M solution). The mixture was heated to 80° C. for 2 h, cooled, and concentrated. Purification by column chromatography, eluting with 25% ethyl acetate/hexane provided 134 mg of ethyl 6-{[(allyloxy)carbonyl]amino}-1H-indole-2-carboxylate as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C:8]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:19][C:8]1([CH2:7][CH2:6][CH2:5][OH:4])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9]1
Reactant: CC(=O)OCCCC1(C)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(CCCO)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of 2-(3-acetoxypropyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 30 (3.2 g, 11.88 mmol), potassium carbonate (320 mg, 2.32 mmol) and methanol (35 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=25/1) to afford 2-methyl-2-(3-hydroxypropyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (2.1 g, 78%) as a light yellow powder.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C(=O)C(=NO)C)CCCCC1.C1(C)C=CC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[O:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=NO)C(=O)C1CCCCC1
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(-c2nc(CI)c(C3CCCCC3)o2)cc1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-cyclohexyl-1,2-propanedione-2-oxime and p-tolu-aldehyde gave 4-iodomethyl-5-cyclohexyl-2-p-tolyloxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(/C=C/C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a solution of ethyl (2E)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D62) (40 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 60° C. for 24 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford (2E)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoic acid (E37) (30 mg). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 3.70 (3H, s), 4.89 (1H, m), 6.38 (1H, d), 7.35 (1H, t), 7.45 (1H, d), 7.53 (1H, d), 7.81 (1H, d), 8.02 (1H, s), 8.14 (2H, m), 8.21 (1H, d), 12.04 (1H, br s). MS (ES): C23H20ClN3O4 requires 437. found 438.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)(=O)[CH3:12]>>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:11]=[CH:12][C:7]([C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
Product: N#Cc1ccc(C=CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
Part A. Employing methods similar to Example 1 Part A but using 4-cyano benzaldehyde (1.80 gm, 13.8 mmol) and 4-acetyl benzonitrile (1.0 gm, 6.89 mmol), 4-[3-(4-cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a pale yellow powder, 0.4 gm (20%) MS 259(M+H)+ 1 H NMR (CDCl3): 7.78(d, 2H), 7.6(t, 1H), 7.5-7.0(m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].O>C(#N)C>[CH:10]([NH:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)(=[O:29])=[O:30])=[CH:7][CH:6]=1)=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(NNC=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=CNNc1ccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
15.1 g of 2-(4-aminophenyl)-1-formylhydrazine and 14 ml of triethylamine were dispersed in 50 ml of acetonitrile. To the dispersion, a solution containing 50 ml of acetonitrile and 22.1 g of 3-nitrobenzenesulfonyl chloride was added dropwise while stirring at room temperature. After heating at 60° C. for 2 hours, the reaction mixture was cooled and then poured into water. The resulting crystals were collected by filtration. 15 g of the object compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:12])[C:8]([CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=1[NH:6]2.[CH:27]1([C:30]([NH:32][C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:31])[CH2:29][CH2:28]1>>[CH:27]1([C:30]([NH:32][C:33]2[CH:34]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[O:12])[C:8]([CH3:21])=[C:7]4[C:3]=3[C:4]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=3[NH:6]4)[CH:36]=[CH:37][CH:38]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1
Reactant: O=C(Nc1cccc(B(O)O)c1)C1CC1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(-c4cccc(NC(=O)C5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropanecarboxamido) phenyl boronic acid using an analogous procedure to that described in the preparation of compound 83. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.82 (m, 4H) 1.53 (qd, J=11.66, 3.41 Hz, 2H) 1.79-1.82 (m, 3H) 1.95 (t, J=10.86 Hz, 2H) 2.15 (s, 3H) 2.27 (s, 3H) 2.59 (s, 3H) 2.74 (d, J=11.12 Hz, 2H) 3.75 (m, 1H) 6.98 (s, 1H) 7.27 (d, J=7.58 Hz, 1H) 7.49 (t, J=7.96 Hz, 1H) 7.69 (d, J=2.02 Hz, 2H) 7.91 (s, 1H) 8.25-8.30 (m, 2H) 10.37 (s, 1H) 11.92 (br. s., 1H); [M+H] calc'd for C30H34N5O2, 496.3; found, 496.4.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1I>C1COCC1.C(N(CC)CC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:3]#[C:2][CH2:1][O:4][CH3:5]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC#Cc1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl propargyl ether (Fluka; 68898; 1.27 mL; 15 mmol; 1.50 eq.) was added dropwise to a suspension of 4-chloro-3-iodobenzoic acid (ABCR; TWC2211-D1; 2 824.60 mg; 10 mmol; 1 eq.), dichlorobis(triphenylphosphine)palladium(II) (701.91 mg; 1 mmol; 0.10 eq.) and cuprous iodide (190.45 mg; 1 mmol; 0.10 eq.) in a mixture of THF (20 mL) and triethylamine (10 mL). The reaction was stirred at RT for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl, and extracted twice with EtOAc. The combined extract were evaporated under vacuo to afford an orange solid. The latter was dissolved in EtOAc and extracted 4 times with NaOH 0.1M. Then the aqueous layer was filtered, acidified to pH=3-4 with HCl 1M, and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a slightly orange powder. 1H NMR (DMSO-d6, 300 MHz) δ 13.42 (br. s., 1H), 8.03 (d, J=2.07 Hz, 1H), 7.92 (dd, J=2.17, 8.38 Hz, 1H), 7.71 (d, J=8.48 Hz, 1H), 4.41 (s, 2H), 3.19-3.37 (m, 3H). LC/MS (Method B): 223.0 (M−H)−. HPLC (Method A) Rt 3.51 min (Purity: 98.8%).
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[CH2:26]([Li])[CH2:27][CH2:28]C.C(Br)C=C>CCCCCC.C(Cl)Cl>[CH2:28]([C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH:27]=[CH2:26]
Reactant: [Li]CCCC
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a stirring, anhydrous ether solution (20 mL) of 16 (0.58 g, 1.8 mmol) under inert atmosphere, n-butyl lithium (1.6 M in hexanes, 1.2 mL, 1.92 mmol) was added slowly at −50° C., and the mixture was stirred at −50° C. for 15 min, and gradually warmed up to 25° C. After 3 h, copper iodide(I) (0.51 g, 2.7 mmol) was added followed by dropwise addition of allyl bromide (0.32 g, 2.7 mmol). The solution was stirred for 12 h, followed by quenching with 100 mL saturated aqueous NH4+Cl− solution and extraction with ether (3×100 mL). The combined ether extracts were washed with water (2×100 mL) and brine (2×100 mL), and dried over anhydrous Na2SO4. Following filtration, solvent was removed in vacuum to yield an oil. Chromatography on silica gel with hexane:methylene chloride (4:1) afforded 0.18 g of 17 as a colorless-oil. Yield, 35%. 1H NMR (CDCl3): δ 3.40 (d, J=7.5 Hz, 2H), 5.11-5.32 (m, 2H), 5.98-6.07 (m, 1H), 6.98-7.15 (m, 8H), 7.22-7.37 (m, 6H). Anal. Calcd for C21H19N: C, 88.36; H, 6.72; N, 4.91. Found, C, 88.34; H, 6.10; N, 4.24.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]([CH:29]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13]>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:30]([F:32])([F:33])[F:31])=[C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]4[NH:5][CH:3]([CH3:4])[CH2:2][N:1]=4)=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:29]=1
Reactant: CC(N)CN
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nc1
Product: CC1CN=C(c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)N1
Yield: 46 %

Procedure:
Following the procedure as described in Example 10, making variations only as required to use 1,2-diaminopropane in place of 1,2-diaminopentane to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]nicotinic acid, the title compound was obtained as a pale yellow solid in 46% yield (0.260 g). 1H NMR (300 MHz, CD3OD) δ 8.63 (d, J=2.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.48-7.35 (m, 2H), 6.99 (d, J=9.2 Hz, 1H), 4.55-4.41 (m, 1H), 3.98-3.33 (m, 10H), 1.44 (d, J=6.3 Hz, 3H). MS (ES+) m/z 436 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Cl-].[Li+].N12CCCN=C1CCCCC2.[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(#N)C.O>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:29]/[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([OH:25])[CH:27]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C/c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A solution of trimethyl phosphonoacetate (9.94 mL, 61.4 mmol), lithium chloride (2.60 g, 12.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.92 mL, 106.5 mmol) in acetonitrile (80 mL) at room temperature under a nitrogen atmosphere was stirred at room temperature for 30 minutes. 3-Hydroxybenzaldehyde (5.00 g, 40.9 mmol) was added, and the mixture was stirred at room temperature for an additional 3 hours. Water was added and the aqueous phase was extracted with diethyl ether. The combined organic fractions were washed with water, brine, dried over magnesium sulfate, and evaporated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave trans-3-(3-hydroxyphenyl)acrylic acid methyl ester as a white crystalline solid (6.30 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([NH2:14])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Br:13])[CH:7]=1.O=C1CCC(=O)N1[O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[CH2:27]1)=O.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.ClCCl>[Br:13][C:8]1[CH:7]=[C:6]([CH:5]([NH:14][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][CH2:36]3)[CH2:27]2)=[O:23])[CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: COC(=O)CC(N)c1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 124.4 %

Procedure:
587.2 mg (2.13 mmol) 3-amino-3-(3-bromo-5-fluoro-phenyl)-propionic acid methyl ester were dissolved in 8.2 ml N,N-dimethylformamide and cooled to 0° C. To this solution was added a solution of 1100 mg (2.36 mmol) tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5c) and 0.89 ml (6.38 mmol) triethylamine in 8.2 ml dichloromethane. The mixture was kept at 6° C. for 20 hours. Saturated ammonium chloride solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 1.66 g (125%) tert-butyl 4-{3-[(3R)-3-{[1-(3-bromo-5-fluorophenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate with 80% purity.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:4]=1.C1COCC1>Cl.O1CCOCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Reaction time: 20 h
Yield: 130.6 %

Procedure:
A solution of tert-butyl {1-[4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (1.07 g, 3.09 mmol) in HCl in Dioxane (4M, 5 mL) and THF (5 mL) was stirred at rt for 6.5 h. HCl in Dioxane (4M, 2 mL) was added and the reaction mixture was stirred for another 20 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.99 g, 100%) as a solid. 1H NMR (500 MHz, CD3OD): 8.19 (d, 1H), 7.82 (s, 1H), 7.22 (d, 1H), 4.64 (d, 2H), 3.66-3.56 (m, 1H), 3.52 (td, 2H), 3.29 (d, 2H), 1.87 (dq, 2H); 13C NMR (CD3OD): 152.6, 144.8, 144.5, 144.2, 143.9, 138.7, 125.3, 123.1, 120.9, 118.7, 111.2, 108.1, 45.3, 29.0; Mass Spectrum: M+H 246
Reaction SMILES: [CH2:1]([N:7]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[OH-].[K+]>C1COCC1>[CH2:1]([N:7]([CH2:13][C:14]([OH:16])=[O:15])[CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCN(CC(=O)OC)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCCCCN(CC(=O)O)CC(=O)O
Reaction time: 8 h

Procedure:
To the obtained approximately 1.4 g dimethyl 2,2′-(hex-5-ynylazanediyl)diacetate was added 20 mL THF and 20 mL of 2 M KOH. The mixture was stirred overnight and monitored by TLC. The organic layer was separated, and the aqueous layer was quenched by addition of 20 mL of 2 M HCl. The solvent (H2O) was removed by rotary evaporation, and the resulting solid was dissolved into acetonitrile (ACN). The insoluble KCl salt was filtered, and the filtrate was concentrated by rotary evaporation. The final product of free acid was obtained as a greasy, transparent oil. Yield was quantitative. ESI-MS: [M+H]+ m/z 214.1.