Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]1[C:27](=[O:28])[NH:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:24]=2[O:23][CH2:22]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@@H:21]2[C:27](=[O:28])[NH:26][C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:24]=3[O:23][CH2:22]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Reactant: N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
100 mg of 32 (390 μmol), 113 mg of 38 (390 μmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2 mL of THF are successively introduced into a Wheaton tube, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The reaction medium is concentrated to dryness. The residues are chromatographed on a silica cartridge (8 g, eluent AcOEt). 79 mg of expected product Ex16 are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:10])[CH3:19]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′,4′-dichloroacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a 1:1 mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether. The purified oil solidified on standing at room temperature.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:3]
Reactant: OCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1ccccc1
Product: Cl

Procedure:
Benzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and benzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a cream solid (0.0833 g, 15% overall); νmax (nujol)/cm−1 2776, 2672, 2568, 2527, 1706, 1581, 1415, and 1329; δH (400 MHz, DMSO-d6) 9.89 (1 H, br), 9.19 (1 H, br), 7.41–7.31 (5H, m), 5.13 (2 H, s), 4.34 (2 H, m), 3.17–3.08 (4 H, m), and 1.31 (6 H, d, J 7.2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.FC(F)(F)C(O)=[O:17].[CH3:21][CH2:22][C:23](=[O:29])[C:24](=O)[CH2:25][CH2:26][CH3:27]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][CH:24]([C:23](=[O:29])[CH2:22][CH3:21])[C:25](=[O:17])[CH2:26][CH3:27]
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Reactant: O=C(O)C(F)(F)F
Reactant: CCCC(=O)C(=O)CC
Product: CCC(=O)C(Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)CC
Temperature: 100 °C

Procedure:
A mixture containing 0.2 g of 3,4-dihydroxy-5-nitrobenzyl alcohol and 0.03 ml of trifluoroacetic acid in 2.5 ml of 3,4-heptanedione was heated for 20 h at 100° C. The solvent was evaporated in vacuo and the residue was recrystallized from 2-propanol. Yield 0.3 g, mp 126°-131° C.
Reaction SMILES: FC(F)(F)C(O)=O.O.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[C:28]([NH:29][C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])=[CH:27][N:26](C5CCCCO5)[N:25]=4)[NH:21][C:20]=3[CH:44]=2)[CH2:12][CH2:11]1>ClCCl>[CH3:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[C:28]([NH:29][C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])=[CH:27][NH:26][N:25]=4)[NH:21][C:20]=3[CH:44]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)[nH]c3c2)CC1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc3nc(-c4n[nH]cc4NC(=O)N4CCCCC4)[nH]c3c2)CC1
Temperature: 22 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
1 mL of trifluoroacetic acid and 100 μL of water are added to a solution of 290 mg of N-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide in solution in 3 mL of dichloromethane. The reaction medium is stirred at 22° C. for 24 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. 0.5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid and 100 μL of water are added. The reaction medium is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 15% of methanol. 40 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated. 123 mg of N-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide are isolated and reacted again with 2.8 mL of TFA and 700 μL of water. The reaction medium is stirred at 22° C. for 72 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 15% of methanol. 37 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated. That is to say, 77 mg of N-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are isolated in total. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.43 to 1.63 (m, 6H); 2.90 (s, 3H); 3.05 (m, 2H); 3.22 (m, 2H); 3.43 (m, 4H); 3.58 (m, 2H); 3.89 (m, 2H); 7.17 (broad s, 1H); 7.31 (broad d, J=9.0 Hz, 1H); 7.65 (d, J=9.0 Hz, 1H); 8.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]n4)n3)CC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate and obtained as the more polar isomer.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[C:7]([N:8]=[N+:27]=[N-:28])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85 lmmol) was added to HCl/H2O (0.85 mL/1.7 mL), cooled to 0° C. Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours then it was extracted with three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane: ethyl acetate; 5:1) gave product (210 mg, 71%). EI-MS m/z 349 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Temperature: 50 °C
Yield: 61 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300 mg, 1.089 mmol) from Example 1A and (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (343.96 mg, 1.119 mmol), from the previous step in THF, was added Cs2CO3 (532.2 mg, 1.63 mmol) and the mixture was heated at 50° C. for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the ethyl acetate layer was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness. The crude compound was purified by column chromatography to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea, (310 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.85 (2, 2H), 1.30 (s, 9H); LC-MS (ESI)m/z 526 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CCO>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Solvent: CCO
Product: O=C(Nc1ccc(OCCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Yield: 64.7 %

Procedure:
A solution of N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide (0.125 g, 0.283 mmol) and morpholine (0.123 g, 1.4 mmol) in EtOH (3 ml) is heated at 180° C. for 30 min by microwave. The mixture is then concentrated under vacuum and the residue purified by column chromatography on silica gel (5% MeOH in EtOAc) to give 3-fluoro-N-[4-(3-morpholin-4-yl-propoxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide as a white powder (90 mg, 64%). Mp: 70-72° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.23 (m, 1H), 7.86 (m, 1H), 7.56 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1, Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.93 (s, 1H), 4.23 (t, J=6.3 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.29 (m, 4H), 2.55 (m, 2H), 2.42 (bs, 4H), 2.04 (q, J=6.6 Hz, 2H), 1.60 (bs, 6H). MS: 492.4 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20](=[O:25])[C:19]=3[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC2=C1CCC(=O)N2C1CCN(Cc2ccccc2)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CCc2c(O)cccc2N1C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 21.4 %

Procedure:
1-(1-Benzyl-4-piperidinyl)-5-oxo-3,4,5,6,7,8-hexahydrocarbostyril (10.0 g) is dissolved in chloroform (500 ml) and thereto is added N-bromosuccinimide (5.78 g). The mixture is refluxed with stirring for 2 hours. Thereto are added N-bromosuccinimide (5.00 g) and triethylamine (50 ml) and the mixture is refluxed with stirring for 3 hours. After cooling, the reaction mixture is washed twice with 30% aqueous sodium thiosulfate solution (200 ml) and once with saline solution (500 ml) and then dried with magnesium sulfate. The solvent is evaporated off and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=40:1) and recrystallized from ethanol/water to give 1-(1-benzyl-4-piperidinyl)-5-hydroxy-3,4-dihydrocarbostyril (2.13 g) as colorless needles, m.p.: 183°-184° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]=12)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[OH:29][CH:28]([C:27]1[CH:26]=[C:25]([O:24][CH3:23])[C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])(=[O:9])=[O:10]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccccc1
Reactant: COc1cc(C=O)cc2c1OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2S(=O)(=O)Nc2ccccc2C)cc2c1OCO2
Temperature: -72 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To tetrahydrofuran (200 mL) was added N-o-tolyl-benzenesulfonamide (4.95 g, 20 mmol). After cooling to −72° C., a solution of n-butyllithium (1.6 M, 25 mL in hexane) was added, and the mixture was stirred for 3 hours at −72° C. A solution of 3-methoxy-4,5-methylenedioxybenzaldehyde (3.60 g, 20 mmol) in tetrahydrofuran (70 mL) was added, and the mixture was stirred and warmed to 0° C. over 1.5 hours. The mixture was poured into 200-mL saturated ammonium chloride solution, and the organic phase was decanted. The solvent was evaporated in vacuo and the residue was suspended in ethyl ether, washed with saturated sodium bicarbonate and brine solutions. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a syrup which was chromatographed on 500 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo and crystallized giving a solid, 4.15 g, 48.6% yield, mp 155-158° C. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[NH:27])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:31])[CH:22]=[CH:21]4)=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: N=C(C=Cc1ccc(-c2ccc3[nH]ccc3c2)cc1)Nc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-c3ccc(C=CC(=N)Nc4ccc(Cl)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A mixture of 0.075 g (0.22 mmol) of 3-(4-bromo-phenyl)-N-(4-chloro-phenyl)-acrylamidine, 0.042 g (0.26 mmol) of 5-indoleboronic acid, and 0.013 g (0.011 mmol) of Pd(PPh3)4 in 3 mL of DME/water/ethanol (4/2/1) in a sealed tube was heated under microwave (45 W, 5 min). The reaction was diluted with 10 mL of saturated NaHCO3, and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 60% ethyl acetate in hexanes plus 1% NH4OH to give 0.036 g of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine. Method M: To a stirred solution of 0.10 g (0.27 mmol) of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine in 3 mL of DMF was added 0.011 g (0.28 mmol) of 60% NaH at 0° C. After 1 h, 0.018 mL (0.28 mmol) of iodomethane was introduced, the reaction was warmed to room temperature overnight and quenched with 10 mL of saturated NaHCO3. It was extracted with three 10 mL portions of dichloromethane. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed eluting with 40% ethyl acetate in hexanes to give 0.028 g of N-(4-chloro-phenyl)-3-[4-(1-methyl-1H-indol-5-yl)-phenyl]-acrylamidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>CCO>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[CH:11]=1
Reactant: CNC
Reactant: Brc1cc(Br)c2ccccc2n1
Solvent: CCO
Product: CN(C)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
A solution of 2,4-dibromoquinoline (273 mg, 1.0 mmol) in EtOH (15 mL) was treated with aqueous dimethylamine (40%, 0.4 mL, 3 mmol), stirred at room temperature for 16 h, concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (119 mg, 50%) as a cream solid: IR νmax (Nujol)/cm−1 2924, 2854, 1598, 1546, 1510, 1463, 1379 and 754; NMR δH (400 MHz, CDCl3) 3.21 (6H, s), 7.21 (1H, s), 7.23-7.26 (1H, m), 7.55 (1H, t, J 8.2 Hz), 7.68 (1H, d, J 8.5 Hz) and 7.94 (1H, d, J 7.1 Hz); M/Z 251 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8]C(OCC)C1C=CC=CC=1)[CH3:7].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:6]([O:8][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1c[nH]cn1
Reactant: CCOC(OCC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOn1ccnc1Cc1ccccc1
Temperature: 110 °C

Procedure:
A mixture of imidazole (1.0 g, 14.7 mmol), benzaldehyde diethylacetal (58.8 mmol), and p-toluenesulfonic acid (84 mg, 0.441 mmol) was heated neat at 110° C. for 1-3 days, accompanied by concurrent distillation of ethanol. After cooling, sodium carbonate (0.47 g, 4.41 mmol) was added and the crude mixture was distilled under vacuum (150-170° C./0.5 mmHg) to give N-ethoxybenzylimidazole derivatives (1-8) (15-75% yield).
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C1COCC1>[F:19][C:20]([F:27])([F:26])[C:21]([C:17]1[S:13][C:14]([SH:18])=[N:15][CH:16]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Sc1nccs1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
iPr2NH (1.0 g, 9.4 mmol) was dissolved in THF (12 mL) and cooled to −10° C. n-Butyllithium (2.5M, 3.8 mL, 9.4 mmol) was added dropwise, and the reaction was cooled to −78° C. Thiazole-2-thiol (1.0 g, 8.5 mmol) in THF (2.5 mL) was added, followed by ethyl trifluoroacetate (1.3 mL, 11.1 mmol), and the reaction was stirred at −78° C. for 1 hours. The reaction was warmed to −10° C. and quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 10a.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl.C(#N)C>[CH3:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])=[C:10]1[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OC(=O)C(C)(C)C)c(=O)ccn1C
Reaction time: 0.25 h

Procedure:
5.6 ml of triethylamine are added to a suspension of 5.56 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 400 ml of methylene chloride and 400 ml of acetonitrile, followed by the addition, over 30 minutes, of 7.38 ml of trimethylacetyl chloride. The reaction is complete after 15 minutes. The resultant solution is concentrated by evaporation under reduced pressure, the residue is taken up in water and extracted with methylene chloride. The residue of the organic extract is crystallised from 500 ml of ethyl acetate, affording 1,2-dimethyl-3-pivaloyloxy-4(1H)-pyridinone, which melts at 112°-113° C. (sinters from 103° C.).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][CH:12]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([NH:25][C@H:26]([C:33]([NH:35][C@H:36]([CH:41]=[N:42][NH:43][C:44]([NH2:46])=[O:45])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:27][C:28]2[N:32]=[CH:31][NH:30][CH:29]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC=Cc1ccccc1)Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 190 mg of (±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoic acid and 400 mg of bis(P-toluenesulfonic acid) salt of L-histidyl-L-leucinal semicarbazone in 7 ml of N,N-dimethylformamide were successively added 0.16 ml of diphenylphosphoryl azide and 0.28 ml of triethylamine under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted withh ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1 by volume) to obtain 151 mg of N-[(±)-2-(1-naphthylmethyl)-5-phenyl-4-pentenoyl]-L-histidyl-L-leucinal semicarbazone as a white powder.