Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]([O:16]C)=[O:15])[CH2:9][CH2:8]1)(=[O:6])=[O:5]>O1CCCC1.O>[CH3:3][S:4]([N:7]1[CH2:8][CH2:9][N:10]([C@@H:13]([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:12]1)(=[O:5])=[O:6]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OC)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
1 ml (1 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N is added to a solution of 260 mg (0.7 mmol) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-methoxybenzoyl-amino)propanoate in 8 ml of tetrahydrofuran and 1 ml of water. The reaction medium is stirred at ambient temperature for 20 h. The solvents are concentrated under vacuum, the reaction medium is brought to pH=6 with an aqueous solution of acetic acid having a concentration of 1N. The product precipitates and the residue is taken up in 10 ml of water and stirred for 1 h. The solid is filtered, rinsed with water and with diethyl ether then dried. 190 mg (76%) of (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-methoxybenzoyl-amino)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]([CH2:23][CH3:24])=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][C:12]([CH2:23][CH3:24])=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)=[N:6][CH:7]=1
Reactant: NC1CCC(N)CC1
Reactant: CCc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (0.0053 g, 0.015 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.017 g, 0.151 mmol). The reaction mixture was then heated at 100° C. for 4 hr. Additional 1,4-diaminocyclohexane (0.017 g, 0.151 mmol) and triethylamine (0.0084 ml, 0.012 g, 0.060 mmol) were added. Heating at 100° C. was continued for 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to give 0.0040 g of trans-N1-(5-chloro-4-(5-ethyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.54 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu](I)I.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 57.5 %

Procedure:
To a 3-L 4-neck flask equipped with mechanical stirrer, N2 inlet and thermocouple was added compound 1a (124 g, 0.71 mol), toluene (0.99 L), 4-fluoro-iodobenzene (cpd 3e, 314.27 g, 1.42 mol), racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (cpd 3f, 30.2 g, 0.21 mol), copper iodide (13.48 g, 0.078 mol) and tribasic-N-hydrate potassium phosphate (330.54 g, 1.56 mol). The mixture was heated to 85° C. for 12 h. A second charge of 4-fluoro-iodobenzene (47.14 g, 0.21 mol) was added and the mixture was heated to 85° C. for 4 h. The reaction mixture was filtered through a diatomaceous earth pad and was washed with CH2Cl2 (2 L). The solvent was evaporated and the residue was purified by column chromatography (2.5 Kg Biotage SiO2 column, 15 column volumes, 10% EtOAc/Heptane) to give 110 g (58%) of compound 1c. 1H NMR (Chloroform-d) δ: 8.45 (d, J=1.5 Hz, 1H), 7.92 (dd, J=8.8, 1.5 Hz, 1H), 7.41-7.50 (m, 3H), 7.34 (d, J=3.2 Hz, 1H), 7.17-7.29 (m, 1H), 6.77 (d, J=3.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc(N)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2 g (9.5 mmol) methyl 3-methoxy-5-nitrobenzoate (7) were dissolved in 50 mL methanol by heating, then 0.3 g Pd/C (10%) were added under a stream of nitrogen, followed by 2.99 g (47.5 mmol) ammonium formate. The mixture was refluxed for 3 h, then stirred overnight at r.t.. The clear layer above the catalyst was decanted off portionwise and filtered through a syringe filter. The catalyst that remained in the flask was washed twice with methanol during this procedure. After concentration, 1.69 g of a brown solid were obtained, which were purified by column chromatography (hexanes/ethyl acetate, 7:3). Drying under vacuum afforded 1.25 g (73%) of a colorless solid. 1H NMR (CDCl3) δ 7.00-6.97 (m, 2H), 6.42 (t, J1=2.2 Hz, J2=2.2 Hz), 3.89 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.78 (sb, 2H); 13C NMR (CDCl3) δ 167.13 160.71, 147.49, 131.95, 109.01, 105.71, 104.36, 55.19, 51.880□ESI-MS m/z 314 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl.C(O[C:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[NH:11])C.[O-]CC.[Na+].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:24](=[O:23])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][N:11]=[C:10]1[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1
Reactant: COCCN
Reactant: CCOC(=N)c1ccsc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(-c2ccsc2)n(CCOC)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2-Methoxy-1-ethylamine (0.86 g, 11.4 mmol) was added to a solution of 3-thiophenecarboximidic acid ethyl ester hydrochloride (2.0 g, 10.4 mmol) in methanol (10 mL), which was then stirred at ambient temperature for 1.5 h. The reaction mixture was then concentrated under reduced pressure and redissolved in ethanol (10 mL). Sodium ethoxide solution (21% w/w in ethanol, 3.4 g, 10 mmol) and diethyl ethoxymethylenemalonate (2.2 g, 10 mmol) were added and the mixture was heated to reflux for 2 h before being concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to provide 1.82 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:31][CH2:32][CH2:33][O:34]C2CCCCO2)=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2].Cl.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:31][CH2:32][CH2:33][OH:34])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1OCCOC1CCCCO1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1OCCO
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.8 %

Procedure:
To a solution of 147 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester in 1.5 mL of tetrahydrofuran was added 1.5 mL of 2N hydrochloric acid, and stirred at room temperature for 19 hours. Thereafter, the reaction solution was added with water and extracted twice ethyl acetate, and the resultant organic layer was washed once with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, to afford 87.1 mg of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH2:6])[CH2:3][CH2:2]1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[S:21])[CH2:3][CH2:2]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1C1CC1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccccc1C1CC1)c1ccccc1
Temperature: 50 °C

Procedure:
To 2-cyclopropylaniline (498 mg, 3.74 mmol) in acetone (10 mL) was added benzoyl isothiocyanate (0.53 mL, 3.93 mmol) and the mixture was heated at 50° C. for 8 hours. The reaction mixture was concentrated to provide N-((2-cyclopropylphenyl)carbamothioyDbenzamide as a orange oil (1.249 g, 100%): 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H), 9.14 (s, 1H), 8.07 (dd, J=7.8, 1.3 Hz, 1H), 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.69-7.63 (m, 1H), 7.59-7.52 (m, 2H), 7.31-7.26 (m, 1H), 7.23 (td, J=7.5, 1.5 Hz, 1H), 7.13 (dd, J=7.6, 1.5 Hz, 1H), 1.95 (qt, J=12.3, 4.4 Hz, 1H), 1.09-1.01 (m, 2H), 0.76-0.69 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.70, 166.72, 137.59, 137.06, 133.71, 131.72, 129.22, 127.51, 127.20, 126.93, 126.12, 125.26, 11.72, 7.03; ESIMS m/z 295 ([M−H]−).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O.O>[NH:26]1[CH2:25][CH2:24][CH2:23][N:22]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:6]([OH:39])=[O:5])=[CH:14][CH:13]=1)=[O:27]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
240 mg of (2S)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-2-(toluene-4-sulfonylamino)-propionic acid tert-butyl ester were dissolved in 5 ml of methylene chloride and 1.6 ml of trifluoroacetic acid/water (95/5). The mixture was stirred for 2 hours at ambient temperature. The solvents were removed in vacuo. The residue was triturated with diethyl ether, filtered and dried in vacuo. Yield 196 mg. MS (ES+): m/e=503.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][NH2:30])[CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:31])[CH2:29][NH:30][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH2:26][CH2:27]1)=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9.5 g of 4-Hydroxy-quinoline-2-carboxylic acid and 12.2 g of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 110 ml of DMF, 7.7 g of HOBT and 9.6 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 23 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In 300 ml of chloroform, 100 g of 4-chloro-3-nitrobenzenesulfonyl chloride was dissolved, and cooled to 0° C. Thereto, a solution of 84.3 g of methyloctadecylamine in chloroform was added dropwise. Then, 39.5 g of triethylamine was added dropwise as the reaction system was kept at a temperature from 0° C. to 10° C. After the conclusion of the addition, the reaction was run for 1 hour. Then, the solvent was distilled away, and the residue was dissolved in 500 ml of methanol under heating. The solution was allowed to stand for a while in order to cool. Thereupon, crystals separated out, and they were filtered off. Yield: 109 g, Percent yield: 71.2%, Melting point: 86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:27][CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:25]=O)=[CH:23][CH:24]=1)=[O:19])[CH3:13].N1C=CC=C1C(OCC)=O>>[CH2:27]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:23][CH:24]=1)=[O:19])[CH3:28]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1ccc(C=O)[nH]1
Agent: CCOC(=O)c1ccc[nH]1
Product: CCN(CC)CCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Yield: 38 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (212 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)amide (prepared from ethyl pyrrole-2-carboxylate by method A, B and then C) to give 162 mg (38%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:8][CH2:7]2.[CH3:18][Mg]Br.C(OCC)C>C1COCC1.[Cu]I>[F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH:11]([C:12]#[N:13])[C:14]#[N:15])([CH3:18])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1F)C(C)(C(C#N)C#N)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 38.2 (260 mg, 1.1 mmol) in THF (7.0 mL) was added copper(I) iodide (260 mg, 1.4 mmol) followed by a 3.0M solution of methylmagnesium bromide in diethyl ether (0.45 mL, 1.4 mmol). The mixture was heated to reflux and stirred for one hour. The reaction was then cooled to room temperature and quenched with a saturated ammonium chloride solution. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate. The residue was purified by medium pressure chromatography (silica, 25 to 50% EtOAc:hexanes) to yield 38.3 (190 mg, 68% yield). MS ESI (neg.) m/e: 243.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[NH:3]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:3][C:4]2=[O:12])=[CH:22][CH:23]=1
Reactant: CC1(c2ccccc2)NC(=O)Nc2ccccc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)(c3ccccc3)c3ccccc32)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.70 g, 2.9 mmol) in DMF (10 mL) is added 1-chloromethyl-4-methoxy-benzene and Cs2CO3 (1.92 g, 5.9 mmol). After the addition the mixture is stirred at −20° C. for 1 h. Then CH3I (2.6 g, 18 mmol) is added dropwise. After the addition the mixture is heated to refluxed overnight. H2O is then added and the mixture extracted with EtOAc which is dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel to give product.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1([CH3:25])[CH2:14][O:13][C:12]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:11]1>C(OCC)C.C(Br)C.BrCCBr>[CH3:9][C:10]1([CH3:25])[CH2:14][O:13][C:12]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:18])=[N:11]1
Reactant: Brc1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Agent: [Mg]
Solvent: CCBr
Solvent: BrCCBr
Solvent: CCOCC
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
Magnesium turnings for Grignard (0.12 g, 4.71 mmoles) in ethyl ether (8 ml) were put under N2 and stirring at room temperature. Ethyl bromide (2 drops) and then, slowly, bromobenzene (0.52 ml, 4.93 mmoles) in ethyl ether (10 ml) and 1,2-dibromoethane (2 drops) were added. The temperature arose to reflux and was kept as such for 1 hour. The mixture was treated with 2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-benzaldehyde (1 g, 4.29 mmoles), prepared as described in example 2, and kept at reflux for a further hour, then cooled, poured into water/ice and extracted more times with ethyl acetate. The organic phases were washed with water, anhydrified and brought to dryness to give 1.44 g of the title compound (yield: 98%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].CS(O[CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)=O.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>CN(C)C=O>[N:1]([CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CN=[N+]=[N-]
Yield: 96.1 %

Procedure:
Using 4.9 g (100 mM) of lithium azide, crude product of 2-cyanomethyl-3-hexadecyloxypropyl methanesulfonate Vn1a obtained in the previous reaction in 30 ml of dimethylformamide is converted by the same procedure as described in the (52) and 3.504 g (96.1% yield) of the titled compound Vn1a is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH:7]([C:19]([OH:21])=[O:20])[CH:8]([O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:9][CH:3]1[CH2:4][CH2:5]2.ON1C(=O)CC[C:24]1=O>O1CCCC1>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:24])=[O:20])[C@@H:8]([O:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2
Reactant: O=C1CCC(=O)N1O
Reactant: CN1C2CCC1C(C(=O)O)C(OC(=O)c1ccccc1)C2
Solvent: C1CCOC1
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
For example, and not by way of limitation, 10 mg of benzoyl ecgonine in 5 ml tetrahydrofuran (“THF”) may be added to 1.1 equivalent N-hydroxysuccinimide (NHS) and 1.1 equivalent of Ethyl 3-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction mixture may be stirred at room temperature for about 30 min. The solvent may then be removed under reduced pressure and the resultant cocaine activated ester, cocaine-NHS (a cocaine pre-hapten), may be dissolved in 0.2 ml of DMF and mixed with 5 mg of carrier Self protein in 1 ml PBS. The mixture may then be stirred for about 3 hour at about 4 C.° to provide cocaine/Self protein conjugate. The foregoing amounts may be varied depending on the desired yield of conjugate. In preferred non-limiting embodiments, the carrier Self protein may be HSA or MSA or TSA.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6].C[Si]([C:32]#[CH:33])(C)C.CCN(CC)CC>C(#N)C.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>[C:32]([C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)[CH:9]=1)=[O:6])#[CH:33]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)Nc2cc(-n3cnc(C)c3)cc(C(F)(F)F)c2)ccc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a pressure tube with one end sealed, add 485 mg 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (1.0 mmol) from Step 2, 500 mg trimethylsilylacetylene (5.0 mmol), 19 mg Cu I (0.1 mmol), 7 mg Pd(PPh3)2Cl2 (0.01 mmol), 1.0 mL Et3N in 3.0 mL acetonitrile, and after Nitrogen replacement, the mixture is stirred at 80° C. for 2 h. After cooling to room temperature, the solution was filtered by 2 cm silica gel column. The filtration is washed three times with ethyl acetate and is concentrated to brown solid which is further dissolved in 5 mL methanol. The solution is then added with 980 mg K2CO3 and stirred at room temperature for 3 h. The solid was filtered off and the solution was concentrated to column chromatography f 344 mg desired product. (90%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>CN1C(=O)CCC1>[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: CC1CCCN1
Solvent: CN1CCCC1=O
Product: Cc1nc(C#Cc2ccc(N3CCCC3C)nc2)cs1
Temperature: 180 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.30 mL (2.5 mmol, 3 eq) 2-methylpyrrolidine and 2 mL NMP were combined. The reaction mixture was heated in the microwave at 180° C. for 30 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 2-(2-methylpyrrolidin-1-yl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001120970). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[O:12]1[CH:14]([CH3:15])[CH2:13]1>>[OH:12][CH:14]([CH3:15])[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CC1CO1
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NCC(C)O
Yield: 44.7 %

Procedure:
2,6-Diethylaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2,6-diethylaniline with a yield of 44.7%; b.p.: 137°-145° C./1 mm Hg.