Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21].C(N(C(C)C)CC)(C)C>C(O)C>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)=[CH:16][C:15]=1[CH3:21]
Reactant: Cc1cc(N)ccc1Br
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2ccc3cc(O)ccc3n2)ccc1Br

Procedure:
The mixture containing 2-chloroquinolin-6-ol (1eq), 4-bromo3-methylaniline (2 eq) and diisopropylethylamine in ethanol (1 M) was refluxed overnight. The resultant mixture was concentrated and purified on silica gel to provide the desired product. The mixture containing 2-chloroquinolin-6-ol (1 eq), 4-bromo3-methylaniline (2 eq) and diisopropylethylamine in ethanol (1M) was refluxed overnight. The resultant mixture was concentrated and purified on silica gel to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Br:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Br
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Br)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.75 g) in N,N-dimethylacetamide (10 mL) was rapidly added thionyl chloride (0.56 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Bromo-4-aminobenzophenone (0.75 g) was then added in one portion and the mixture was allowed to stir at room temperature overnight. The solution was poured into ice water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride) gave the title compound (0.43 g) as a white solid; mp 138-40° C. Analysis for C17H13BrF3NO3 : Calculated: C, 49.06; H, 3.15; N, 3.37; Found: C, 49.06; H, 3.10; N, 3.35.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Linoleoyl chloride (25.0 g, 83.6 mmol) was added, dropwise, to a cooled (0° C.) solution of Meldrum's acid (1) (13.3 g, 92.0 mol) and pyridine (14.8 mL, 184 mmol) in CH2Cl2 (180 mL) and the solution was allowed to warm (rt, 16 h). The reaction mixture was washed with an equal volume of HCl (5%, aq., 2×), dried (Na2SO4), filtered and concentrated. The residue was dissolved in dry methanol (200 mL) and heated at reflux (6 h). The solution was cooled (rt), concentrated and the crude oil was purified by flash chromatography (4% EtOAc-hexanes) to yield (11Z,14Z)-methyl 3-oxoicosa-11,14-dienoate (2) (24.5 g, 87%) as a pale yellow oil. Rf 0.38 (10% EtOAc-hexanes). FW 336.51, C21H36O3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:6]=[CH:5]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(Cl)ccc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(Cl)ccc4n3)cc21

Procedure:
2-(6-Chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:8].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[C:24]=1[Cl:32]>C1COCC1>[C:18]([C:4]1[NH:3][C:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[C:24]=2[Cl:32])=[O:31])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]2([CH3:16])[CH3:17])=[O:8])[CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c(N)[nH]1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c(NC(=O)Nc2cccc(Cl)c2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To 4-(2-amino-5-tert-butyl-1H-pyrrole-3-carbonyl)-3,3-dimethyl-piperazin-2-one 7 (60 mg, 0.21 mmol) in THF (1 mL) was added 1,2-dichloro-3-isocyanatobenzene (58 mg, 0.31 mmol) in THF (1 mL). The resulting reaction mixture was stirred at room temperature for 1 h, at which time, TLC indicated the completion of the reaction. The solvent was then removed in vacuo, and the residue was purified by prep. TLC (EtOAc/MeOH: 9.5/0.5) to provide 1-(5-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1H-pyrrol-2-yl)-3-(2,3-dichlorophenyl)urea (14.6 mg, 15%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ (ppm) 7.93 (t, J=4.9 Hz, 1H), 7.20 (q, J=1.9 Hz, 2H), 5.68 (s, 1H), 3.87 (t, J=5.1 Hz, 2H), 3.44 (t, J=5.0 Hz, 2H), 1.75 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[C:13]3[N:18]([CH2:19][C:4]=12)[C:17](=[O:20])[C:16]([CH3:21])=[C:15]([CH:22]([O:25][C:26](=[O:36])[CH2:27][NH:28]C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:14]=3)#[N:2].C(C(O)=O)(F)(F)F>O>[NH2:28][CH2:27][C:26]([O:25][CH:22]([C:15]1[CH:14]=[C:13]2[N:18]([CH2:19][C:4]3[C:5]2=[N:6][C:7]2[C:12]([C:3]=3[C:1]#[N:2])=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17](=[O:20])[C:16]=1[CH3:21])[CH2:23][CH3:24])=[O:36]
Reactant: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1C#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(OC(=O)CN)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1C#N

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-12-cyano-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (CDCl3 /MeOH-d4) d 8.28 (d, J=8.5 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.95 (m, 1H), 7.82 (m, 1H), 7.36 (s, 1H), 6.00 (apparent t, J=6.6 Hz, 1H), 5.41 (s, 2H), 3.92 (br s, 2H), 2.33 (s, 3H), 2.08-1.82 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). Anal. Calcd for C22H20N4O3.3/2 CF3CO2H.5/2 H2O: C, 49.67; H, 4.42; N, 9.27. Found: C, 49.41; H, 4.23; N, 9.29.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:20]2[C:15](=[C:16]([O:39][CH2:40][CH2:41][CH3:42])[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:25]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH3:43])(=[O:10])[CH3:9]>ClCCl>[CH3:43][C@H:12]1[CH2:13][CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)[CH:25]=3)[C:16]=2[O:39][CH2:40][CH2:41][CH3:42])[N:11]1[C:8](=[O:10])[CH3:9]
Reactant: CCCOc1c(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1c(-c2cnn(C3CCNCC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.063 g, 0.127 mmol) in dichloromethane (2.0 mL) and the reaction mixture stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.045 g, 89%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.12 (m, 6H), 1.18-1.37 (m, 1H), 1.57-1.88 (m, 5H), 1.97 (br d, J=10.26 Hz, 2H), 2.07 (s, 3H), 2.16-2.40 (m, 2H), 2.53-2.66 (m, 2H), 2.73-2.89 (m, 1H), 3.03 (br d, J=12.61 Hz, 2H), 3.46-3.65 (m, 2H), 4.09-4.30 (m, 1H), 4.62 (br d, J=5.86 Hz, 1H), 7.11 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.21 Hz, 1H), 7.84 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 397 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCCC3)cc2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(4-methylphenyl)-4-(4-(2-piperidinoethoxy)phenyl)chromane (0.458 g, 1.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>CN(C=O)C>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution containing 2.76 g of 4-nitroaniline (20 mmol) in 20 mL DMF was added 1.60 g of NaH (60% dispension in oil, 40 mmol). After 2 hours at room temperature, 2-(dimethylamino)ethyl chloride hydrochloride (3.46 g, 24 mmol) was added, and the reaction mixture was heated at 60° C. for 12 hours. The solvent was evaporated in vacuo to yield a residue which was partitioned between ethyl acetate and brine. The organic phase was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield a residue. Purification of the residue by flash chromatography with 2% MeOH in CH2Cl2 as the eluent yielded N,N-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine (2.34 g, 56%) and the title compound (1.23 g, 22%). MS (ES+) m/e 281 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 87.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.02 g) as an oil. ESMS:MH+ 490.4
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][NH:14][C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][CH:40]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][N:14]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[CH:44][CH:43]=2)[C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1Cc2ccccc2CNC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2Cc3ccccc3C[C@@H](NC(=O)OCc3ccccc3)C2=O)cc1

Procedure:
Prepared from 4(R)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (Step H) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) by the procedure described in Example 1, Step E. 1H NMR (400 MHz, CDCl3): δ1.40 (s, 9H), 3.02 (dd; 12, 16 Hz; 1H), 3.55 (dd; 5, 16 Hz; 1H), 3.87 (d, 18 Hz, 1H), 4.18 (d, 6 Hz, 2H), 4.43 (d, 15 Hz, 1H), 4.60 (br t, 6 Hz, 1H), 4.95 (d, 15 Hz, 1H), 5.07 (d, 18 Hz, 1H), 5.13 (s, 2H), 5.29 (dd; 5, 12 Hz; 1H), 6.25 (d, 6 Hz, 1H), 6.87 (d, 8 Hz, 1H), 7.04 (t, 8 Hz, 1H), 7.10 (d, 8 Hz, 1H), 7.13-7.45 (m, 14 H). FAB-MS: calculated for C37H39N3O5 605; found 612 (M+Li,100%).
Reaction SMILES: [H-].I[CH3:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][C:19]=3[C:20]=2[S:21][CH3:22])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15]>C1COCC1>[CH3:3][O:29][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:18]2[O:17][C:16]([C:8]3[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][CH3:15])=[C:6]([O:5][CH3:4])[CH:7]=3)=[C:20]([S:21][CH3:22])[C:19]=2[CH:23]=1
Reactant: COCOc1ccc(-c2oc3ccc(CCO)cc3c2SC)cc1OC
Reactant: CI
Agent: [H-]
Solvent: C1CCOC1
Product: COCCc1ccc2oc(-c3ccc(OCOC)c(OC)c3)c(SC)c2c1
Temperature: 25 °C

Procedure:
642 mg of hydride substance (16.1 mM) and 2.26 g of iodomethane (15.9 mM) were added to the solution containing 595 mg of 2-[2-(3-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol (13a; 1.59 mM) dissolved in 40 ml of THF. The reaction mixture was performed to reflux distillation for 16 hours and cooled to room temperature. The reaction mixture was extracted with 50 ml of water and ethylacetate to divide into water layer and organic solvent layer. The organic solvent layer was dried with magnesium sulfuric acid, filtrated and the filtrate was concentrated with vaccuo.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][S:27]([CH2:30][CH2:31][NH2:32])(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][CH2:31][NH:32][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24])(=[O:29])=[O:28]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CS(=O)(=O)CCN
Product: CC1(C)c2cc(C(=O)NCCS(C)(=O)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methanesulfonylethylamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[H][H]>[Pd].C(=O)([O-])[O-].[K+].[K+]>[NH2:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]3[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[N:19]=[C:3]3[C:2]([CH3:1])=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1nc2c(C)cnc(-c3cccc([N+](=O)[O-])c3)n2n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(C)cnc(-c3cccc(N)c3)n2n1

Procedure:
A 5.0 g portion of N-[8-methyl-5-(3-nitrophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]acetamide in a solution of 20 ml of trifluoroacetic acid containing 500 mg of 10% palladium on carbon catalyst was shaken under 46 lb. of hydrogen pressure on a Paar hydrogenator overnight. The mixture was filtered and the filtrate evaporated, giving an oil. This oil was neutralized with 20 ml of saturated aqueous potassium carbonate, saturated with salt and extracted into 100 ml of ethyl acetate. The organic phase was dried, filtered and evaporated. The residue was recrystallized from ethanol, giving 3.4 g of N-[5-(3-aminophenyl)-8-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]acetamide. A 282 mg portion of the above compound and 210 mg of p-toluene sulfonyl chloride were dissolved in 100 ml of pyridine with stirring and sealed overnight. A 105 mg portion of p-toluene sulfonyl chloride was added and the mixture was warmed under a drying tube on a steam bath for 1/2 hour. The mixture was cooled, evaporated and the residue taken up in chloroform and passed through a hydrous magnesium silicate pad. The filtrate was taken up in chloroform, washed with 0.1N hydrochloric acid, dried and evaporated. This residue was recrystallized from ethyl acetate-cyclohexane, giving the desired product as white crystals, mp 215°-218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: O=C1NCCNC1c1ccc(F)cc1
Reactant: ClCc1ccccc1
Product: O=C1NCCN(Cc2ccccc2)C1c1ccc(F)cc1

Procedure:
25 g (0.129 mol) of 3-(4-fluorophenyl)-piperazin-2-one, prepared in accordance with Example 13, are alkylated with 18.1 g (0.143 mol) of benzyl chloride, as described in Example 2.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:5]=1[NH:6][C:7](=[O:30])[C:8]1[C:9](=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([S:16][C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[Cl:25])[C:14]=1[CH3:15])[OH:10]>C(O)(=O)C>[Cl:3][C:4]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:5]=1[NH:6][C:7](=[O:30])[C:8]1[C:9](=[C:11]([C:26]([CH3:29])([CH3:27])[CH3:28])[CH:12]=[C:13]([S:16]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[Cl:25])=[O:1])[C:14]=1[CH3:15])[OH:10]
Reactant: OO
Reactant: Cc1c(Sc2cc(Cl)c(Cl)cc2Cl)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Product: Cc1c(S(=O)c2cc(Cl)c(Cl)cc2Cl)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C

Procedure:
30% w/v Aqueous hydrogen peroxide solution (1.5 ml.) is added to a solution of 2'-chloro-4'-nitro-5-(2,4,5-trichlorophenylthio)-3-t-butyl-6-methylsalicylanilide (0.4 g.) in acetic acid (15 ml.) at 50°-60° C. The mixture is heated at 95°-100° C. for 30 minutes and is then poured into ice cold water (200 ml.). The precipitated solid thus obtained is crystallised twice from acetic acid to give 2'-chloro-4'-nitro-5-(2,4,5-trichlorophenylsulphinyl)-3-t-butyl-6-methylsalicylanilide, m.p. 245°-246° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1

Procedure:
The method described in Part E of Example 1 can be used to treat 7-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (7-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine. The same method can be used to treat 6-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (6-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11]C1C(=O)C2C=COC=2CC1>>[CH3:11][CH:8]1[CH:9]([NH2:10])[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH2:6][CH2:7]1
Reactant: NC1CCCc2occc21
Reactant: CC1CCc2occc2C1=O
Product: CC1CCc2occc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: MS (EI) m/z (rel. intensity) 151 (M+, 64), 151 (64), 134 (86), 110 (83), 109 (99), 108 (55), 88 (56), 86 (87), 84 (92), 80 (76), 51 (67). HRMS (FAB) calcd for C9H13NO+H 152.1075, found 152.1066.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[OH-].[Na+:11]>>[C:1]([O-:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Na+:11].[Na+:11]
Reactant: O=C(O)C[C@@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C[C@@H](O)C(=O)[O-]

Procedure:
The sodium D-malate was prepared by neutralization of D-malic acid (SIGMA M 0750) using 4N sodium hydroxide. This product contains 2.5% of L isomer.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18])[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:21].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[O:18]=[C:6]1[N:5]([CH2:1][CH2:2][CH:3]=[O:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCC=O)C(=O)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-but-3-enyl-3-oxopiperazine-1-carboxylate (0.246 mg, 0.97 mmol) in 10 mL of 1:1 acetone:water was added sodium metaperiodate (621 mg, 2.90 mmol), followed by a solution of 0.25 M aqueous osmium tetraoxide (0.192 mL, 0.048 mmol). After stirring overnight, the reaction was partitioned between EtOAc and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 257.3 [M+H]+.