Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[C@H:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[CH:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C(=O)O)C(c1ccc(Cl)c(NC(=O)C(c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
250 mg (0.47 mmol) of ethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate (diastereomer mixture; Example 129A) were dissolved in a mixture of 1.0 ml of methanol, 0.5 ml of THF and 0.5 ml of water, and 40 mg (0.94 mmol) of lithium hydroxide monohydrate were added at 0° C. The mixture was stirred initially at 0° C. for 1 h and then at RT overnight. Another 40 mg (0.94 mmol) of lithium hydroxide monohydrate were then added, and the reaction solution was warmed to 50° C. After further stirring at this temperature overnight, 1 ml of methanol was metered into the reaction mixture, and the mixture was stirred at 60° C. for a further 12 h. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 204 mg (86% of theory) of the title compound as a diastereomer mixture.
Reaction SMILES: CSC(=NC)[N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9]C=1)[CH3:5].C[NH:17]C(N(C)CC1C=CN=CC=1)=S>[N+](C)([O-])=O>[CH3:5][NH:4][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:17]=1
Reactant: CN=C(SC)N(C)Cc1ccc(Cl)cc1
Reactant: CNC(=S)N(C)Cc1ccncc1
Solvent: C[N+](=O)[O-]
Product: CNCc1ccccn1
Reaction time: 6.5 h

Procedure:
To 4.98 g (0.0205 mole) of S-methyl-N-(4-chloro-benzyl)-N-methyl-N'-methylisothiourea prepared in (1) was added 25 ml of nitromethane and the mixture was reflexed for 6.5 hours. The nitromethane was distilled off and the residue was subjected to silica gel (240 g) column chromatography using MeOH-CHCl3 (1:10) as an eluent to give 5.23 g of an orange-colored oil. To this oil were added small amounts of EtOH and ether and the mixture was cooled in a dry ice-acetone bath and triturated to give crystals. After addition of ether, the crystals were collected by filtration, washed with ether and dried. The procedure gave 3.69 g of the title compound-as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]([NH:31][C@@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:27]([O:26][C:24](=[O:25])[NH:31][CH:32]([C:36](=[O:37])[NH:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:33]([CH3:34])[CH3:35])([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1ccc(NCc2ccccc2)c(N)c1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2ccccc2)c(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N1-benzyl-4-methyl-benzene-1,2-diamine (1.24 mmol) and triethylamine (0.26 mL, 1.86 mmol) in dry DMF (5 mL), was added boc-D-valine (296 mg, 1.36 mmol) followed by TBTU (400 mg, 1.24 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[BrH:11].OS(O)(=O)=O.[CH2:17]=O>ClCCl.O.[Zn+2].[Br-].[Br-]>[Br:11][CH2:17][C:6]1[S:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(C)cs1
Reactant: C=O
Reactant: Br
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C)c(CBr)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-methylthiophene-2-carboxylate (2.7 g, 6.4 mmol) in dichloromethane (20 mL) is added 48% aq. HBr (12 mL), H2SO4 (6 mL), ZnBr2 (5.4 g), and HCHO (2.2 mL, 37%) at 0-5° C. The mixture is stirred at room temperature for 16 hours. The solution is diluted with water, extracted with dichloromethane, washed with NaHCO3 solution, saturated brine solution, water, dried over sodium sulfate, and concentrated to give the title compound as an off white solid (3.5 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15]CC)=O)=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:19]>C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([NH2:19])=[O:15])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: NC(=O)c1c[nH]cc1-c1ccc(N)cc1
Temperature: 80 °C

Procedure:
A suspension of 0.07 g (0.304 mmol) of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate in 10 cm3 of a 22% aqueous ammonium hydroxide solution is heated in an autoclave at a temperature in the region of 80° C. for 84 hours. After stopping the heating and then returning to ambient temperature and pressure, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give an orange solid which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (98/1/1 by volume)]. After concentrating the fractions under reduced pressure, a residue is obtained which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.02 g of 4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a brown solid: EI: m/z=201 (M+) base peak, m/z=185 (M−NH2+), m/z=157 (M-CONH2+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH3:23][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20]([OH:21])[CH3:23])[C:3]=1[OH:22]
Reactant: C[Mg+]
Reactant: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (86.4 mg, 271 μmol; Intermediate 96) in THF (3 mL) was treated with MeMgBr (774 μL of a 1.4 M solution in Toluene/THF, 4 eq) at rt and stirred for 30 min. After 30 min another 2 eq and after 45 min another 4 eq. of Grignard solution were added and stirring continued for 15 min. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc (3×), the combined org. phases washed with brine, dried and the solvent removed in vacuo to give a yellow-brownish solid (95.6 mg). This material was purified by prep. HPLC (15-45% MeCN/50 mM NH4HCO3) to yield the title compound as an yellowish solid (31.8 mg, 11% over 3 steps). MS (ESI+) for C16H14FNO4S m/z 318 (M-OH)+, 358 (M+Na)+.
Reaction SMILES: COC1C=CC(S(N[C@H](C(O)=O)CCC(O)=O)(=O)=O)=CC=1.[CH:22]1[CH:23]=[CH:24][C:25]([CH:28]2[N:35]=[C:34]3[N:30]([CH2:31][CH2:32][S:33]3)[CH2:29]2)=[CH:26][CH:27]=1>CC(=O)C.O>[CH:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[N:35]=[C:34]3[N:30]([CH2:31][CH2:32][S:33]3)[CH2:29]2)=[CH:24][CH:23]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Agent: COc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Yield: 125.1 %

Procedure:
A suspension of 31.73 g of L-N-[(4-methoxyphenyl)sulfonyl-glutamic acid (0.1 mol) in 400 ml of 2-propanone and 20 ml of water was stirred and heated till all solid entered solution. Then there were added 20.43 g of tetramisole. The whole was stirred and heated to reflux and additionally stirred at reflux for 10 minutes. The mixture was further stirred for 4 hours while the temperature was allowed to reach room temperature. The precipitate was filtered off, washed with 100 ml of 2-propanone and 5 ml of water and dried under vacuo at 50° C., yielding 25.55 g of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield 98%) αD20 =-62.4° (c5. 1N HCl); mp. 127.3°-129° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:33])[CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:11][N:12]=1.[CH3:34]N(C)CCC(S(C1C=CC(C2N=C(C3OC(C4C=CC=CC=4F)=NN=3)C(N)=NC=2)=CC=1)(=O)=O)C.FC1C=CC=CC=1C1OC(C2C(N)=NC=C(C3C=CC(S(C4CCOC4)(=O)=O)=CC=3)N=2)=NN=1>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:33][CH2:34][O:32][CH2:31][CH2:30]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:6]=2)=[N:12][N:11]=1
Reactant: CC(CCO)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4F)o3)n2)cc1
Reactant: CC(CCN(C)C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4F)o3)n2)cc1
Agent: Nc1ncc(-c2ccc(S(=O)(=O)C3CCOC3)cc2)nc1-c1nnc(-c2ccccc2F)o1
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCOCC3)cc2)nc1-c1nnc(-c2ccccc2F)o1

Procedure:
Compound IA-339 3-[4-[5-amino-6-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]phenyl]sulfonylbutan-1-ol 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 3H), 1.37-1.46 (m, 1H), 1.99-2.02 (m, 1H), 3.38-3.43 (m, 2H), 3.52 (s, 1H), 4.66 (t, 1H), 7.50-7.59 (m, 2H), 7.77 (d, 1H), 7.97 (d, 2H), 8.20 (s, 1H), 8.37 (d, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 470 Compound IA-343 5-[4-[3-(dimethylamino)-1-methyl-propyl]sulfonylphenyl]-3-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 3H), 1.76-1.82 (m, 1H), 2.14-2.20 (m, 1H), 2.79 (s, 6H), 3.21 (s, 2H), 3.47-3.55 (m, 1H), 7.50-7.59 (m, 2H), 7.75-7.81 (m, 1H), 8.01 (d, 2H), 8.19 (m, 1H), 8.40 (d, 2H), 9.10 (s, 1H) and 9.58 (s, 1H) ppm; MS (ES+) 497 Compound IA-349 3-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]-5-(4-tetrahydrofuran-3-ylsulfonylphenyl)pyrazin-2-amine 1H NMR (400.0 MHz, DMSO) d 2.13-2.19 (m, 2H), 3.65 (m, 1H), 3.74-3.80 (m, 1H), 3.86 (dd, 1H), 4.04 (dd, 1H), 4.22-4.28 (m, 1H), 7.50-7.60 (m, 2H), 7.75-7.80 (m, 1H), 8.04 (d, 2H), 8.20 (m, 1H), 8.38 (d, 2H) and 9.09 (s, 1H) ppm; MS (ES+) 468
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>C(#N)C.C(OCC)C>[Br-:20].[Cl:32][C:26]1[CH:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([CH2:21][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Product: [Br-]
Temperature: 60 °C
Yield: 80.1 %

Procedure:
Triphenylphosphine (1.83 g, 6.99 mmol) was added portionwise to a magnetically stirred solution of 2-bromomethyl-7-chloroquinoline (1.2 g, 4.69 mmol) in dry acetonitrile (10.0 ml) at 60° C. The resulting yellow solution was heated at 60° C. for 27 h with the precipitation of a cream solid. The cooled solution was diluted with diethyl ether (8.0 ml) and filtered to afford the title compound as a cream solid (1.95 g, 80%). Crystallised from ethanol and ethyl acetate as a cream microcrystalline solid, m.p. >200° C.; (Found: C, 64.61; H, 4.22; N, 2.62; Cl, 6.82. C28H22ClBrNP requires C, 64.82; H, 4.27; N, 2.70, Cl, 6.83%). νmax (nujol)/cm-1 1610.0, 1594.0. δH (270 MHz) 5.94 (2H, d, CH2P, 3J=14.2 Hz); 7.43 (1H, dd, 6-H, Jo =8.6, Jm =2.0 Hz); 7.50 (1H, d, 8-H, Jm =2.0 Hz); 7.57-7.95 (16H, m, ArH); 8.03 (1H, d, 3-H, Jo =8.6 Hz); 8.11 (1H, d, 4-H, Jo =8.6 Hz); m/z 437.4 (1.18), 262.3 (11.01), 177.1 (3.13), 43.1 (100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CNc1nc(Cl)nc2c(C(C)C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC)c2scc(C(C)C)c2n1
Yield: 91.7 %

Procedure:
90 mg (0.37 mmol) of 2-chloro-7-isopropyl-4-methylaminothieno[3,2-d]pyrimidine and 340 mg (5.96 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 89 mg (yield: 91.1%) of the title compound.
Reaction SMILES: [Mg].Br[CH:3]([CH3:7])[CH:4](Br)[CH3:5].CN(C)CCN(C)C.[C:16]1([C@H:22]([N:24]2[C@H:28]3[CH2:29][S:30][C:31](=O)[C@H:27]3[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:25]2=[O:40])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:41](=[O:43])=[O:42].Cl>O1CCCC1>[C:16]1([C@H:22]([N:24]2[C@H:28]3[CH2:29][S:30][C:31](=[C:7]([CH2:3][CH2:4][CH3:5])[C:41]([OH:43])=[O:42])[C@H:27]3[N:26]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:25]2=[O:40])[CH3:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N(Cc2ccccc2)[C@@H]2C(=O)SC[C@@H]21
Reactant: O=C=O
Reactant: CC(Br)C(C)Br
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
0.802 g (33 mmol) of magnesium chips were put into 5 ml of tetrahydrofuran. Then 2.37 g (11 mmol) of dibromobutane in 30 ml tetrahydrofuran was added in 1 hour. The reaction mixture was refluxed for 2 hours, then 2.55 g (22 mmol) of tetramethylethylenediamine was added and refluxed for another hour. To the suspension, cooled to 0° C., was then added 3.52 g (10 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-thieno[3,4-d]imidazol-2,4(3H,3aH)-dione in 50 ml of tetrahydrofuran. Then the reaction mixture was stirred for 2 hours at room temperature and then cooled to 0° C. Carbon dioxide gas was introduced in 1 hour at 0° C. and 1 hour at room temperature. The reaction mixture was poured onto a mixture of 85 g of ice and 11.5 ml of conc. hydrochloric acid and then extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and finally concentrated. 50 mg of p-toluenesulfonic acid was added to the residue, which was then taken up in 170 ml of toluene. The reaction water was refluxed and distilled off by means of a water separator. The remaining toluene solution was concentrated and the resulting oil was chromotographed over silica gel with acetic acid ethyl ester/toluene. 1.22 g (28 percent) of the title product was obtained as a light yellowish oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>>[F:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:18]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C(CBr)c1ccc(F)cc1F
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)cc3F)cs2)c1
Yield: 69 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 2,4-difluorophenacyl bromide to obtain methyl 3-[4-(2,4-difluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 69%. Pale yellow prisms. Melting point: 121 to 122° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([O:14][CH3:15])[N:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([N:29]=[C:30]=[O:31])(=[O:28])=[O:27])[CH2:17][CH3:18]>C(Cl)Cl>[CH3:15][O:14][C:4]1[N:5]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:7]=[C:2]([NH:1][C:30]([NH:29][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])(=[O:28])=[O:27])=[O:31])[N:3]=1
Reactant: COc1nc(N)nc(OCC(F)(F)F)n1
Reactant: CCCOc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.0 g of 2-amino-4-(2,2,2-trifluoroethoxy)-6-methoxy-1,3,5-triazine suspended in 35 mL of dry methylene chloride was added 4.4 g of a 50% solution of 2-n-propoxybenzenesulfonyl isocyanate in methylene chloride. The mixture was stirred overnight at ambient temperature and the resulting solution stripped to an amber oil which was triturated with ethanol to give 1.42 g of white solid with m.p. 161°-163° (dec).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>>[NH2:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCCCO
Agent: NN
Product: C=CCCCCCCCCCN
Yield: 66 %

Procedure:
Compound XXXI was prepared as described in Scheme I from 10-undecen-1-ol, 1, by a three step procedure in an overall yield of 31%. Alkylation of phthalimide with alkanol, 1, under Mitsunobu conditions, followed by reaction with hydrazine gave 1-aminoundec-10-ene, 2, in 66% yield. The amine was derivatized with O-acetylsalicyloyl chloride and the resulting alkene, 3, was oxidized to the acid using potassium permanganate. Removal of the acetate, followed by acid precipitation provided compound XXXI in 47% yield based on amine 2.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH2:4]1.C(N([CH2:26][CH3:27])CC)C.C[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(OCC)(=O)C>[CH2:26]([S:29]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[C:3]([CH3:20])([CH3:2])[CH2:4]1)(=[O:31])=[O:30])[CH3:27]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CN2
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CC(C)(C)c2cc(-c3ccc(C#N)n3C)ccc21
Reaction time: 3 h
Yield: 69.9 %

Procedure:
5-(3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile hydrochloride (288 mg, 1.0 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.43 mL, 3.0 mmol) was added. The mixture was treated with methanesulfonyl chloride (0.104 mL, 1.1 mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 10-60% ethyl acetate in hexane) to afford 5-[1-(ethylsulfonyl)-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.24 g). MS (EI) m/z 343.8; HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CN(C)CCO
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(dimethylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(dimethylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(C(=O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
1.0 g of 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketone and 8.0 g of pyridine hydrochloride are held at 200° for 60 minutes. The dark solution is poured while still warm into ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained 2-benzimidazolyl (3,4-dihydroxy-5-nitrophenyl) ketone in the form of yellow crystals of m.p. 240°-250°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.CC(C)=O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccccc1Cc1ccc(Cl)nn1
Agent: BrB(Br)Br
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccccc1Cc1ccc(Cl)nn1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2-(6-Chloro-3-pyridazinylmethyl)anisole (prepared as described in Example 33(c)) (2.35 g) was dissolved in dry dichloromethane (20 ml) and cooled with stirring to -50°. Boron tribromide (3 ml) was then added dropwise, and the solution was allowed to warm to room temperature. After 0.5 hours the orange reaction mixture was poured into ice/water (200 ml) and acetone added to dissolve the precipitated solid. The mixture was extracted with dichloromethane, the organic extracts were separated, washed with water, dried, and evaporated. The residue was recrystallised from ethyl acetate and petroleum spirit to give 2-(6-chloro-3-pyridazinylmethyl)-phenol (1.75 g, 80%), m.p. 132°-132.5°.