Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])([CH2:16][CH3:17])[CH3:15]>>[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][C:25]1[C:26](=[O:27])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:29]=1[OH:30])([CH2:16][CH3:17])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CCC(C)c1ccccc1SC(C(=O)O)C(=O)O
Product: CCC(C)c1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.0 g, 6.17 mmol) and diethyl ester of [(2-sec-butylphenyl)thio]propanedioic acid (1.0 g, 3.09 mmol). m.p. 170-171° C.; 1H NMR (400 MHz, DMSO-d6) δ0.86(t, 3H), 1.22 (d, 3H), 1.57 (m, 1H), 1.67 (m, 1H), 3.22 (m, 1H), 6.89 (s, 1H), 6.97 (d, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.22 (d, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:37]([CH:34]1[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COc1ccc(CNCc2cc(Br)c(Cl)cc2OC)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2cc(Br)c(Cl)cc2OC)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of N-(5-bromo-4-chloro-2-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (190 mg, 0.47 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (109 mg, 0.47 mmol), HATU (180 mg, 0.47 mmol) and Et3N (101 mg, 1 mmol) in DMF (5 mL) was stirred at room temperature for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product. The crude product was used directly in the next step without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[C:30]2[C:29](=[O:31])[NH:28][C:27]([C:32]([O:34]CC)=O)=[N:26][C:25]=2[S:24][CH:23]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:80]2[CH:84]=[N:83][C:82]([O:85][CH2:86][CH2:87][O:88][C:89]3[CH:90]=[C:91]([CH2:95][NH2:96])[CH:92]=[CH:93][CH:94]=3)=[N:81]2)C=CC=CC=1>>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[C:30]2[C:29](=[O:31])[NH:28][C:27]([C:32]([NH:96][CH2:95][C:91]3[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH2:87][CH2:86][O:85][C:82]4[N:83]=[CH:84][NH:80][N:81]=4)[CH:90]=3)=[O:34])=[N:26][C:25]=2[S:24][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccco3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccco3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-furan-2-yl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 40 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (23.0 mg, 7%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1.[OH-].[Li+]>>[C:22]1([N:15]2[C:14]3[CH:28]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[S:18][CH2:19][CH2:20][CH3:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: CCCSc1nc2ccc(OCCCCCC(=O)O)cc2n1-c1ccccc1

Procedure:
109 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted according to general operating instructions 3 with lithium hydroxide. 104 mg was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[O:11]=[C:10]1[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:3][C:4]1=2
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 2-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 200 mg, 0.89 mmol) and triethylamine in tetrahydrofuran (10 mL) was cooled to 0° C. (ice-water bath). To this was added acetic anhydride (90.6 mg, 0.89 mmol) dropwise over a period of 10 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated at reduced pressure and the residue was chromatographed on silica gel (80% ethyl acetate/20% hexanes then 100% ethyl acetate and finally 2% methanol/ethyl acetate) to give a yellow solid (120 mg, 50.4%). H1 NMR (DMSO d6) δ: 9.82 (s, 1H), 9.80 (s, 1H), 7.82-7.81 (d, 1H, J=4.0), 7.68 (s, 1H), 7.58-7.55 (m, 11H), 6.95-6.86 (m, 5H), 1.97 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:31]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:38][C:39]([F:42])([F:41])[F:40])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[OH:37][C:31]1([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:38][C:39]([F:41])([F:42])[F:40])[CH:11]=2)[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Yield: 70.7 %

Procedure:
A mixture of tert-Butyl 4-[[4-(benzyloxy)-3-(trifluoromethoxy)phenyl](1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (1.7 g, 2.87 mmol) (See Example 268, Step 5), ammonium formate (0.95 g, 15.0 mmol), and a catalytic amount of palladium on carbon was heated at 50° C. for 1 hr in methanol (25 mL). At the end of this time the solution was concentrated and the residue taken up in ethyl acetate and filtered through a plug of silica gel eluting with 30% ethyl acetate:hexane. The filtrate was concentrated to afford 1.02 g of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate. MS (ESI) m/z 503; HRMS: calcd for C24H33F3N2O6+H+, 503.23635; found (ESI, [M+H]+), 503.2343.
Reaction SMILES: ClC1C=CC(C[O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.[F:36][C:37]([F:41])([F:40])[CH2:38]I>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:38][C:37]([F:41])([F:40])[F:36])=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: FC(F)(F)CI
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCC(F)(F)F)cn1

Procedure:
Compound 12 was prepared in a similar manner to compound 1 from 1,1,1-trifluoro-2-iodoethane to afford a pale yellow solid (23.0 mg, 50%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.27 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.21 (br s, 1H), 6.78-6.73 (m, 1H), 6.69-6.66 (m, 1H), 5.55 (d, J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 4.43 (q, J=8.0 Hz, 2H). MS(ESI): m/z 452.1 [M++1]. HPLC: 98.05%.
Reaction SMILES: [CH:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](C2CCCCC2)N1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](C3CCCCC3)N2C(=O)N1Cc1ccccc1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-cyclohexyl-9H-pyrido[3,4-b]indole-3-carboxylate (see J. Cook et al., Heterocycles, 4(7), 1249-1255 (1976)) and benzyl isocyanate gave after recrystallization from methanol, the title compound as white crystals m.p.: 130-135° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[NH2:28]>C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:28][C:21]3[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:29])[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCN(CCC)c1ccc(Br)c2nc(Cl)n(C)c12
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1ccc(Br)c2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-2-chloro-1-methyl-N,N-dipropyl-1H-benzimidazol-7-amine (220 mg, 0.638 mmol) and mesityl amine (1.79 ml, 12.8 mmol) was heated at 120° C. for 60 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 5% n-hexane/ethyl acetate to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]=3[CH:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Br:29])[CH:23]=3)[C:11]=2[C:10](=[O:30])[CH2:9]1)C1C=CC=CC=1.Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1>[Br:29][C:24]1[CH:23]=[C:22]([CH:12]2[C:11]3[C:10](=[O:30])[CH2:9][N:8]([C:32]([O:34][C@@H:35]4[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]4[C:41]([CH3:42])([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:43])=[O:33])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]2=3)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Reactant: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2CC(=O)C3=C(C2)NC2=C(C(=O)CC2)C3c2ccc(F)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the product from Example 5A (1.9 g, 4.0 mmol) in THF (30 mL) was treated with 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121-125) (1.45 g, 4.92 mmol) in THF (10 mL), stirred for 3 days at ambient temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer as separated, dried with sodium sulfate, filtered and concentrated to provide a mixture of diasteromeric carbamates. The diastereomeric mixture was subjected to column chromatography over silica gel (20% hexanes/ethyl acetate) to provide the title compound (0.32 g) as the less polar diastereomer and mixed fractions containing both diastereomers (0.9 g).
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: O=C(CCl)Cc1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(Cc2ccccc2)cs1
Yield: 30.1 %

Procedure:
5.0 g of benzyl chloromethyl ketone (Example 211a) was dissolved in 20 ml of ethanol and 2.3 g of thiourea was added thereto, followed by heating under reflux for 3 hours. After cooling as it was, the solvent was removed and the residue was subjected to NH-silica gel column chromatography using 50% ethyl acetate/hexane and ethyl acetate as an eluent for separation and purification, to give 1.7 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:20]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[O:13][CH2:12][CH2:11][N:7]([CH2:8][CH2:9][OH:10])[C:6]([NH:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])=[O:14])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: O=C(NCc1ccccc1Cl)N(CCO)CCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCCN(CCO)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (2.3 g, 8.46 mmol), in THF were added DMAP and 4-ethylphenylisocyanate (1.24 g, 8.46 mmol). The reaction mixture was stirred for 1 h and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2-chlorobenzyl)-1-(2-hydroxyethyl)ureido)ethyl 4-ethylphenylcarbamate (1.7 g, 48%). LRMS (M+H+) m/z 420.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][CH:11]([CH2:17][Br:18])[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:12](=[O:13])[CH:11]([Br:10])[CH2:17][Br:18])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1ccc(Cl)c(Cl)c1
Temperature: 5 °C

Procedure:
16 g of 3,4-dichloroaniline are dissolved in 200 ml of dry benzene and a solution of 26.0 g of 2,3-dibromopropionyl isocyanate in 50 ml of benzene is added dropwise with cooling at 5° C. The urea formed is immediately precipitated in crystalline form. After stirring for 3 hours at 20° C., the reaction mixture is diluted with the same volume of petroleum ether, filtered and dried. Yield: 39.0 g, m.p: 174° - 175° C.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[CH2:15][C:16]1[N:17]([CH3:42])[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH2:40][CH3:41])[N:19]=2.Cl[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([CH2:15][N:9]4[CH2:10][C@@H:11]5[CH2:14][C@H:8]4[CH2:13][N:12]5[CH2:44][C:45]([NH2:47])=[O:46])[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: NC(=O)CCl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4CC(N)=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
Triethylamine (85 μL, 0.61 mmol) was added to a solution of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol) and 2-chloroacetamide (60 mg, 0.64 mmol) in DCM (10 mL) The mixture was stirred at ambient temperature for 24 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 99:1 to 98:2) to afford 597 as a cream solid (175 mg, 62%). LCMS (method I): RT=2.35 min, M+H+=531. 1H NMR (CDCl3, 400 MHz) δ 12.12 (bs, 1 H), 8.01 (m, 1 H), 7.77 (m, 1 H), 7.26 (m, 2 H), 5.62 (bs, 1 H), 4.34 (m, 4 H), 3.92-3.83 (m, 9 H), 3.54 (m, 2 H), 3.37 (q, J=7.4 Hz, 2 H), 3.09 (m, 4 H), 2.93 (m, 2 H), 2.00 (m, 2 H) and 1.42 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]=CC)=O)[CH3:2].[C:12]([CH:17]=[C:18]1[NH:22][CH2:21][CH2:20][NH:19]1)([O:14][CH2:15][CH3:16])=[O:13].[CH2:23](O)[CH3:24]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]([CH3:8])[C:17]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:18]2[NH:19][CH2:20][CH2:21][N:22]2[C:23]=1[CH3:24])=[O:11])[CH3:2]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CC=CC(=O)CC(=O)OCC
Reactant: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1C
Yield: 58 %

Procedure:
Upon heating a solution of 6 g of ethylideneacetoacetic acid ethyl ester and 6 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 10 hours, 5,7-dimethyl-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 138° (ethanol) is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18]#[C:19][C:20]1[CH:25]=[CH:24][N:23](NC)[CH2:22][N:21]=1.[CH3:28][N:29]1C(=O)CCC1>>[CH3:28][NH:29][C:22]1[N:21]=[C:20]([C:19]2[NH:7][C:8]3[C:9]([CH:18]=2)=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[CH:25]=[CH:24][N:23]=1
Reactant: CNN1C=CC(C#Cc2cc(C(=O)OC)ccc2N)=NC1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CNc1nccc(-c2cc3cc(C(=O)OC)ccc3[nH]2)n1
Reaction time: 24 h

Procedure:
73 mg (0.7 mmol) of potassium tert-butoxide were dissolved in 1 ml of NMP and admixed with a solution of 140 mg (0.5 mmol) of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate in 1 ml of NMP. Subsequently, stirring was continued at RT for 24 h. Aqueous workup afforded 115 mg of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate (HPLC: 92.3 area %).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1
Yield: 90 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-methoxyphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (90%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CC(C)=O>[C:1]([OH:12])(=[O:11])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCC(=O)O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCC=CC(=O)O
Temperature: -35 °C

Procedure:
To a mixture containing 50 g of the liquid fraction 4 (Liquid 4) prepared in Comparative Example 4 and 50 g of decanoic acid, there was added 300 g of acetone to thus form a mixed solution and the resulting solution was cooled at −35° C. for 3 hour with stirring. Then the solution was fractionated into a solid phase and a liquid phase through filtration under reduced pressure, followed by the removal of the acetone from the solid and liquid phases through distillation to thus give 53 g of a solid fraction 8 (Solid 8) and 46 g of a liquid fraction 8 (Liquid 8), respectively. The concentration results for CLA isomer are listed in the following Table 23 and the concentration results for octadecenoic acid isomer are listed in the following Table 24.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine (10.54 g) in dry pyridine (105 ml) was added p-toluenesulfonyl chloride (14.35 g) at 0° C., followed by stirring at 25° C. for 23 hours. The reaction mixture was diluted with water and extracted with diethyl ether-dichloromethane (9:1). The extract was washed successively with saturated aqueous sodium chloride, 1N hydrochloric acid, saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried over anhydrous sodium suflate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>>[NH:14]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:15]
Reactant: NN
Reactant: Cc1cc(Cl)nc2c(C)cccc12
Product: Cc1cc(NN)nc2c(C)cccc12

Procedure:
A solution of 2-chloro-4,8-dimethylquinoline (1.00 g, 5.2 mmoles) in NH2NH2 was reacted as outlined in Scheme 1 above to give the desired title compound which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([N:8]([CH3:9])[S:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:23])=[O:22])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in DMF (5.0 ml), 4-chloro-N-methyl-2-nitroaniline (0.34 g (1.82 mmol)) was added with stirring at room temperature. To the resulting mixture, after 30 minutes' stirring at room temperature, 5-chloro-2-thiophenesulfonyl chloride (0.67 g (3.11 mmol)) was added. The reaction mixture was stirred at room temperature for 24 hours and then poured into water and extracted with chloroform. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with acetone-hexane (1:4) as eluent, to give 0.11 g (16%) of the title compound as pale yellow crystals.