Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=[C:5]([CH:19]([CH3:24])[C:20]([O:22]C)=[O:21])[CH:4]=1.[OH-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=[C:5]([CH:19]([CH3:24])[C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: COC(=O)C(C)c1cc(OC)c2c(=O)c3ccccc3ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)C(=O)O)cc2ccc3ccccc3c(=O)c12

Procedure:
The product of step (a) is dissolved in tetrahydrofuran (10 ml) and 0.1 N aqueous sodium hydroxide (12 ml) is added. After 30 minutes the solution is added to water and washed with ether. The aqueous layer is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is dried, evaporated and the residue chromatographed on silica gel (10 g) eluting with hexane:ethyl acetate:acetic acid 60:40:2, to afford dl-2-(4-methoxy-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionic acid, mp 144°-147° (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([CH:5]1[N:10](C(=O)CCC2NC=NC=2)[CH2:9][CH2:8][N:7]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[N:22]=[C:6]12)[CH2:2]CC.N(C(OCC1C=CC=CC=1)=O)[C@H:32](C(O)=O)[C@H](CC)C>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:22]=[C:6]2[CH:5]([CH:1]([CH3:32])[CH3:2])[NH:10][CH2:9][CH2:8][N:7]2[CH:20]=1
Reactant: CCCCC1c2nc(-c3ccccc3OC)cn2CCN1C(=O)CCc1cnc[nH]1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COc1ccccc1-c1cn2c(n1)C(C(C)C)NCC2

Procedure:
through 5.g. were carried out in a manner analogous to Steps 1.c. through 1.f of example 1, starting with Cbz-(L)-Ile-OH in place of Cbz-(L)-Nle-OH, and yielding 2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine (compound vii, where R3 is isobutyl, R4 is 2-methoxyphenyl and R5, R6, and R7 are H,).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: Cc1nc(C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 133; 116 mg, 0.24 mmol) in tetrahydrofuran (6 mL) at −20° C. After 15 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 37 mg, 0.26 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (15 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution (15 mL) and brine. The organic layer was dried (MgSO4), filtered, evaporated, chromatographed over silica gel (60% ethyl acetate/hexanes) and crystallized from diethyl ether/hexanes to (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (98 mg, 82% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24]([OH:27])(=[O:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24]([O-:27])(=[O:26])[CH3:25]
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CC(=O)[O-]
Temperature: 100 °C

Procedure:
Sucrose (34.2 g; 0.1 moles) can be mixed with acetic acid (50 g; 0.83 moles) and p-toluenesulfonic acid (0.2 g; 0.001 moles). The reaction mixture can then be heated to 100° C. for three hours. Sodium carbonate (0.1 g; 0.001 moles) can be added in order to neutralize the acid catalyst. Excess acetic acid can be removed at reduced pressure in a rotary evaporator. About 40 g of a partially esterified sucrose acetate (about 95 percent yield) containing about 70 weight percent sucrose diacetate and about 15 weight percent sucrose triacetate should be obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10])[CH3:16]
Reactant: Nc1ccc(Cl)cc1CO
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1CO
Reaction time: 1 h

Procedure:
To a solution of (2-amino-5-chloro-phenyl)-methanol (1.58 g, 10 mmol, 1 equiv) in 15 mL of DCM was slowly added ethyl chloroformate (1.05 mL, 1.1 equiv) and pyridine (1.2 mL, 1.5 equiv). After stirring for 1 h, the resultant mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the crude product, (4-Chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71), which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.Br[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:19]=2[CH:20]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:19]=2[CH:20]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
N-Methyl-4-nitrophenethylamine (0.41 g, 2.3 mmole), 2-bromomethyl-5-nitrobenzofuran (0.66 g, 2.6 mmole), sodium iodide (0.39 g, 2.6 mmole) and potassium carbonate (0.36 g, 2.6 mmole) were heated at reflux temperature in acetonitrile (50 ml) for 8 days. The solvent was then evaporated, water was added, and the mixture extracted three times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to give a semi-solid which was recrystallised from isopropanol to give the title compound, yield 380 mg.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:9]3[CH2:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=4)=[O:36])=[CH:38][CH:39]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccccc2Nc2ccccc21
Reaction time: 8 h

Procedure:
5,11-Dihydro-10H-dibenzo[b,e][1,4]diazepine (1.96 g) in dichloromethane (50 mL) containing N,N-diisopropylethyl amine (1.3 g) was reacted with the crude 4-cyclohexylbenzoyl chloride prepared as described above (2.22 g). The reaction mixture was kept at room temperature overnight, then washed with water and saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and filtration afforded the title compound as colorless crystals (1.28 g), m.p. 175–176° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([O:46][CH3:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:57])=[C:34]([O:46][CH3:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(OC)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(OC)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.39 g) was dissolved in methylene chloride (7.8 ml), a solution of m-chloroperbenzoic acid (152 mg) in methylene chloride (15.6 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 240) (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:27]([N:9]1[CH2:10][CH2:11][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[C:3]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH2:14][CH2:13]3)[N:4]=2)[CH2:8]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: BrCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
Benzyl bromide was purified by passage through a plug of basic alumina prior to use. A solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (736.2 mg, 1.954 mmol) in ACN (9.77 mL) was divided into two equal portions. Each solution was treated with a half portion of benzyl bromide (232 μL, 1.954 mmol) and stirred at 80° C. for 3 h. The reaction mixtures were allowed to cool to room temperature, and Each solution was treated with a half portion of sodium triacetoxyborohydride (1.242 g, 5.86 mmol). The reaction mixtures were stirred at room temperature for 1 h, then were quenched with saturated aqueous NaCl. The reaction mixtures were combined and partitioned between EtOAc with Et2O added to assist in phase separation and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 20% to 60% gradient of EtOAc in heptanes gave the title compound (522.2 mg, 56.8%). ESI-MS m/z [M+H]+ 471.4.
Reaction SMILES: [CH2:1]([N:5]([CH2:27]CCC)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1)[CH2:2]CC.ClC1C=CC(C2SC=C(C3C=CC=CC=3OCCCN(CCCC)CCCC)[N:42]=2)=CC=1>>[N:5]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:19][CH:20]=2)[CH:1]=[CH:2][N:42]=[CH:27]1
Reactant: CCCCN(CCCC)CCCOc1ccccc1-c1csc(-c2ccccc2)n1
Reactant: CCCCN(CCCC)CCCOc1ccccc1-c1csc(-c2ccc(Cl)cc2)n1
Product: c1ccc(-c2nc(-c3ccccc3OCCCn3ccnc3)cs2)cc1

Procedure:
By substituting m-hydroxyacetophenone for the p-hydroxyacetophenone, p-hydroxypropiophenone or p-hydroxybutyrophenone of Examples 1-26, the corresponding 4-(3-aminoalkoxyphenyl)-2-substituted thiazoles are produced. For example, 4-(3-dibutylaminopropoxyphenyl)-2-phenylthiazole, 4-[3-(4-methylpiperazol-1-yl)propoxyphenyl]-2-phenylthiazole and 2-(4-chlorophenyl)-4-(3-dibutylaminopropoxyphenyl)thiazole are produced by using m-hydroxyacetophenone in Examples 1, 6 and 16, respectively.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:1]1([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 267, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CC=C(CCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(CCc2ccccc2)CC1
Yield: 94 %

Procedure:
To a solution of the product of STEP 1 (1.33 g) in EtOAc (40 mL), add 10% Pd/C (0.2 g) and hydrogenate overnight at 58 psi. Filter the catalyst and concentrate the reaction mixture to give ethyl 4-(2-phenylethyl)-cyclohexanecarboxylate (1.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[C:20]([N:11]3[C:10]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[Br:24]Br.C(O)(=O)C.CO.C(Cl)Cl>O1CCOCC1.[Zn]>[Br:24][C:18]1[CH:19]=[C:20]2[C:15]([NH:14][CH:13]=[C:12]3[C:21](=[O:22])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:10](=[O:23])[N:11]32)=[CH:16][CH:17]=1
Reactant: BrBr
Reactant: COc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-n2c(=O)c3c[nH]c4ccc(Br)cc4n-3c2=O)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) in anhydrous dioxane (4mL) was added bromine (200 mg). The reaction was stirred at 20° C. for 15 min, and was then poured directly into boiling acetic acid (50 mL) containing zinc powder (500 mg). The reaction was refluxed for 5 min and allowed to cool to room temperature. After dilution with 10% methanol/methylene chloride (100 mL). the mixture was filtered through silica gel, the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 mL) followed by dilution with water (100 mL). The mixture was cooled to 0° C. and the solid was filtered and dried to yield 8-Bromo-2-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 33) as a yellow solid. m.p. 154° (dec).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.Cl.Cl.[NH:13]1[C:17]2[CH2:18][CH2:19][CH2:20][NH:21][C:16]=2[N:15]=[CH:14]1.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:21]2[CH2:20][CH2:19][C:18]3[N:15]=[CH:14][NH:13][C:17]=3[CH2:16]2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: c1nc2c([nH]1)CCCN2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g 2,4-dichloro-5-methoxy-pyrimidine are dissolved in 4 mL butanol and combined with 1.04 g 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 2.96 mL ethyldiisopropylamine. This mixture is stirred for 16 h at 50° C. and then the solvent is eliminated in vacuo. The crude mixture is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water and 5% acetonitrile and at the finishing point of 70% water and 30% acetonitrile. 0.2% formic acid is added to both eluants. The suitable fractions are freeze-dried.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Br:10][C:11]1[N:16]=[C:15]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cccc(Br)n2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 25.2 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 6-bromo-pyridine-2-carboxylic acid (52.03 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 80% EtOAc in Hexane as eluent) to afford 32 mg (24.6% yield) of biphenyl-4-carboxylic acid {2-[4-(6-bromo-pyridine-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 93.11%. 1H NMR (CDCl3): δ 8.0-7.9 (d, 2H), 7.8-7.66 (m, 4H), 7.66-7.58 (m, 7H), 7.52-7.46 (t, 2H), 7.44-7.38 (m, 1H), 7.38-7.32 (m, 1H), 4.4-4.3 (dd, 2H), 3.92-3.74 (m, 6H), 3.7-3.6 (m, 2H).
Reaction SMILES: COC(/C=C/C1C=CC(C2C=CC(C3CCC(CCCOC(C(C)=C)=O)CC3)=CC=2)=CC=1)=O.[O:34]=[CH:35][CH2:36][CH2:37][C@H:38]1[CH2:43][CH2:42][C@H:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1.[BH4-].[Na+]>CO.CCOCC>[OH:34][CH2:35][CH2:36][CH2:37][C@H:38]1[CH2:39][CH2:40][C@H:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([C:56]#[N:57])=[CH:54][CH:55]=3)=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCC=O)CC3)cc2)cc1
Agent: C=C(C)C(=O)OCCCC1CCC(c2ccc(-c3ccc(/C=C/C(=O)OC)cc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1

Procedure:
The polymerization of 3-[4-[4'-[(E)-2-methoxycarbonyl-vinyl]-biphenyl-4-yl]-cyclohexyl]-propyl trans-2-methyl-acrylate to poly [1-[3-[4-[4'-[(E)-2-methoxycarbonyl-vinyl]-biphenyl-4-yl]-cyclohexyl]-propoxycarbonyl]-1-methyl-ethylene] was effected analogously to Example 1. The polymer has the following phase succession (° C.): G 156 C 208 l The 3-[4-[4'-[(E)-2-methoxycarbonyl-vinyl]-biphenyl-4-yl]-cyclohexyl]-propyl trans-2-methyl-acrylate used as the starting material was prepared according to the following procedure: ##STR28## A solution of 12 g of trans-4'-[4-(3-oxo-propyl)-cyclohexyl]-biphenyl-4-carbonitrile (preparation: Mol. Cryst. Liq. Cryst. 1985, Vol. 131, 327) in 100 ml methanol/ether (9:1) was added dropwise at 0° C. within 5 minutes to a suspension of 1.39 g of sodium borohydride in 30 ml of methanol/ether (9:1). After 45 minutes a further 1 g of sodium borohydride was added. After a further hour the reaction was interrupted and the mixture was partitioned between methylene chloride and 1N hydrochloric acid. Thereupon, the organic phase was washed several times with water, dried over magnesium sulphate, filtered and evaporated. Crystallization from ethyl acetate/methylene chloride gave 11.5 g of trans-4'-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carbonitrile as yellowish crystals. ##STR29##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13]([C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[O:31])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc2c(Sc3nc4ccccc4[nH]3)cccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccnc2c(S(=O)c3nc4ccccc4[nH]3)cccc12

Procedure:
The product of step (b) above (390 mg) in ethyl acetate (20 ml) was cooled to -5° and treated with m-chloroperbenzoic acid (273 mg of 85% pure material). The temperature was allowed to rise to ambient. The reaction mixture was then diluted with ethyl acetate and methylene chloride, and then washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The solution was dried and evaporated. Column chromatography (SiO2 /ethyl acetate) gave the title compound 140 mg, mp 178°-9° (d).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[C:16]([C:21]([F:24])([F:23])[F:22])=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:3]1.[CH3:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:25][C:26]1[S:30][C:29]([NH:31][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4]([C:15]2[C:16]([C:21]([F:24])([F:22])[F:23])=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:3][C:2]3=[O:1])=[O:14])=[N:28][CH:27]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cccc3c(=O)cc(-c4cccnc4C(F)(F)F)oc23)s1
Temperature: 55 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
A mixture of 4-oxo-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromene-8-carboxylic acid 41 (210 mg, 0.6 mmol), 5-methyl-1,3-thiazole-2-ylamine 47 (68 mg, 0.6 mmol), HATU (274 mg, 0.72 mmol), and DIPEA (155 mg, 1.2 mmol) in DMF (4 mL) was stirred at 55° C. for 12 h. The reaction mixture was poured into H2O (25 mL) and extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give Compound 305 (85 mg, 32% yield). MS (ESI) calcd for C20H12F3N3O3S: 431.06. found: 432 [M+H].