Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[OH-].[Na+].[O:8]=[C:9]([CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10]([O:12]CC)=[O:11].Cl>C(O)C>[OH:8][C:9]1([C:10]([OH:12])=[O:11])[CH2:5][C:3](=[O:4])[CH2:1][CH2:2][C:15]1([CH3:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CC(C)=O
Reactant: CCOC(=O)C(=O)C(C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)CCC(=O)CC1(O)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
3.5 cm3 (39 mmol) of methyl vinyl ketone and 72 cm3 (71.5 mmol) of a normal aqueous sodium hydroxide solution were successively added to a solution, cooled to the region of 7° C., of 6.7 g (32.5 mmol) of ethyl (RS)-2-oxo-3-phenylbutyrate in 68 cm3 of ethanol and then the reaction mixture was stirred at a temperature in the region of 20° C. for two hours. The reaction mixture was cooled to 15° C. and 72 cm3 of a normal aqueous hydrochloric acid solution were added. After concentrating the ethanol, the precipitate formed was filtered off, washed with water and then dried at 50° C. 4.4 g (50%) of (1RS,2RS)-1-hydroxy-2-methyl-5-oxo-2-phenylcyclohexane-1-carboxylic acid were thus obtained in the form of a beige powder, the characteristics of which were as follows:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([F:30])=[C:14]([C:17]#[C:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH:15]=3)[S:10][C:9]([CH3:32])([CH3:31])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([F:30])=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH:15]=3)[S:10][C:9]([CH3:32])([CH3:31])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2cc3c(cc2F)SC(C)(C)C=C3c2ccc(C)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3cc(F)c(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 45 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl 4-[[4-(5-methyl-2-thienyl)-2,2-dimethyl-7-fluoro(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 214, 58.0 mg, 0.125 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 50 mg (90%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.05 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.3 Hz), 7.61 (1H, d, J=7.4 Hz), 7.31 (1H, d, J=9.6 Hz), 6.89 (1H, d, J=3.5 Hz), 6.79 (1H, d, J=3.5 Hz), 6.06 (1H, s), 2.49 (3H, s), 1.46 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:39])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[N:13][O:12][C:9]2=[C:10]([I:39])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2onc(-c3cccc(Cl)c3)c2c1O
Reactant: Cc1cc(C)c([IH+])c(C)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2onc(-c3cccc(Cl)c3)c2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
A mixture of 3-(3-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (377 mg, 1.18 mmole), bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.22 g, 2.36 mmole), and dichloromethane (12 ml) was stirred at room temperature for 20 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (440 mg); MS: (+) m/z 445.02 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][C:6]1[N:2]([CH3:1])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)n1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 1-methyl-1H-pyrrole-2-carboxylate (100 mg, 0.719 mmol) in CHCl3 (5 mL) at 0° C. was added N-bromosuccinimide (128 mg, 0.719 mmol). The reaction was stirred at 0° C. for 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 6.94 (d, J=4.2 Hz, 1H); 6.21 (d, J=4.1 Hz, 1H); 3.94 (s, 3H); 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([CH2:34][NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:35]([CH2:34][C:32]1[CH:31]=[N:30][N:29]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:33]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 59.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.61 g) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19]OC)=[CH:15][C:14]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.[CH3:32][CH2:33][CH2:34]CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:34]=[CH:33][CH:32]=1)=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCCCCC
Reactant: CCCCOC(=O)c1ccc2[nH]c3cnc(C(=O)OCC)c(COC)c3c2c1
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OCc4ccccc4)cc3c2c1C

Procedure:
6-butoxycarbonyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 150°-152° C. (ethanol/hexane); and
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][Si:24]([CH:27](O)[CH3:28])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(O)[Si](C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Reaction time: 3 h

Procedure:
The starting material can be obtained, for example, as follows: 14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253,310) are dissolved in 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilylethanol are added. The mixture is treated at 0° with 15.1 g of dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. After this, the reaction mixture is evaporated in a high vacuum, the residue is treated with ether, and dicyclohexylurea is filtered off. After flash chromatography (ethyl acetate/hexane 95:5), 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl is obtained as a slightly yellowish oil. (TLC: ethyl acetate/hexane 95:5) Rf : 0.42. 312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm aromatics.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH:40]1[C:48]2[C:43](=[CH:44][C:45]([Br:49])=[CH:46][CH:47]=2)[CH2:42][CH2:41]1)[C:7]([NH:9][CH:10]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[C:11]([O:13]C)=[O:12])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[Br:49][C:45]1[CH:44]=[C:43]2[C:48](=[CH:47][CH:46]=1)[CH:40]([CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:20]=1)=[O:8])[CH2:41][CH2:42]2
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)C(CSC(C)=O)C1CCc2cc(Br)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)C(CS)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained in Example 37 is dissolved in 5 ml of degassed methanol. After 10 minutes' stirring at room temperature, 4 eq. of a degassed 1M sodium hydroxide solution are, added to that solution. The resulting solution is stirred at room temperature under argon for 5 hours. The progress of the reaction is monitored by HPLC. When the reaction is complete, the solution is rendered acidic to pH=1 with 1N hydrochloric acid. The methanol is removed in vacuo, 10 ml of water are added to the residue and extraction is carried out with 10 ml of chloroform. The organic phase is separated off, dried over Na2SO4, concentrated in vacuo and purified by HPLC chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25](N)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.N1C=CC=CC=1.C(#N)C.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:39][N:40]([CH3:45])[S:41]([C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3=[N:11][N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:13]3[N:14]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:43])=[O:42]
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(N)c4)nn23)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(S(=O)(=O)N(C)C)c4)nn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine (compound A2) (1.90 g) and DMAP (304 mg) in a 3:1:1 mixture of anhydrous pyridine, anhydrous acetonitrile and anhydrous dichloromethane (100 mL) is added dimethylsulfamoyl chloride (2.67 mL). The mixture is stirred at RT for 3 days and filtered. The filtrate is concentrated in vacuum and a non-saturated solution of NaHCO3 (250 mL) is added to the residue. The suspension is filtered and the solid washed with a minimum of MeOH and AcOEt. Purification of residue by column chromatography (CH2Cl2/MeOH, 98:2) gives 1.43 g of the title compound as white powder.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]([CH3:10])([O-])[CH3:8].[K+].[C:12]([C:16]1[CH:17]=[C:18]([CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[CH:19]=[CH:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH:29]=[CH:30][C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=2)[CH:28]=1)[CH:24]=O)([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([C:16]1[CH:17]=[C:18]([CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[CH:19]=[CH:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH:29]=[CH:30][C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=2)[CH:28]=1)[CH:24]=[CH:6][C:7]1[C:10]2[C:8]([C:7]([CH:6]=[CH:24][C:23]3[CH:26]=[C:27]([CH:29]=[CH:30][C:31]4[CH:32]=[C:33]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[C:35]([C:37]([CH3:38])([CH3:39])[CH3:40])[CH:36]=4)[CH:28]=[C:21]([CH:20]=[CH:19][C:18]4[CH:45]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=[C:16]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:17]=4)[CH:22]=3)=[C:10]3[C:8]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:47][CH:16]=[CH:12][CH:13]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C=Cc3c4ccccc4c(C=Cc4cc(C=Cc5cc(C(C)(C)C)cc(C(C)(C)C)c5)cc(C=Cc5cc(C(C)(C)C)cc(C(C)(C)C)c5)c4)c4ccccc34)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
Dry N,N-dimethylformamide (10 ml) was added to a rapidly stirred mixture of 9,10-bis(dimethylmethylphosphonate)anthracene (395 mg, 0.935 mmoles), potassium t-butoxide (220 mg, 1.963 mmoles) and 3,5-bis(3′,5′-di-t-butylstyryl)benzaldehyde (1.000 g, 1.87 mmoles) under nitrogen and stirred at room temperature for 90 minutes. Distilled methanol (60 ml) was then added and the precipitate filtered and dried under suction. The crude product (925 mg) was recrystallized from dichloromethane-methanol and then chromatographed on flash silica using dichloromethane-pet. ether (40-60) (1:3) as the eluent. The solvent was removed to give 9,10-bis[3′,5′-bis(3″,5″-di-t-butylstyryl)styryl]anthracene (206 mg, 18%). lamdamax(film)/nm 308, 420.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)Nc1ccccc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 50.8 mg (0.54 mmol) of aniline. Yield: 4.7 mg.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1.O>C1COCC1>[Br:29][C:14]1[C:15]2[C:20]([C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
4 g (1 eq, 14.9 mmol) of 9-p-tolyl-anthracene, 5.3 g (2 eq, 29.8 mmol) of NBS were dissolved in 200 ml of THF in a 500-ml round-bottomed flask and stirred for 1 hour. 200 ml of water was added to the solution to obtain yellow crystals. The yellow crystals were filtered, dissolved in a small amount of toluene, and separated using column chromatography (silica and hexane) to obtain 4.6 g (89%) of yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([O:18]CC3C=CC=CC=3)[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]>CO>[CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)co2)cc1
Solvent: CO
Product: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Reaction time: 2 h

Procedure:
A solution of 2-(4-acetonylphenoxymethyl)-5-benzyloxy-4H-pyran-4-one, ethylene ketal (2.0 g) in methanol was hydrogenated at ambient temperature and pressure over 10% palladium on carbon until absorption of hydrogen was complete. The catalyst was filtered off and the solvent removed in vacuo. The residue was dissolved in acetone (75 ml) and treated with 2N-hydrochloric acid solution (2 ml) and allowed to stand at room temperature for 2 h. The solvent was then removed in vacuo, the residue dissolved in ethyl acetate, washed with water (2×50 ml), brine (1×50 ml) and dried (magnesium sulphate). After filtration and evaporation of the solvent, the residue was purified by column chromatography on silica using methanol-chloroform (2:98) as eluent to give 2-(4-acetonylphenoxymethyl) -5-hydroxy-4H-pyran-4-one, (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:43])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[C:27]([O:38][CH3:39])=[CH:26][C:25]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:46][S:47]([CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:49])=[O:48]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:43])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:56]3[CH2:55][CH2:54][N:53]([CH2:52][CH2:51][CH2:50][S:47]([CH3:46])(=[O:48])=[O:49])[CH2:58][CH2:57]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[C:27]([O:38][CH3:39])=[CH:26][C:25]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H50N5O7S2Cl2 [(M+H)+] 834.2523, observed 834.2524.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[C:20]([CH3:35])=[N:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:35][C:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=2)=[CH:24][CH:23]=[C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[N:21]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
To a solution of {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (20 mg, 0.04 4 μmol) in THF/methanol 2/1 (3 ml) was added a 1 N aqueous LiOH solution (1 ml). The reaction mixture was stirred for 14 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (18 mg, 0.04 μmol, quant.) as white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].O.[ClH:34]>C(O)C.ClCCl>[ClH:34].[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16](=[CH:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCOC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The above ester (2.0 g, 4.9 mmol) was dissolved in ethanol (20 ml) and a 4 N sodium hydroxide solution (4.9 ml) was added. The mixture was stirred at 50° C. for 2 h. Water (10 ml) was added and ethanol was evaporated in vacuo to give an aqueous residue. A 4 M aqueous hydrochloric acid solution (6.2 ml) was added followed by dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with water (10 ml) and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue dried in vacuo to give 1.71 g of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)[CH:9]=[N:8]1)[C:3]([OH:5])=O.C1C=CC2N(O)N=[N:37]C=2C=1.C(Cl)CCl.[Cl-].[NH4+].C(N(CC)CC)C>CCOC(C)=O.O.[Cl-].[Na+].O.CN(C=O)C>[OH:1][C:2]([CH3:30])([CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)[CH:9]=[N:8]1)[C:3]([NH2:37])=[O:5]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)C(=O)O)c2)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid (142 mg, 0.26 mmol), HOBT (61 mg, 0.4 mmol), EDC (76 mg, 0.4 mmol), and ammonium chloride (42.5 mg, 0.8 mmol) were combined with DMF (2.5 mL) in a flask. Triethylamine (0.35 mL, 2.51 mmol) was added and the mixture was stirred for 3 days at room temperature. The mixture was diluted with EtOAc and diluted with 1:1 water:brine (3×). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanamide. MS ESI calcd. for C19H19F3N6O2 [M+H]+ 421. found 421.