Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2C=[C:19]3[C:25]([NH:26][C:27](=[O:59])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:38][CH2:37][C@H:36]([NH:39]C(=O)C(F)(F)F)[CH2:35]5)=[CH:30][C:29]=4[N:46]([CH:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C:25]3[C:19]4[C:20](=[N:21][CH:22]=[C:17]([S:16][C:11]5[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([F:15])[CH:12]=5)[N:3]=4)[NH:23][N:24]=3)=[O:59])=[C:29]([NH:46][CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:30]=2)[CH2:35]1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12)c1ccc(N2CC[C@H](NC(=O)C(F)(F)F)C2)cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Product: N[C@H]1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
876 μl (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)—N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide in 6 ml of methanol. The reaction medium is stirred at 65° C. for 4 hours. After returning to room temperature, 8 ml of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80° C. for 24 hours. After returning to room temperature, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromethane/methanol as eluent) to yield 87 mg (yield=49%) of (S)-4-(3-aminopyrrolidin-1-yl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a brown powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1.[BH4-].[Na+]>C1COCC1.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)[OH:20])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 88.3 %

Procedure:
To a solution of bis(4(2-quinolylmethoxy)phenyl ketone (1.25 g, 2.5 mmol), prepared as in step 1, in THF/CH3OH (1:1, 60 mL) at room temperature was added NaBH4 (0.37 g, 10 mmol) and the mixture was refluxed for 3 hours, concentrated in vacuo, suspended in water and neutralized with citric acid. The resulting precipitate was collected by filtration, washed with 20% Et2O/hexane and dried in vacuo to afford bis(4-(2-quinolylmethoxy)phenyl)methanol (1.1 g, 88%) as white solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[H-].[Na+].C(O[C:13](=O)[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C.O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]1[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC(=N)NO
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Hydroxy-butyramidine (0.425 g, 4.16 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.183 g of a 60% dispersion in oil, 4.58 mmol) in the presence of molecular sieves (0.4 g). The reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min. 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.904 g, 4.16 mmol) in DMF (2 ml) is added over 5 min followed by more DMF (2 ml). After 3 h at 50° C. the mixture is cooled to 0° C. and water (3 ml) is added. The mixture is allowed to warm to room temperature then filtered through Celite™ filter material, washing with ethyl acetate, and the solvent is removed. Purification by chromatography, eluting with DCM:MeOH (95:5 increasing to 85:15) affords the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C1COCC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:18][C:6]([C:5]3[CH:19]=[CH:20][C:2]([NH2:1])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=3)=[N:8][N:9]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a 20 mL microwave vial was added 1.00 g (2.99 mmol) of 4-Chloro -benzoic acid N′-(4-amino-3-nitro-benzoyl)-hydrazide, 12 mL of THF, and 1.9934 g (8.36 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 30 min. To the orange/yellow suspension was added 5 mL of MeOH and the resulting precipitates were collected by filtration and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.31 (d, J=8.97 Hz, 1H) 7.80 (d, J=8.59 Hz, 2H) 8.12-8.19 (m, 2.7 H) 8.25 (d, J=8.59 Hz, 2 H) 8.77 (d, J=2.02 Hz, 1 H). MS (m/z) 317.0 M (+1), tR=1.33, Meth 10
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)n1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of 6.5 g of the compound of Example 1 in 50 ml of chloroform and 2.4 g of triethylamine is added dropwise 1.9 g of acetyl chloride over 15 minutes under cooling and stirring. After addition, the resulting mixture is stirred under cooling for 2 hours and then at room temperature for 3 hours. The reaction solution is washed with water, dried and then concentrated. The obtained residue is recrystallized from ethanol to give 5.7 g of 1-acetyl-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as oale yellow crvstals. melting at 169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11]/[CH:12]=[CH:13]\[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C(O)=[O:18].O>>[OH:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:18])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O=CO
Reactant: Nc1nc(Cl)c2ncn(C/C=C\CO)c2n1
Solvent: O
Product: Nc1nc2c(ncn2C/C=C\CO)c(=O)[nH]1

Procedure:
cis-4-(2-Amino-6-chloropurin-9-yl)-2-buten-1-ol (50 mg) in formic acid-water 7+3 (5 ml) was heated at 45° C. under a nitrogen atmosphere for 20 hours. The solvent was evaporated in vacuum and the residue was dried. Water (0.5 ml) was added and the solution was neutralized with aqueous ammonia. The precipitate was filtered, washed with water, ethanol and ether, and dried to give the compound cis-9-(4-hydroxy-2-butenyl)guanine (40 mg).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:54])([F:53])[C:46]1[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:49]3[CH:50]=[N:51][C:46]([C:45]([F:54])([F:44])[F:53])=[CH:47][CH:48]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C(F)(F)F)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-trifluoromethyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as a pale yellow foam. MS (ESI): m/z=424.2 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH:10]([C:12]1[CH:49]=[CH:48][CH:47]=[CH:46][C:13]=1[CH2:14][CH2:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[N:31][CH:32]=2)[N:17]=1)[CH3:11]>C(Cl)Cl>[NH:36]1[CH2:37][CH2:38][CH:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:13]4[CH:46]=[CH:47][CH:48]=[CH:49][C:12]=4[CH:10]([CH3:11])[C:9]([NH2:8])=[O:50])[C:21]([C:22]([F:24])([F:23])[F:25])=[CH:20][N:19]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Reaction time: 2 h
Yield: 134 %

Procedure:
TFA (0.50 mL, 6.5 mmol) was added to tert-butyl 4-(5-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A72 (0.060 g, 0.099 mmol) in DCM (5 mL) and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and quenched with 25% aq. NaOH (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL) before the combined organics were dried (phase separation cartridge) and concentrated under reduced pressure. The suspension was sonicated with hexane and concentrated under reduced pressure to give the title compound (0.066 g, 134% residual solvent/water). LCMS-D: rt 3.025 min; m/z 499.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][N:21]4[CH:25]=[CH:24][CH:23]=[CH:22]4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nn1cccc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nn2cccc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine was reacted with 1-aminopyrrole to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.16 (s, 1H), 7.95 (d, 1H, J=3.5 Hz), 7.16-7.12 (m, 2H), 6.69 (dd, 2H, J=2.3 and 4.7 Hz), 6.61 (d, 1H, J=8.8 Hz), 5.99 (dd, 2H, J=2.3 and 4.7 Hz), 4.12-4.15 (m, 4H). LCMS: ret. time: 19.86 min.; purity: 92%; MS (m/e): 328 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=1.B([C:29]1[CH:40]=[CH:39][C:32]([CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[CH:31][CH:30]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:35][C@@H:34]([CH2:33][C:32]1[CH:39]=[CH:40][C:29]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:25])[N:3]=2)=[CH:30][CH:31]=1)[C:36]([OH:38])=[O:37]
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 17.8 %

Procedure:
In a microwave vial, 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (30 mg, 0.081 mmol), 4-borono-L-phenylalanine (20 mg, 0.098 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 7.2 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.96 (m, 3H), 7.61 (m, 5H), 6.81 (s, 1H), 6.77 (d, J=6.8 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 4.27 (q, J=5.6 Hz, 1H), 3.36 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1.[Cl:15]N1C(=O)CCC1=O>O>[Cl:15][C:6]1[C:7](=[O:14])[N:8]([CH3:13])[C:9](=[O:12])[N:10]([CH3:11])[C:5]=1[Cl:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: CC#N
Solvent: O
Product: Cn1c(Cl)c(Cl)c(=O)n(C)c1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To 70 ml of an acetonitrile solution containing 21 g of 6-chloro-1,3-dimethyluracil thus obtained was added 16 g of N-chlorosuccinimide under cooling with ice (at the solution temperature of 5° C.). The temperature was gradually raised to 35° C. After further stirring for 1 hour, 70 ml of water was added to the reaction solution, and the crystals thus deposited were collected by filtration, washed with a cold solvent mixture of 18 ml of acetonitrile and 18 ml of water and dried to obtain 18 g of 5,6-dichloro-1,3-dimethyluracil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[C:13](=O)[CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>CN(C)C=O>[CH:26]1([C:24]([C:23]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=3[C:13]=2[CH3:14])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COCCOc1ccc(O)c(C(C)=O)c1
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
1-[2-Hydroxy-5-(2-methoxyethoxy)phenyl]ethanone (7.0 g) synthesized in the above-mentioned (1) was dissolved in N,N-dimethylformamide (140 mL). Potassium carbonate (13.8 g) and 2-bromo-1-cyclohexylethanone (8.9 g) synthesized in Example A51(1) were added to the reaction mixture at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was filtered through celite, water (200 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide solution (100 mL), DBU (5.3 mL) was added at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20, volume ratio) to give the title object compound (10.3 g, 98%) as a pale-yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16](Cl)[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[C:15]([CH:16]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1
Reactant: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3 H) 5.93 (q, J=7.17 Hz, 1 H) 7.64-7.70 (m, 2 H) 7.71-7.76 (m, 2 H) 7.77-7.83 (m, 2 H) 7.88-7.93 (m, 1 H) 8.95 (s, 1 H). LC-MS (+esi, M+H+=371.0)
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:38])([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH:7]1[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>C(O)C>[OH:1][CH:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([CH3:38])([CH3:37])[C:33]([OH:35])=[O:34])=[CH:30][CH:31]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH:7]1[CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(O)CC2C(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(O)CC2C(c2ccccc2)c2ccccc2)cc1

Procedure:
Methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetate (1.2 gm) was combined with potassium hydroxide (0.4 gm) and ethanol (5 ml), and the mixture was heated to reflux for 7 hours. The ethanol was removed on a rotary evaporator and the residue was dissolved in water (2 ml). The aqueous solution was acidifed with glacial acetic acid to provide a solid which was recrystallized from 1:1 methanol/ethyl acetate to give 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-α,α-dimethylbenzeneacetic acid (terfenadine carboxylate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:24]([OH:27])(=O)[CH3:25].S(=O)(=O)(O)O.Cl>O>[NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:17][O:18][C:24](=[O:27])[CH3:25])([CH2:19][O:20][C:13](=[O:14])[CH3:4])[CH2:21][O:22][C:7](=[O:8])[CH3:6])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8]
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Reactant: CC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCC(COC(C)=O)(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 5-amino-2,4,6-triiodo-N-[tris(hydroxymethyl) methyl]isophthalamic acid and glacial acetic acid is heated in the presence of a catalytic amount of mineral acid (such as sulfuric acid or dry hydrogen chloride) or a dry cation exchange resin (strong acid form). Molecular sieves may be used to act as a water scavenger. After the reaction is complete the acid catalyst is neutralized, or in the case of use of molecular sieves and the cation-exchange resin, the reaction mixture is filtered. The solution is then concentrated in high vacuum to provide the desired 5-amino-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]isophthalamic acid in sufficient purity for use as an intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:30])[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=2[NH:18][CH2:19]S(C2C=CC(C)=CC=2)(=O)=O)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([N:8]([CH3:30])[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=2[NH:18][CH3:19])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)CNc2c(C)nn(C)c2C(=O)N(C)c2cccnc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CNc1c(C)nn(C)c1C(=O)N(C)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 40.8 gm (0.091 mol) of N-(2-chloro-3-pyridinyl)-4-[[(4-methylphenyl)-sulfonyl]methylamino]-N,1,3-trimethyl-1H-pyrazole-5-carboxamide (prepared from N-(2-chloro-3-pyridinyl)-4-[[(4-methylphenyl)-sulfonyl]amino]-N,1,3-trimethyl-1H-pyrazole-5-carboxamide by reaction with sodium hydride in anhydrous N,N-dimethylformamide and subsequent reaction with methyl iodide) and 0.6 kg of polyphosphoric acid (content of phosphorpentoxide: 85%) was heated with stirring for 6 hours up to 60° C. The warm reaction mixture was stirred into cracked ice and subsequently mixed by means of external cooling with ice water with 40% aqueous sodium hydroxide solution until the precipitation was finished. After standing for 2 hours at +5° C., the strongly acidic reaction mixture was filtered off by suction filtration. The filtration residue was carefully washed with water and subsequently dried in the air. Yield: 20.9 gm (78% of theory).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:9]=2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCC(CC)(O[Si](C)(C)C)c1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(O[Si](C)(C)C)c1cccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H]4CCC(=O)O4)c(C)c3)cc2C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 49.1 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-ethyl-propoxy]-trimethyl-silane (Example 17-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).