Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[CH2:29]([NH:36][C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[CH:40]=[C:39]([C:50]2[CH:51]=[N:52][CH:53]=[C:54](Br)[CH:55]=2)[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:29]([NH:36][C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[CH:40]=[C:39]([C:50]2[CH:51]=[N:52][CH:53]=[C:54]([C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)[CH:55]=2)[CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NCc3ccccc3)n2)n1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cccc(-c2cc(-c3cncc(-c4ccc(N5CCN(C)CC5)cc4)c3)cc(NCc3ccccc3)n2)n1

Procedure:
To a solution of 1-Methyl-4[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-piperazine (1.2 eq, 0.083 mmol, 0.025 g) and 2M Na2CO3 (4.0 eq, 0.138 mmol, 0.1 ml) in DME (1 ml) is added Benzyl-(5″-bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.40; step1) (1 eq, 0.069 mmol, 0.03 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0069 mmol, 5 mg). The reaction mixture is heated using microwave radiation at 90° C. for 1 hour 15 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 527.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: Cc1ccc(C(N)c2ccccc2N2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccc(C)cc2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from α-(4-methyl-phenyl)-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].C1([C@@H]2CN[C@H](C(O)=O)C2)C=CC=CC=1.N[C@H](C(N1C[C@@H](CC2C=CC=CC=2)C[C@H]1C(O)=O)=O)C.O=[C:55]([CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57]>[Pd].C(O)C>[CH2:59]([O:58][C:56]([C@@H:55]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:57])[CH3:60]
Reactant: C[C@H](N)C(=O)N1C[C@@H](c2ccccc2)C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Pd]
Agent: C[C@H](N)C(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Agent: O=C(O)[C@@H]1C[C@H](c2ccccc2)CN1
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C[C@@H](c2ccccc2)C[C@H]1C(=O)O

Procedure:
A mixture of 0.85 grams of 1-(L-alanyl)-4-(R)-phenyl-L-proline [prepared by employing cis-4-phenyl-L-proline in the procedure of Example 2(a) to (d)], 0.2 grams of ethyl 2-oxo-4-phenylbutyrate and 1.5 grams of molecular sieves in 10 ml. of ethanol is hydrogenated under 40 psi with 1 gram of 10% palladium on carbon as the catalyst. The mixture is filtered when the uptake of hydrogen has ceased, and the filtrate is concentrated. The crude product is absorbed on an ion exchange resin (Dowex 50, H+) and eluted with 2% pyridine in water to yield the desired 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(R)-phenyl-L-proline.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]1=[O:9].[C:10](=O)([O-:12])[O-:11].[K+].[K+]>>[C:10]([C:5]1[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:9])[C:4]=1[OH:8])([OH:12])=[O:11]
Reactant: Cn1cccc(O)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(C(=O)O)c(O)c1=O
Yield: 87.7 %

Procedure:
1-Methyl-3-hydroxy-2(1H)-pyridinone (1) (6.25 g, 50 mmol) is mixed with anhydrous potassium carbonate (36 g, 0.26 mol). The vacuum dried mixture is put in a Parr bomb which is then filled with dry carbon dioxide gas (850 psi) and heated to 175°-185° C. for 3 days. The cooled bomb is opened and the resultant pale yellow solid is dissolved in ice water and acidified with 6N HCl to produce a beige crystalline product (7.42 g, 87.5%), m.p. 243°-245° C. (dec). 1H NMR (250 MHz, DMSO-d6): δ 3.469 (s, 3H), 6.357 (d, 1H, J=7.33), 7.166 (d, 1H, J=7.19), 7.27 (s,br, 1H). 1H NMR (250 MHz, D2O-NaOD): d 3.342 (s, 3H), 6.176 (d, 1H, J=6.94), 6.487 (d, 1H, J=7.00). Anal. for C7H7NO4 (169.14): Calcd. found): C, 49.71 (49.74); H, 4.17 (4.30); N 8.28 (8.16).
Reaction SMILES: CO[C:3](=[O:19])[C@H:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]([NH:28][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:7])=[N:13][NH:12]1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Nc1n[nH]c(=S)s1
Reactant: NCCc1ccccc1
Product: CC(C)C[C@H](NC(=O)Nc1n[nH]c(=S)s1)C(=O)NCCc1ccccc1

Procedure:
Following the general procedure outlined in EXAMPLE 5, and making non-critical variations but starting with N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-leucine methyl ester (prepared according to the procedure described in EXAMPLE 1) and phenethylamine, the title compound is obtained (mp 215°-217° C., decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3OC=C[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:36](O)(=[O:38])[CH3:37]>CO.CCOCC>[O:38]1[CH:36]=[CH:37][C:18]([C:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:23])[CH2:17][CH:16]=2)=[N:22]1
Reactant: CC(=O)O
Reactant: OC(CCCN1CC=C(c2ncco2)CC1)c1ccc(F)cc1
Agent: O=[Cr](=O)(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: O=C(CCCN1CC=C(c2ccon2)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1.58 g. portion of 3,6-dihydro-α-(p-fluorophenyl)- 4-(2-oxazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 15, in 45 ml. of acetic acid is stirred at room temperature. A 30 ml. portion of chromic acid in acetic acid is added dropwise. The mixture is stirred for 2 hours and allowed to stand overnight. A few drops of methanol are added, the mixture is poured into ice water and neutralized with sodium carbonate. The mixture is extracted with ether. The ether extract is dried over magnesium sulfate, filtered and evaporated yielding an oil which solidifies. This solid is dissolved in ether, alcoholic HCl is added and the mixture is filtered. The solid is slurried in acetone, filtered and recrystallized twice from ethanol, m.p. 178°-178.5° C.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(=O)C.[K+].[B:21]1(B2OCC(C)(C)CO2)[O:26]CC(C)(C)C[O:22]1>O1CCOCC1>[F:15][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:26])[OH:22]
Reactant: Fc1ccc(Br)c(F)c1-c1cccnc1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 3-(3-bromo-2,6-difluorophenyl)pyridine (2.97 g, 11 mmol), potassium acetate (2.16 g, 22 mmol) and bis(neopentyl glycolato)diboron (2.86 g, 12.7 mmol) in 1,4-dioxane (30 mL) was heated at 90° C. for 16 h. The reaction was cooled, filtered (washing the filter cake with a small quantity of diethyl ether) and the filtrate concentrated in vacuo. The residue was partitioned between diethyl ether (100 mL) and 1 M sodium hydroxide (100 mL) and the organics discarded. The aqueous was washed with more diethyl ether and then cooled in an ice-water bath. The pH was adjusted to approximately 6 with 36% hydrochloric acid, and allowed to stand for 1 h. The resulting solid was collected by filtration and dried under vacuum to afford 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (2.2 g, 85%) as a grey solid: m/z (ES+) 236 (M++H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:15]1([CH2:21][CH2:22][NH:23][C:9]([C@@H:8]2[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (32.2 mg) in tetrahydrofuran (1 ml) was added 2-phenylethylamine (20.1 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.027 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried over magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily (2S,4S) -N-(2-phenylethyl)-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarboxamide.
Reaction SMILES: C(O[CH:4]([C:22]([OH:24])=[O:23])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.S(=O)(=O)(O)O.Cl>C(O)(=O)C>[C:22]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])([OH:24])=[O:23]
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCC(OCC)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C)cccc2n1CCCC(=O)O
Temperature: 72.5 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A mixture of ethyl 1-(3-ethoxycarboxypropyl)-4-methyl-1H-indole-2-carboxylate (15.4 g, 48.5 mmol), acetic acid (250 ml) and 30% sulfuric acid (125 ml) was stirred at 70-75° C. for 1.5 hours. The reaction mixture was cooled to room temperature and then poured into ice water, followed by extraction with ethyl acetate (twice). Subsequently, the organic layer was extracted with aqueous ammonia (prepared from 130 ml of 28% aqueous ammonia and 100 ml of water), and the aqueous layer thus obtained was adjusted to pH 3 to 4 with 35% hydrochloric acid. The solid precipitated was collected by filtration, washed with water and then dried under reduced pressure to obtain 9.2 g of ethyl 1-(3-carboxypropyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])=O)(C)(C)C>C(Cl)Cl>[CH3:7][NH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Product: CNc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrochloric acid in dioxanes (4M, 7 mL) was added to a solution of N-tert-butoxycarbonyl-N-methyl-3-aminobenzophenone (2.2 g, 7.4 mmol) in methylene chloride (5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was partitioned between chloroform and saturated sodium bicarbonate solution and the organic layer was washed with saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuo to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:7])[CH2:4][CH:5]=O.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18]/[CH:5]=[CH:4]/[C:3](=[O:7])[C:2]([CH3:15])([CH3:1])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(Cc1ccccc1)C(=O)CC=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(Cc1ccccc1)C(=O)/C=C/Cl

Procedure:
A solution of 6.6 g. of 4,4-dimethyl-3-oxo-5-phenylpentanal in 25 ml. of dry benzene was treated with 4.7 g. of thionyl chloride and refluxed for 21/2 hours. Solvent was evaporated and the residue was distilled under reduced pressure to afford 5.8 g. of the title product as a colorless oil, B.P. 86°-90°/0.1 mm. λmaxfilm 3.45, 5.92, 6.32, 6.70, 6.82, 9.30, 9.48, 10.65, 11.95, 12.50, 13.0, 13.54 and 14.23 μ.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC)=O.[NH2:46][C@H:47]([C:56]([NH:58][C@H:59]([C:66]([NH:68][C@H:69]([C:71]([OH:73])=[O:72])[CH3:70])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:20]([NH:46][C@H:47]([C:56]([NH:58][C@H:59]([C:66]([NH:68][C@H:69]([C:71]([OH:73])=[O:72])[CH3:70])=[O:67])[CH2:60][O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:57])[CH2:48][C:49](=[O:55])[O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: C[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C)C(=O)O)cc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
In 290 ml of dimethylformamide is dissolved 16.2 g (35 millimoles) of Z-Arg(Tos)-OH, and 3.85 ml of N-methylmorpholine is added to the solution and the mixture is cooled to -5° C. Then, 3.35 ml of ethyl chloroformate is dropped to the mixture under agitation and the mixture is stirred for 15 minutes and is then mixed with a cooled liquid formed by suspending 15.5 g (38.5 millimoles) of H-Asp(OBut)-Ser(But)-Ala-OH (having a melting point of 122° to 133° C.) in 290 ml of dimethylformamide and adding 4.3 ml of N-methylmorpholine. The resulting mixture is stirred for 3 hours, and the insoluble substances are removed by filtration. The filtrate is concentrated under reduced pressure and solidification is effects by addition of ether to obtain 26.6 g of intended glassy Z-Arg(Tos)-Asp(OBut)-Ser(But)-Ala-OH (the yield being 90%).
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:3].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)SC1CCNC/C1=C\c1ccccc1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-benzylidene-piperidine hydrochloride and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (713 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (256 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:17) as the eluent to afford the title compound (531 mg, yield: 68%) as a yellow oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:45])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][CH3:44])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:45])=[O:4])[CH2:19][CH:20]1[CH2:43][CH3:44])=[O:42])=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
LiOH (0.61 g, 25.5 mmol) is added to a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 35, (3.5 g, 5.9 mmol) in THF/H2O (2:1, 36 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in a ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The organic layers are combined and concentrated in vacuo to afford 3.4 g (98% yield) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1cc([N+](=O)[O-])ccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-4-nitroaniline to yield 2-[(2-methoxy-4-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])[C:5]2[N:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.[CH3:21][C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([CH3:36])[O:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O>[CH:16]1([NH:15][S:12]([C:4]2[C:5]3[N:6]=[CH:7][CH:8]=[N:9][C:10]=3[CH:11]=[C:2]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:36])[CH:3]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(NC1CCCC1)c1cc(Cl)cc2nccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2nccnc2c1
Temperature: 90 °C

Procedure:
To a mixture of 7-chloro-N-cyclopentylquinoxaline-5-sulfonamide (0.07 g, 0.22 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (0.15 g, 0.66 mM, Aldrich catalogue number 643882), Peppsi-iPr (0.014 g, 0.022 mM, Aldrich catalogue number 669032) and cesium carbonate (0.143 g, 0.44 mM) under nitrogen was added dimethoxyethane (3 mL) and water (1 mL). The reaction mixture was heated to 90° C. for 1 hour. The mixture is partitioned between water and ethyl acetate, the aqueous phase is discarded and the products are purified by silica gel (rf=0.36 in 1:1 hexanes/ethyl acetate) to give N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoxaline-5-sulfonamide as an off-white solid.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4](OCC)=[O:5])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[CH3:28][C:29]1([CH3:37])[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH:30]1[OH:36]>>[C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:36][CH:30]1[CH:31]([CH3:35])[CH2:32][CH2:33][CH2:34][C:29]1([CH3:37])[CH3:28])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: CC1CCCC(C)(C)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CCCC(C)(C)C1OC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 74 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 ml of 2,2,6-trimethylcyclohexanol and 4 g of Na2CO3 were reacted with one another at 184-186° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 3 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, it was distilled under reduced pressure, giving 55 g (74%) of 2,2,6-trimethylcyclohexyl 2-cyano-3,3-diphenylacrylate [λmax=304 nm, E11=351] as a colorless solid.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4[O:20]C=CC=4)=C3C(C(C)C)=N2)C=CC=1C#N.[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35]2[CH:42]=[C:41]([N:43]3[C:47]4=[N:48][CH:49]=[CH:50][C:51]([C:52]5[O:53][CH:54]=[CH:55][CH:56]=5)=[C:46]4[C:45]([CH:57]([CH3:59])[CH3:58])=[N:44]3)[CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:30][CH2:29]1>>[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35]2[CH:42]=[C:41]([N:43]3[C:47]4=[N:48][CH:49]=[CH:50][C:51]([C:52]5[O:53][CH:54]=[CH:55][CH:56]=5)=[C:46]4[C:45]([CH:57]([CH3:59])[CH3:58])=[N:44]3)[CH:40]=[CH:39][C:36]=2[C:37]([NH2:38])=[O:20])[CH2:30][CH2:29]1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3ccco3)c12
Reactant: CC(C)c1nn(-c2ccc(C#N)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3ccco3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3ccco3)c12

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-hydroxycyclohexylamino)-4-{(3-isopropyl-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (10a) instead of compound (1e) and was used in the subsequent reaction without being purified. According to Example 1(7), compound (10) (the second stage yield: 59%) was prepared as a white solid using 2-(trans-4-hydroxycyclohexylamino)-4-{3-isopropyl-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).