Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)[CH2:14]1.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[CH:49]=2)[CH:42]=[CH:43][C:44]=1[CH3:45]>CN(C=O)C.O>[CH3:45][C:44]1[CH:43]=[CH:42][C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)[CH:49]=2)=[CH:40][C:39]=1[NH:38][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(O)c1cccc(OC2CCOC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCOC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.165 g) was added to a stirred mixture of 3-(tetrahydrofuran-3-yloxy)benzoic acid (0.15 g), 1-hydroxybenzotriazole (0.146 g) and DMF (5 ml) which had been cooled to 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and a solution of N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (0.224 g) in DMF (1 ml) was added. The reaction mixture was allowed to come to ambient temperature and was stirred for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated and purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd6) 1.99 (m, 1H), 2.18 (s, 3H), 2.25 (m, 1H), 3.17 (t, 4H), 3.72 (t, 4H), 3.88 (m, 4H), 5.13 (m, 1H), 7.11 (m, 2H), 7.21 (d, 1H), 7.39 (m, 5H), 7.56 (m, 2H), 7.79 (m, 2H), 9.83 (s, 1H), 10.11 (s, 1H); Mass Spectrum: M+H+ 502.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[O-:14][C:15]#[N:16].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:15]([NH2:16])=[O:14])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: N#C[O-]
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Agent: Cl
Agent: [Na+]
Product: COc1cc(NC(N)=O)c2c(c1)OC(C)C2

Procedure:
2.5 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine are dissolved in 16 cc of 0.1N HCl and upon gradual addition of 1.1 gram of sodium cyanate to the resulting solution a white crystalline solid precipitates. The reaction mixture is then heated in a water-bath and, after 90 minutes, cooled and filtered. By recrystallizing the obtained precipitate from ethyl alcohol 1.9 gram (61 percent of theoretical) of the desired product is obtained. M.p. 204°-06° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][CH:9]=2)[NH:4][N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH:20](Cl)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:4]2[C:5]3=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][CH:9]=[C:10]3[C:2]([Br:1])=[N:3]2)[CH2:19][CH2:18]1
Reactant: OC1CCC(Cl)CC1
Reactant: CCCCNc1ncc2c(Br)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ncc2c(Br)nn(C3CCC(O)CC3)c2n1
Temperature: 150 °C

Procedure:
To a solution of 3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (122 mg, 0.45 mmol) and 4-hydroxy-cyclohexyl chloride (260 mg, 1.9 mmol) in DMF (6.0 mL) was added K2CO3 (270 g, 2.0 mmol). The mixture was heated at 150° C. for overnight. After the reaction was cooled to room temperature, the reaction was quenched with H2O. The reaction mixture was partitioned in H2O and EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic phase were dried (Na2SO4) and concentrated. The residue was purified by Isco to provide a mixture of cis- and trans-1-(4-hydroxy-cyclohexyl)-3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (90 mg, 54%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([CH2:14][NH2:15])[OH:13]>O1CCCC1>[OH:13][CH2:12][CH2:14][NH:15][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Benzyl chloroformate (63 mL, 443 mmol) was added dropwise to a solution of ethanolamine (60 g, 984 mmol) in tetrahydrofuran (300 mL). After being stirred overnight, the mixture was concentrated in vacuo, and partitioned between methylene chloride and dilute aqueous HCl. The separated organic layer was washed with dilute aqueous NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (36 g) which was used without further purification in the next step.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])=O.[CH3:13][N:14]([CH3:18])[C:15]([NH2:17])=[S:16]>>[CH3:13][N:14]([CH3:18])[C:15]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[OH:12])[N:17]=1
Reactant: CN(C)C(N)=S
Reactant: Cc1ccc(O)c(C(=O)CCl)c1
Product: Cc1ccc(O)c(-c2csc(N(C)C)n2)c1
Yield: 96 %

Procedure:
17.5 g or 2-chloroacetyl-4-methylphenol and 10.9 g of N,N-dimethyl thiourea are heated for 20 minutes to 110° C. After cooling, the solidified mass is recrystallised from aqueous methanol, affording 14.2 g (96% of theory) of 2-dimethylamino-4-(2'-hydroxy-5'-methylphenyl)-thiazole of the formula (101) ##STR13## with a melting point of 108°-110° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(=[O:21])[NH:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:20]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:21])=[CH:3][CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(N2CCCC2=O)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2.61 g (0.01 mole) of 4-bromobenzophenone and 1.13 ml of butyrolactam (0.015 mole) are fused together at 180° C., and 1.4 g of K2CO3 and 0.63 g of Cu powder are added. The mixture is stirred at this temperature for 2 h, allowed to cool to 140° C. and then dissolved in ethyl acetate. Chromatography on silica gel eluting with toluene/ethyl acetate provides N-(4-benzoylphenyl)-2-pyrrolidinone of melting point 162°-164° C., which is immediately dissolved in 10 ml of methanol and 10 ml of 5 N NaOH and boiled under reflux for about 2 h. After the methanol has been removed by distillation, the mixture is acidified to pH 5, and the product is filtered off with suction. Melting point: 156°-158° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18][OH:19])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][S:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccc1SCCN1CCN(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1SCCN1CCN(c2ccccc2)CC1
Yield: 93.1 %

Procedure:
6.0 g of 2-[2-(4-phenylpiperazin-1-yl)ethylthio]benzylalcohol, 2.60 g of oxalyl chloride, 3.2 g of dimethylsulfoxide and 9.3 g of triethylamine are treated in the same manner as described above. 5.55 g of 2-[2-(4-phenylpiperazin-1-yl)ethylthio]benzaldehyde are obtained. Yield: 93%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: CN(C)c1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(-c2cnc(N)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
A solution of 3.30 g of 2-amino-5-(4-dimethylaminophenyl)-3-nitro-pyridine (compound G2) and 330 mg of Pd/C (10%) in 260 ml of methanol is treated with hydrogen under vigorous stirring at room temperature for 17 h. The suspension is filtered with suction through a celite pad. The colorless filtrate is evaporated to dryness to afford 2.85 g of the pure title compound of m.p. 155° C. MS: 229.3 (MH+). TLC: Rf=0.38 (dichloromethane/methanol 10:1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:12]1[CH:11]=[CH:10][C:15]([O:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 150 °C
Reaction time: 7.5 h
Yield: 98.8 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (24.1 g) and p-cresol (21 g) in N,N-dimethylformamide (400 ml) was added powdered potassium carbonate (26.8 g) and the reaction mixture was stirred at 150° C. for 7.5 hours. After cooling, the reaction mixture was poured into ice water (1.4 kg). The mixture was extracted with ethyl acetate (1 l), washed with water (1 l×3), brine (1 l), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 4-(4-methylphenoxy)benzaldehyde (40.7 g) as a light yellow oil.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31].C(OC)(C)(C)C>C(O)CCC>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(=O)[O-]
Temperature: 20 °C

Procedure:
Sunitinib base (3 g) was suspended in n-butanol (15 ml) with stirring at 20° C., then 1.05 eq (0.45 ml) of acetic acid were added observing dissolution and after 1-2′precipitation of an orange solid. The mixture was heated to 60° C. and other 6 ml of n-butanol were added. Then methyl tert-butyl ether (60 ml) was added at 60° C. within 10 min with stirring, the mixture was cooled to −10° C. in 2 hours. After 1 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE and dried on the filter for 1 h.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:12]3[CH:13]=[C:14]([F:15])[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:20])[CH:11]=3)[N:23]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: OB(O)Oc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Yield: 199.2 %

Procedure:
4-Benzyloxy-3,5-difluorophenylboric acid (1.97 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (5.20 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.50 g) in toluene (250 ml) and a 10% aqueous solution of sodium carbonate (150 ml) in nitrogen atmosphere for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added thereto, and the mixture was heated under reflux for 1 hr. 4-Benzyloxy-3,5-difluorophenylboric acid (1.15 g) was additionally added to the resulting mixture, and then heated under reflux overnight. The organic layer was separated and extracted with 2N hydrochloric acid twice. The resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3,5-difluorophenyl)isoquinoline (6.44 g) as a brown viscous oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]1([NH2:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:6]1([NH:12][C:1](=[O:4])[CH:2]=[CH2:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccccc1
Reaction time: 3 h
Yield: 79 %

Procedure:
Acryloyl chloride (28.5 mL; 350 mmol) was added to a stirred solution of phenylamine (30 mL; 320 mmol) and TEA (56 mL; 400 mmol) in THF (1 L) at 0° C. The reaction mixture was stirred for 3 h, poured onto brine and extracted with diethyl ether. The organic layer was dried, concentrated and recrystallized from hexane:EtOAc (3:1) to give the sub-title compound in a 79% yield.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[O:19])[C:9]=2[CH:20]=1.O>C(O)C.[OH-].[Na+]>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH:10]([OH:19])[C:9]=2[CH:20]=1
Reactant: CSc1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In operations carried out in a manner similar to that described in Example VI, 0.5 gram (13 millimoles) of sodium borohydride was added to a solution of 0.8 gram (3.2 millimoles) of 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-one in 20 milliliters of ethanol to which 1 drop of 40 percent sodium hydroxide had been added and the resulting mixture stirred overnight at room temperature. Thereafter, water was added to the reaction mixture, the aqueous mixture subjected to reduced pressure to remove the ethanol, the remaining aqueous solution extracted with ether, the ether solution washed successively with water and saturated sodium chloride, and then dried over magnesium sulfate. The dried solution was subjected to reduced pressure to obtain the 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-ol intermediate as a white solid.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:14][CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[OH:4])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Reactant: COCOc1cnccc1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtained in Example 2 and triphenylphosphine (4.50 g, 17.0 mmol) are dissolved in THP (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (3.00 g, 15.0 mmol) and 2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is further stirred at 40° C. for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 47% aqueous hydrobromic acid solution (20 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/ethanol), recrystallized from ethanol/diethyl ether to give the title compound (3.10 g) as colorless crystals, m.p. 116-118° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28]O)[N:27]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH3:22][C:23]1[O:24][C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:27]=1
Reactant: Cc1nc(CO)c(C(F)(F)F)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c(C(F)(F)F)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.281 g, 1.0 mmol) and (2-methyl-5-(trifluoromethyl)oxazol-4-yl)methanol (0.18 g, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added tributylphosphine (0.30 g, 1.5 mmol) at 0° C., followed by additional of N,N,N′,N′-tetramethylazodicarboxamide (0.26 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and stirred at ambient temperature for 16 h. The reaction mixture was quenched with aqueous ammonium chloride (25%, 50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 1′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.30 g, 68%) as a colorless solid: mp 136-137° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 7.32 (ddd, J=7.7, 1.2, 1.2 Hz, 1H), 7.19 (dd, J=7.6, 1.0 Hz, 1H), 7.07-7.03 (m, 2H), 6.70 (s, 1H), 6.29 (s, 1H), 5.93 (dd, J=5.0, 0.7 Hz, 2H), 4.98 (q, J=16.4 Hz, 2H), 4.75 (dd, J=20.8, 9.4 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 163.6, 155.1, 148.2, 141.9, 141.5, 137.6 (d, 3JCF=2.1 Hz), 133.5 (q, 2JCF=42.7 Hz), 131.6, 128.7, 123.5, 123.0, 119.8, 119.2 (q, 1JCF=266.9 Hz), 109.0, 103.0, 101.3, 93.1, 79.3, 57.2, 34.9, 13.4; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14](OC)[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(#N)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: COC(c1c(C)nn(-c2ccccc2)c1Cl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(methoxy)methyl)-1H-pyrrolo [2,3-b]pyridine (P-0079, 0.030 g, 0.085 mmol) was added acetonitrile (10 mL, 0.2 mol). Trifluoroacetic acid (500 uL, 0.006 mol) and triethylsilane (500 uL, 0.003 mol) were added and the reaction allowed to stir at room temperature for 16 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed 5% methanol in dichloromethane to give the compound as a yellowish foam (P-0080, 29 mg, 98%). MS (ESI) [M+H+]+=323.2.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(OCC)(=O)C.[OH-].[Na+]>O>[NH2:5][C@H:4]([C:3]([OH:13])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A mixture of 1.15 grams of D,L-phenylalanine methyl ester in 2.5 milliliters of water was added to 5.0 milliliters of ethyl acetate. The pH was adjusted to 6.5 with 2.5 milliliters of sodium hydroxide. Two milligrams of chymotrypsin was added and the reaction was stirred gently at room temperature. A white precipitate appeared after 1.5 hours. The precipitate was isolated after 2 hours yielding 0.22 grams with an optical rotation equivalent to 98% pure L-phenylalanine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([N:17]1[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]1[CH2:19]3)=[O:16])[CH:9]=[C:8]2[C:35](=[O:37])[CH3:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:35]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[N:10]([CH2:14][C:15]([N:17]2[C@H:22]([C:23](=[O:34])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[CH2:21][C@@H:20]3[C@H:18]2[CH2:19]3)=[O:16])[CH:9]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2CC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 3-acetyl-1-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indole-5-carboxylic acid methyl ester (141 mg, 0.268 mmol) in THF (3 mL) and water (0.3 mL) was added 2N LiOH (1.07 mL, 2.14 mmol). Stirring of the reaction mixture was continued at 50° C. for 60 h. After cooling to RT, a 1N HCl solution was added to adjust to pH=2-3, and the resulting aqueous suspension was extracted with CH2Cl2 (3×). The combined organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 512 [M+H]+; tR (HPLC conditions c): 4.33 min.