Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]3[C:20]([OH:22])=O)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[N:25]1[CH2:31][CH2:32][NH2:33]>>[NH3:10].[CH3:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[N:25]1[CH2:31][CH2:32][NH:33][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[C:11]1[O:12][C:13]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=1)=[O:22]
Reactant: COC(=O)c1cccc2nc(N3CCCC[C@H]3C(=O)O)oc12
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: COC(=O)c1cccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc12
Product: N

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-[7-(methoxy)carbonyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylic acid [see Preparation 51] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J.Med.Chem., 27(5), (1984), 684-691]. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 100:0:0 changing to 99:1:0 then 80:20:10, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-[7-(methoxy)carbonyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][CH2:26][C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:27](=[O:28])[CH2:26][O:25][CH3:24])[CH2:14][CH2:13]3)[CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine (see Method 7a; 615 mg, 2.0 mmol) in DMF (8 mL) were added methoxy acetic acid (272 mg, 3.0 mmol), DIPEA (310 mg, 2.4 mmol) and TBTU (770 mg, 2.4 mmol). The reaction mixture was stirred at RT for 12 h and then partitioned between methylene chloride and aqueous NaHCO3. The aqueous phase was extracted twice with methylene chloride and then the combined organic solutions were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the product was purified by means of reversed phase chromatography is using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate as eluent. There was obtained 610 mg (80%) of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-(methoxyacetyl)-piperazine. 1H NMR (500 MHz, CD3OD): 2.3-2.4 (m, 4H), 3.0 (m, 3H), 3.4 (s, 3H), 3.4 m, 2H), 3.5 (m, 2H), 3.6 (m, 2H), 4.1 (s, 2H), 4.5 (s, 1H), 7.2 (t, 2H), 7.3 (t, 4H), 7.4 (d, 41-1); LCMS: m/z 380 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@@H:4]([N:16]1[CH2:21][CH2:20][N:19](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@@H:18]([CH2:34][CH:35]=[CH2:36])[C:17]1=[O:37])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.SC1C=CC(O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:38])[C@@H:4]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:34][CH:35]=[CH2:36])[C:17]1=[O:37])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Oc1ccc(S)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1NCCN([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)C1=O
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of (S,S)-2-[3-allyl-4-(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 4, (4.8 g, 8.9 mmol) and 4-mercaptophenol (4.5 g, 35.7 mmol) in DMF (35 mL) is added potassium carbonate (7.4 g, 53.4 mmol). The reaction mixture is stirred 18 hours then quenched with saturated NaHCO3 solution and extracted with EtOAc (200 mL). The extract is dried over Na2SO4 and concentrated in vacuo to afford a bright yellow oil which is purified over silica gel (hexanes/EtOAc, 1:1 to EtOAc/MeOH, 10:1) to afford 2.45 g (79% yield) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:20])=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc(N)n1
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
57.2 Using general method A, with THF instead of DMF as solvent, (3-amino-pyrazol-1-yl)-acetic acid ethyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid ethyl ester. Light yellow solid. MS 314.0 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH:18]([O:20]CC3C=CC=CC=3)[CH3:19])[N:15]=[C:14](Cl)[N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].Cl.C([O-])=O.[NH4+]>C(O)(C)C>[CH3:29][N:2]([CH3:1])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CC(OCc1ccccc1)c1nc(Cl)nc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(O)c1ncnc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-(1-benzyloxy-ethyl)-6-chloro-[1,3,5]triazin-2-yl]-piperazine-1-sulfonic acid dimethylamide (0.73 mmol, 320 mg), (Pd—C 910%, 640 mg), HCl (2 M in ether, 4.4 mmol, 2.2 mL), ammonium formate (15 mmol, 915 mg) and isopropanol (10 mL) was heated at 90° C. for 2 h. The reaction was cooled and filtered, and to the filtrate was added chloroform (20 mL) and aq. saturated sodium bicarbonate (20 mL). The chloroform layer was collected, dried, filtered and the filtrate was evaporated to dryness. The resulting residue was purified by silica gel chromatography (eluent, 96:4 chloroform-methanol) to yield the title compound of this example (59%, 136 mg); mp 124-125° C.; NMR 1.5 (d, 3H), 2.8 (s, 6H), 3.3 (m, 4H), 4.0 (s, 4H0, 7.2 (s, 1H, 8.6 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([NH:6][NH2:7])[CH2:3][CH2:4][CH3:5].[CH3:8][N:9]=[C:10]=[O:11]>O1CCCC1>[CH3:8][NH:9][C:10]([N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[NH2:7])=[O:11]
Reactant: CCCCNN
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCN(N)C(=O)NC
Yield: 82.7 %

Procedure:
A suspension of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was degassed and stirred under nitrogen with cooling (water bath) while 1.68 g of powdered potassium hydroxide was added. Stirring and cooling continued as 0.86 g (0.015 mole) methyl isocyanate in 15 mL tetrahydrofuran was added dropwise. The resulting mixture was allowed to stir at room temperature overnight. The solution was filtered and the filtrate evaporated to yield a colorless liquid. Vacuum distillation gave 82.7% N-methyl-1-butylhydrazine-carboxamide, b.p. 116°-118° C. at 0.06 torr. The compound crystallized upon standing m.p. 48°-50° C. Its structure was confirmed by NMR analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Si:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36]C=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)CCCC.Br[CH2:41][C:42]([F:47])([F:46])[CH:43]([F:45])[F:44]>>[CH2:34]([Si@H:27]1[CH2:28][CH2:29][C@H:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:41][C:42]([F:47])([F:46])[CH:43]([F:45])[F:44])=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:32]1)[CH2:39][CH2:38][CH2:37][CH3:36]
Reactant: FC(F)C(F)(F)CBr
Reactant: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCC(F)(F)C(F)F)cc3)cc2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4'-bromo-4-(t-butyldimethylsiloxy)biphenyl, 4-pentyl-4-phenyl-4-silacyclohexanone, and 1-bromo-2,2,3,3-tetrafluoro-n-propane, thereby obtaining the intended compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([NH:18][C:19]([C@H:21]4[NH:25][CH2:24][CH2:23][S:22]4)=[O:20])[S:16][CH:17]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C=O)C>[CH2:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][S:22][C@H:21]1[C:19](=[O:20])[NH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[N:14]=1)=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3NCCS3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3SCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C

Procedure:
A solution of (S)-thiazolidine-2-carboxylic acid [4-(4-cyclopropylcarbamoyl-phenyl)-thiazol-2-yl]-amide (50 mg, 0.13 mmol) in DMF (1 mL) was cooled to 0° C. DIEA (35 μL, 0.20 mmol) was added followed by benzyl chloroformate (30 μL, 0.21 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature over 2 hours. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 36.9 mg. MS: 509.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.55-0.74 (m, 4H), 2.80-2.91 (m, 1H), 3.10-3.27 (m, 2H), 3.65-3.75 (m, 1H), 3.90-4.04 (m, 1H), 4.94-5.17 (m, 2H), 5.51-5.55 (s, 1H), 7.06-7.41 (m, 5H), 7.79-7.98 (m, 5H), 8.41-8.48 (d, 1H), 12.50-12.60 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1.[CH:36]1([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:44][C@@H:43]([CH2:45][CH:46]([CH3:47])[CH3:48])[C:42]([O:41][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:49])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCOS(C)(=O)=O)cc3F)c2N)ccc1F
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Product: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCN[C@@H](CC(C)C)C(=O)OC4CCCC4)cc3F)c2N)ccc1F

Procedure:
From Intermediate 4D and L-leucine cyclopentyl ester (Intermediate 8), LCMS purity 100%, m/z 614 [M+H]+, 1H NMR (400 MHz, d6-DMSO), δ: 0.90 (6H, m), 1.60-1.70 (10H, m), 1.90 (2H, m), 2.15 (2H, m), 2.30 (3H, s), 3.00-3.20 (2H, m), 4.10 (1H, s), 4.20 (2H, m), 5.25 (1H, m), 5.70 (1H, d), 7.05 (1H, d), 7.25 (1H, m), 7.40 (1H, m), 7.50 (1H, m), 7.60 (1H, d).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.CC([Si](C)(C)[O:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:40][CH:41]=[CH2:42])C(=O)OC(C)(C)C)(C)C>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH2:42][CH2:41][CH2:40][NH:32][CH2:31][CH2:30][CH2:29][OH:28])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: C=CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(CCCNCCCO)ccc12
Yield: 13 %

Procedure:
Prepared according to the method of example 1(b)/(c), using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (130 mg) and [3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-2-propenyl-carbamic acid, 1,1-dimethylethyl ester (example 22(a)) (152 mg). Purification (SiO2, methanol:dichloromethane 1:9 as eluant) gave the title compound as a colourless solid (21 mg).
Reaction SMILES: C(Cl)Cl.[NH:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:16]([OH:18])=O)[C@@H:6]([CH3:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CCN=C=NCCCN(C)C>C(OCC)(=O)C>[NH:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:16]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:18])[C@@H:6]([CH3:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To 200 ml of methylene chloride, were added 31.0 g of Boc-Thr(Bzl)-OH and 27.6 g of Phe-OEt.HCl, and 18.3 ml of WSC were added to the mixture under cooling at 0°--5° C., which was then subjected to stirring for 2 hours at 0°--5° C. then for 18 hours at room temperature. The methylene chloride in the reaction solution was exchanged with ethyl acetate and the exchanged solution was washed successively with 1 N HCl, 5% aqueous NaHCO3 solution and water and dried over MgSO4. The organic layer was concentrated and the produced material was crystallized from hexane, which gave 39.0 g (yield=81%) of the title compound. m.p. 99°-100.5° C. [α]D25 +6.2° (C 2.7, DMF). Analysis--Calculated for C27H36O6N2 : C, 66.92; H, 7.49; N, 5.78. Found: C, 66.91; H, 7.57; N, 5.75.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[I:15][CH3:16]>CN(C=O)C>[I-:15].[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([CH3:16])=[CH:7]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reactant: CI
Solvent: CN(C)C=O
Product: C[n+]1ccc2c(Br)ccc([N+](=O)[O-])c2c1
Product: [I-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round bottom flask, was placed a solution of 5-bromo-8-nitroisoquinoline (25.59 g, 101.11 mmol) in DMF (200 mL). To the mixture was added iodomethane (71.8 g, 505.99 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 40° C. A filtration was performed. The filter cake was washed 2 times with 250 mL of ether. This resulted in 33.33 g (83%) of 5-bromo-8-nitro-N-methylisoquinolinium iodide as a red solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([Cl:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1Cl
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1Cl

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-chloro-4-methoxy-phenylboronic acid, 5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=66%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1>C1(C)C=CC=CC=1>[O:6]1[CH2:2][CH2:3][N:4]=[C:5]1[NH:7][N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1
Reactant: NN1Cc2ccccc2C1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CN(NC1=NCCO1)C2
Reaction time: 1 h

Procedure:
3.2 ml of (0.027 M) chlorethyl isocyanate in 15 ml of toluene are added dropwise to 5 g of (0.027 M) 2-amino-isoindoline in 100 ml toluene at a temperature of 20° to 30° C. After 1 hour, the precipitate is sucked off, washed with toluene and dried.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0645 g, 0.131 mmol) in methylene chloride (1 mL) was added with trifluoroacetic acid (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate (6 mL), and the mixture was extracted five times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0500 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:65])[CH:48]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[NH:49]C(=O)CC6CCOCC6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:67][N:68]([CH2:70][C:71]([OH:73])=O)[CH3:69]>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:65])[CH:48]([NH:49][C:71](=[O:73])[CH2:70][N:68]([CH3:69])[CH3:67])[C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CN(C)CC(=O)O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CN(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 99 %

Procedure:
This compound was prepared using the procedure used to prepare {2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester using Dimethylamino-acetic acid (0.018 g, 0.172 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-(2-Dimethylamino-acetylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.106 g, >99%) as a white solid. LCMS-ESI+: calc'd for C49H55N9O5: 849.43 (M+); Found: 850.60 (M+H+).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:13]1[N:18]=[C:17]([NH2:19])[C:16]2[N:20]=[CH:21][N:22]([C@@H:23]3[O:27][C@H:26]([CH2:28][O:29][P:30]([OH:33])([OH:32])=[O:31])[C@@H:25]([OH:34])[C@H:24]3[OH:35])[C:15]=2[N:14]=1.C1SC(N=C(N)N)=NC=1CSCC/C(/N)=N/S(N)(=O)=O>CO>[P:30]([O:29][CH2:28][C@H:26]1[O:27][C@@H:23]([N:22]2[C:15]3[N:14]=[CH:13][N:18]=[C:17]([NH2:19])[C:16]=3[N:20]=[CH:21]2)[C@H:24]([OH:35])[C@@H:25]1[OH:34])([O:33][P:30]([OH:32])([OH:31])=[O:29])(=[O:32])[OH:31]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: NC(N)=Nc1nc(CSCC/C(N)=N/S(N)(=O)=O)cs1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A transformant (1-1 strain) and its parent strain (TK62 strain) were cultured side by side in a medium containing methanol or glucose as the major carbon source, while monitoring the cell number and intracellular adenylate kinase activities over the course of time (FIG. 5). The medium for methylotrophic yeasts is disclosed by Sakai et al. [Sakai, Y., et al., Appl. Environ. Microbiol., 53, 1812-1818 (1987)]. Methanol or glucose was added at 2%. The method for determining the adenylate kinase activities is disclosed by Brolin et al. [Brolin, S. E., et al., Methods of Enzymatic Analysis, vol. 3, Third Edition, 540-544 (1983)], wherein 1 unit of the enzyme is defined as the enzymatic activity required to yield 2 μmole of ADP at 24° C. in 1 minute. After culturing in the methanol medium for 72 hours, 1-1 strain showed 93.5 U of adenylate kinase activity per mg of cell protein. Compared with the adenylate kinase activity of the parent strain (0.0328 U), the enzymatic activity of the transformant was greater by 2900 times. This increase of the enzymatic activity was never observed in the glucose medium, indicating that the expression of the adenylate kinase was induced by methanol.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1OCCN1CCCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
A stirred DMF suspension (5 mL) of 2-methoxy-5-nitrophenol (0.5 g, 2.96 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.75 g (4.43 mmol) and K2CO3 (1.02 g, 7.4 mmol) was heated at 80° C. for 2 hr. After cooling to RT, the reaction was diluted with 20 mL of H2O and extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed brine and dried over MgSO4. After concentration under vacuum, the resulting residue was chromatographed on silica gel. Gradient elution CH2Cl2 to 10% MeOH/CH2Cl2 eluted N-(2-(2-methoxy-5-nitrophenoxy)ethyl)pyrrolidine (507 mg) as a light orange solid. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished in 87% yield following the procedure described in step C of Example 6. MS (ESI) 237 (M+H)+.