Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12](OC)=[O:13])=[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([C:24]([O:26][CH3:27])=[O:25])=[N:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:17]([O:16][C:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[N:8][N:7]2[CH2:6][CH2:5][CH2:4][NH:1][C:12](=[O:13])[C:11]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nn(CCCN=[N+]=[N-])c(C(=O)OC)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 1-(3-azidopropyl)-4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (152 mg, 0.407 mmol) in THF (2 mL) were added triphenylphosphine (107 mg, 0.407 mmol) and water (37 μL, 2.036 mmol). The reaction was stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was dissolved in toluene and heated to 110° C. overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 2H), 7.34-7.28 (m, 3H), 6.70 (br s, 1H), 5.29 (s, 2H), 4.46-4.42 (t, 2H), 3.96 (s, 3H), 3.06-3.00 (m, 2H), 2.20-2.13 (m, 2H); ES MS (M+1)=316.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:11][C:12]([NH:14][C:15]1[S:16]C(C(O)=O)=[CH:18][N:19]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl.O1CCCC1.CN(C)C=O>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]1[S:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:18][N:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The third step involves adding a 2M solution of oxalyl chloride in dichloromethane to a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid in tetrahydrofuran and N,N-dimethylformamide, and then stirring the solution at room temperature for 4 hours. The solvent was evaporated under reduced pressure and in vacuo to obtain tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate.
Reaction SMILES: [C:1]([S:5]([C:8]#[C:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N:17]([CH2:20][N:21]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=2[CH:33]([CH3:35])[CH3:34])[S:22]1(=[O:24])=[O:23])=[N+:18]=[N-:19]>C1C=CC=CC=1>[C:1]([S:5]([C:8]1[N:19]=[N:18][N:17]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[CH:28][C:29]=3[CH:33]([CH3:35])[CH3:34])[S:22]2(=[O:23])=[O:24])[C:9]=1[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)(=O)C#CS(=O)(=O)C(C)(C)C
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CN=[N+]=[N-])C2=O
Solvent: c1ccccc1
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(Cn1nnc(S(=O)(=O)C(C)(C)C)c1S(=O)(=O)C(C)(C)C)C2=O

Procedure:
Di(t-butylsulfonyl)acetylene (1.50 g.) was added to part (75 mL) of the above-described solution of 2-azidomethyl-4-isopropyl-6-methoxysaccharin in benzene. The resulting solution was heated under reflux for 65 hours, then chromatographed on silica gel (Kieselgel 60, 68 g) using first benzene and then cyclohexane-ethyl acetate (90:10, then 85:15, then 75:25) as eluant. The fractions containing the product, which were identified by thin layer chromatography, were combined and recrystallized from benzene-cyclohexane. Part (0.5 g) of the resulting product (1.5 g, m.r. 204°-205° C., 26% yield for both steps) was recrystallized twice from ethyl acetate affording 2-[4,5-di(t-butylsulfonyl)-1,2,3-triazol-1-yl]methyl-4-isopropyl-6-methoxysaccharin as pale yellow elongated prisms (0.15 g, m.r. 207.5°-209° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10](OCC)OCC)=[CH:4][C:3]=1[F:17]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[CH:10][C:4]=2[C:3]=1[F:17]
Reactant: CCOC(COc1ccc(Br)c(F)c1)OCC
Solvent: Cc1ccccc1
Product: Fc1c(Br)ccc2occc12
Yield: 60.3 %

Procedure:
1-Bromo-4-(2,2-diethoxyethoxy)-2-fluorobenzene (11.4 g, 0.037 mol) was dissolved in toluene (78 mL). Polyphosphoric acid (11.9 g) was added and the mixture was heated to reflux for 5 h. The solvent was removed and the residue was diluted with water and ethyl acetate. The organic phase was washed with 2M NaOH solution and then dried over Na2SO4. A mixture of 5-bromo-6-fluorobenzofuran and 5-bromo-4-fluorobenzofuran (4.8 g, 60.3%) were obtained as a mixture after purification via column chromatography.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24].O>CCO>[NH:23]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)=[O:17])[NH2:24]
Reactant: COC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
To a suspension of methyl 4-[(phenoxyacetyl)amino]benzoate (843 mg, 2.95 mmol) in EtOH (10 mL) was added hydrazine hydrate (2.15 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt. Water (10 mL) was added to the reaction mixture and a white solid precipitated out. Filtration, washing with EtOH/water (2×2 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 6 hrs gave 389 mg of the title compound (46%) as a white solid in 95.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCC.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15][Br:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol (0.88 g, 3.2 mmol) and CBr4 (1.3 g, 4.0 mmol) were dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over 0.5 h. The mixture was stirred at 0° C. for 10 min., then diluted with pentane (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was separated and washed with ethyl ether, and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (99:1 ethyl ether-hexane) to yield 0.8 g, (74%) of the 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccn2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccn2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-2-ylmethyl-benzenesulfonamide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 619.3 [(M−H−]; mp 229° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:17][O:16][C:14](=[O:15])[CH:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1.87 g of p-fluorophenol in 50 ml of methanol is added 1.07 g of sodium methoxide. To this solution is added 5.4 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate and the mixture is refluxed for 18 hours. The mixture is concentrated to 1/2 volume and poured into 150 ml of ice and water. The mixture is extracted with ether and the cold extracts washed with 50 ml of 2N NaOH and with saline. After drying (MgSO4), the extracts are concentrated under vacuum to give the product as an amber colored oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][CH:14]([CH3:17])[CH2:15][NH2:16].O>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:16][CH2:15][CH:14]([CH3:17])[CH3:13])[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)CN
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CNc1cc(Cl)nn2c(I)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 200 mg (0.558 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 4 mL N,N-dimethylformamide were added 122 mg 2-methylpropan-1-amine and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 188 mg (96%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:25][CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methoxyphenyl)phthalazine described in 3.4 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:25]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:6]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCCCOc2ccccc2)cc1
Yield: 69.4 %

Procedure:
A mixture of alpha-oxo-4-[[(6-phenoxy)hexyl]oxy]benzeneacetic acid methyl ester (0.75 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.5 g of colorless alpha-oxo-4-[[(6-phenoxy)hexyl]oxy]benzeneacetic acid, mp 121°-122° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])=[O:4].[CH3:15][C:16](=[CH2:18])[CH3:17]>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([O:10][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:9])=[O:4]
Reactant: C=C(C)C
Reactant: CNC(=O)CC=C(CC(C)C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)CC=C(CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A suspension of 4-methylaminocarbonyl-2-(2-methylpropyl)but-2-enoic acid (2.4 g) in chloroform (35 ml) was treated with an excess of isobutylene (30 ml) and concentrated sulphuric acid (3 drops) was added as catalyst. The mixture was stirred at room temperature in a sealed vessel for 8 days. The product was purified by silica gel chromatography [chloroform(2.5 g, 81%), m.p. 35°-36° C. (pentane).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:13])[C:10]=1[CH:11]=O>CC(O)C>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:13])[C:10]=1[CH:11]=[N:3][NH:2][CH3:1]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: CNN
Solvent: CC(C)O
Product: CNN=Cc1c(Br)cncc1Br
Reaction time: 3 h

Procedure:
Methylhydrazine (1.06 mL, 19.3 mmol) was added to a solution of 3,5-dibromopyridine-4-carbaldehyde (3.4 g, 13 mmol) in 2-propanol (20 mL). After 3 hours at room temperature, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, and washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the product as a solid. Yield: 3.20 g, 10.9 mmol, 84%. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.24-7.26 (m, 1H), 2.89-2.91 (m, 3H).
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([CH2:18]OS(C)(=O)=O)[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([SH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([S:37][CH2:18][C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=3)[N:17]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(SCc2nc(-c3ccncc3)no2)CC1
Reaction time: 1.67 h

Procedure:
t-BuOK (92 mg, 823 μmol) and methanesulfonic acid 3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl ester (Preparation 12, 150 mg, 588 μmol) were added to a stirred solution of 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (191 mg, 881 mol) in anhydrous THF (10 ml). After 100 min, the reaction mixture was diluted with Et2O, before being washed with NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated, then the residue was purified by column chromatography (IH-EtOAc, 3:2) to afford the title compound: RT=3.77 min; m/z (ES+)=377.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH:13]([OH:17])[C:14]=2[C:15]=1[OH:16])=[O:5])C>[OH-].[Na+]>[OH:16][C:15]1[C:14]2[CH:13]([OH:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c(c1O)C(O)CCC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2c(c1O)C(O)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
4,5-Dihydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester (4.7 g) was dissolved in 40 ml of 1 N sodium hydroxide. The resulting solution was stirred on an oil bath at 50° C. for 3 hours and then allowed to stand at room temperature overnight. After the small amount of insoluble matter was removed, the solution was adjusted to pH 2.4 with dilute hydrochloric acid. The precipitate so formed was separated by filtration to obtain a yield of 3.8 g of the desired compound. Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3400, 3060, 2960, 1700, 1650, 1530, and 1510 cm-1, and its n.m.r. spectrum (CF3COOH, 60Mc, TMS) had signals at δ values of 1.8-2.6 (4H, m), 2.9-3.5 (2H, m), 5.55 (1H, bs), and 8.9-9.2 (1H, m).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:18][C:19]([CH3:26])([CH3:25])[C:20](=O)[CH2:21][C:22]#[N:23].C(=O)([O-])O.[Na+]>C(O)C.Cl>[C:19]([C:20]1[CH:21]=[C:22]([NH2:23])[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=1)([CH3:26])([CH3:25])[CH3:18]
Reactant: NNc1cccc(CC(=O)N2CCOCC2)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:12]([O:17]C)=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.Cl>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:12]([OH:17])=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11]
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 0 °C
Yield: 89.1 %

Procedure:
In a three-necked flask, disperse 40.8 g of aluminium chloride in 200 ml of dichloromethane with stirring. Cool the solution to 0° C. Pour in dropwise a solution of 20 g (0.101 mol) of 3,4,6-trimethoxybenzaldehyde dissolved in 100 ml of dichloromethane. Allow the temperature to rise again to 19° C. and stir for 45 min. Hydrolyse the reaction mixture with 400 g of water and ice and then add 100 ml of 1N HCl and stir for 30 minutes. Allow to separate and then extract with 200 ml of dichloromethane. The organic phase is washed with 100 ml of 1N HCl, 100 ml of water and 100 ml of saturated aqueous NaCl solution, and then dried over MgSO4, filtered and evaporated to dryness. 16.4 g of title product are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24](C)(C)N=3)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:29]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:22][CH2:23][CH3:24])=[O:29])=[CH:19][CH:20]=2)([OH:14])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)COC(c2ccc(C3(O)CCN(Cc4ccccc4)CC3)cc2)=N1
Solvent: CCO
Product: CCOC(=O)c1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
1-Benzyl-4-(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)piperidin-4-ol described in Production Example 7-1 (13.4 g, 36.8 mmol) was dissolved in ethanol (300 mL), then sulfuric acid was added, and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was cooled to room temperature and then the solvent was evaporated under vacuum. The resultant residue was dissolved in dichloromethane, the resultant was washed with a saturated aqueous sodium bicarbonate solution, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum and the resultant residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (7.23 g, 58%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CO>[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:25][CH2:26]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (80 mg, 0.170 mmol), N,N-dimethylglycine (18 mg, 0.170 mmol) and diisopropylethylamine (0.089 mL, 0.509 mmol) in DMF (1 mL) is added TBTU (55 mg, 0.170 mmol) and the reaction mixture is stirred at room temperature for 1 hour. Methanol (0.5 mL) is added and the reaction mixture purified by silica gel chromatography (gradient of 0-10% 2M NH3 in methanol/dichloromethane) to give 7-cyclopentyl-2-{5-[4-(2-dimethylamino-acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, which is further purified by trituration with acetonitrile, as an off white solid (69 mg, 78%).