Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH2:29][N:30]1[CH:34]=[N:33][N:32]=[CH:31]1>>[N:33]1[N:32]=[CH:31][N:30]([NH:29][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH:34]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: Nn1cnnc1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nn4cnnc4)s3)c2cc1OC
Yield: 5 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 4-amino-1,2,4-triazole (8.4 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid [1,2,4]triazol-4-ylamide (2.4 mg, 5.0%) as a white solid. MS m/z 482 (M+1).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15](CON4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1>C(O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nncn1-2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reated at 65° C. with 8-bromo-1-[(phthalimidooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-(aminooxy)methyl]-8-bromo-6-(2pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Na].[C:2]([SH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25]Cl>C(O)C>[C:2]([S:21][CH2:25][C:24]([NH:23][CH3:22])=[O:27])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)CCl
Agent: [Na]
Solvent: CCO
Product: CNC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of 26.55 g of sodium in 1800 ml of ethanol is added 288.8 g of tritylmercaptan. Then with ice-cooling a solution of 111.8 g of N-methylchloracetamide in 1000 ml of ethanol is added dropwise whereupon a grey-white precipitate is formed. After completion of the addition stirring is continued at room temperature for 45 minutes and the mixture then concentrated to half its volume. The precipitate is filtered, washed with isopropanol, water and again isopropanol and dried to give the title product. m.p. 200°-210°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:21]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: Cc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Yield: 87 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-methyl-2-nitrophenyl)piperidin-3-ylcarbamate (87%). LCMS (m/z): 336.1 (MH+); LC Rt=3.41 min.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:13]([Cl:15])=[CH:14][C:8]=2[O:7]1)=O)C.[NH3:26].Cl>ClCCl>[Cl:15][C:13]1[C:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:9]2[O:10][CH:6]([C:4]([NH2:26])=[O:3])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Reactant: N
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Reaction time: 18 h

Procedure:
4.03 mol of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester are dissolved in room temperature in 50 ml of dichloromethane. While stirring vigorously, 50 ml of a concentrated aqueous ammonia solution are added, and stirring is continued for 18 hours. A thick crystalline suspension is formed from the initial emulsion. This suspension is then adjusted by 6N HCl to pH 2-3 at room temperature, filtered and subsequently washed with water. After drying, colourless crystals of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid amide having a melting point of 240°-242° are obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3]>O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O
Product: C[C@H](O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. 4-chloroacetophenone (0.500 g; 0.0032 moles) I(b) was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 24 hr at 15–20° C. Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (340 mg). Pure 1-(4-chlorophenyl-(1S)-ethan-1-ol II(b) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)(C)C.ClCCl>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1
Reactant: COc1ccccc1-n1ccnc1OCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Oc1ccccc1-n1ccnc1OCC1CCN(Cc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
2.7 ml of a solution of hydrochloric acid (0.5 N) in isopropanol are slowly added, at 0° C. to a solution of 0.5 g (1.32 mmol) of 1-(2-methoxyphenyl)-2-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-1H-imidazole in 15 ml of dichloromethane. The solvents are removed by evaporation and then the product is taken up in 15 ml of dichloromethane. The solution is cooled to −15° C. and 1.05 ml of boron tribromide is slowly added. The reaction medium is stirred for 3 h 30 min while allowing the temperature to return to 20° C. The reaction mixture is poured over ice and sodium bicarbonate is added until a pH=8 is obtained. After separating upon settling out, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then with brine. The medium is dried over magnesium sulphate, filtered and concentrated. The expected compound is purified on a silica gel, eluting with a 99:1 to 93:7 CH2Cl2/CH3OH mixture. 0.355 g of product is obtained. (Yield 74%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH:30]3[CH2:32][CH2:31]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O:36]CC)=[O:35].[OH-].[Na+].C(Cl)(Cl)Cl.CO.CC(O)=O>O1CCCC1.C(O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH:30]3[CH2:32][CH2:31]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4C4CC4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1C1CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a stirred solution of ethyl 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (83 mg; 0.15 mmol) in a mixture of 1.4 mL tetrahydrofuran and 0.7 mL ethanol at ambient temperature was added 0.60 mL of 1M aqueous sodium hydroxide. The resulting slightly cloudy mixture was vigorously stirred at ambient temperature for 1 hour, after which the reaction was determined to be complete by thin layer chromatography (90/10/1 chloroform/methanol/HOAc). The reaction mixture was diluted with 5 mL EtOAc and 2.5 mL of 1M HCl, then transferred to a separatory funnel. After shaking, the organic layer was washed with 2 mL brine, then dried over sodium sulfate and evaporated to give 61 mg of 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as a colorless oil. MS (apci, pos) m/z=526
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1)=[O:14]>C1COCC1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:21](=[O:22])[C:18]1[CH:17]=[CH:16][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:20][CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)Oc2ccccc2[N+](=O)[O-])cc1
Yield: 93.4 %

Procedure:
A solution of 2-nitrophenol (1.55 g, 11.2 mmol) and methyl 4-chlorocarbonyl benzoate (2.44 g, 12.2 mmol) in THF (14 mL) and pyridine (2.8 mL) was stirred for 2 h at room temperature. The reaction was diluted with saturated sodium bicarbonate (30 mL) and EtOAc (20 mL), the phases separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford terephthalic acid 1-methyl ester 4-(2-nitrophenyl) ester (3.15 g, 94%). 1H NMR (CDCl3) δ 3.98 (s, 3H), 7.43 (d, 1H, J=7.8 Hz), 7.48 (t, 1H, J=7.8 Hz), 7.73 (t, 1H, J=7.8 Hz), 8.20 (m, 4H), 8.27 (m, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:7]=1[NH2:8].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>O>[F:14][B-:15]([F:18])([F:17])[F:16].[Br:13][C:10]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([N+:8]#[N:1])[CH:9]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1[N+]#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (0.56 g) in water(2.0 mL) was slowly added to a mixture of 2-methyl-5-bromoaniline (1.50 g) in tetrafluoroboric acid (6.0 mL) and water (4.0 mL) at 0-5° C. After addition, the reaction was stirred at room temperature for 30 min. The mixture was cooled to 0° C., filtered, washed with cold water, cold methanol and ether. The mixture was then dried to provide the product 5-bromo-2-methylphenyldiazonium tetrafluroborate (1.90 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31](OCC)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[N:14]=3)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Reactant: Cc1nn(Cc2ccn(C(C)C)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccn(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Temperature: 0 °C
Yield: 52 %

Procedure:
3-Methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-amino-1H-indazole (1 equivalent) and ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (Example 7 step D; 1 equivalent) were dissolved in dry THF (0.2 M) and the resulting solution was cooled to 0° C. Lithium bis(trimethylsilyl)amide (2.3 equivalents) was slowly added and the resulting mixture was allowed to warm to ambient temperature overnight. THF was removed under vacuum and the remaining material was partitioned between water and ethyl acetate. The bottom aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were combined, dried over sodium sulfate, filtered and \ concentrated to give desired compound (52% yield).
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[CH3:10][C:11]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]1=O>CO>[CH3:10][C:11]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]1=[N:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1(C)CCCC1=O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCCC1(C)C
Yield: 76.9 %

Procedure:
A solution of tert-butyl hydrazinecarboxylate (4.1 g) and 2,2-dimethylcyclopentanone (3.5 g) in methanol (50 mL) was stirred at 70° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the title compound (5.4 g). 1H NMR (400 MHz, CDCl3) δ 1.17 (6H, s), 1.50 (9H, s), 1.61-1.64 (2H, t, J=6.8 Hz), 1.80-1.87 (2H, m), 2.24-2.27 (2H, t, J=7.2 Hz), 7.12 (1H, brs).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[CH2:23]=[C:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[F-].[K+].O>CS(C)=O>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][C:24](=[CH2:23])[CH2:25][CH2:26]3)=[C:3]([C:21]#[N:22])[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5]2)=[N:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Reactant: C=C1CCC(CO)CC1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=C1CCC(COc2c(C#N)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)CC1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (351 mg, 1 mmol) and (4-methylene-cyclohexyl)-methanol (252 mg, 2 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (5 ml) and potassium fluoride (116 mg, 2 mmol) was added to the DMSO solution. The resulting mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (15 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product was isolated by chromatography on silica gel column. MS: 441, r.t.: 3.0 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:16][CH2:17][CH3:18])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([O:14]C)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CCO.O>[CH:1]1([CH2:4][N:5]([CH2:16][CH2:17][CH3:18])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=[O:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of methyl 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylate (5.10 g; 20.5 mmol) in THF/EtOH/H2O (3/2/1, total volume 400 mL) was treated with an aqueous solution (1N) LiOH (60 mL; 60 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvents were concentrated under vacuum and then water (200 mL) was added. The aqueous layer was washed with DCM then acidified to pH 5 by addition of 1N HCl solution (60 mL). The aqueous layer was extracted with DCM (3 times) and the combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow solid (3.71 g, 77.1%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:18])[C:5]2=[O:19].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C1COCC1>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:6](=[O:18])[C:5]([C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:8]=1[NH:7][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydroindole-1-carboxylate are dissolved in dried THF, and 18.98 ml of 2,3-dihydro-1H-isoindole are added. The mixture is stirred at 25° C. for 30 min, evaporated to dryness in vacuo, and the residue is triturated with petroleum ether, filtration gives 82.3 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate (beige solid); LC-MS retention time: 2.63 min;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[CH:15]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>>[F:14][C:5]1[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[N:7][C:2]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:25][CH:24]=2)=[N:3][CH:4]=1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nn1cccc1
Product: CC(C)Oc1ccc(Nc2ncc(F)c(Nn3cccc3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with 4-isopropoxyaniline to produce 5-fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.69 (s, 1H), 9.03 (s, 1H), 8.06 (d, 1H, J=3.5 Hz), 7.30 (d, 2H, J=9.3 Hz), 6.82 (t, 2H, J=2.3 Hz), 6.58 (d, 2H, J=9.3 Hz), 6.11 (t, 2H, J=2.3 Hz), 4.41 (sept, 1H, J=5.8 Hz), 1.18 (d, 6H, J=5.8 Hz). LCMS: ret. time: 21.21 min.; purity: 90%; MS (m/e): 328 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCn2ccnc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1cccc(OCCn2ccnc2)c1

Procedure:
1.85 g of 5-(3-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 80 h in 40 ml of THF in the presence of 0.4 g of 5% palladium/carbon. After filtration through Celite and crystallization from ethanol, 5-(3-hydroxyphenyl)-7-[3-(2-(1-imidazolyl)-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 165°-167° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](I)[CH2:13][CH3:14]>[Na].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: Cc1ccc(O)c(C(N)=O)c1
Reactant: CCCI
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(C)cc1C(N)=O

Procedure:
5-Methylsalicylamide (30.2 g; prepared as described in French Pat. No. M21) was dissolved in a solution of sodium (4.6 g.) in ethanol (200 ml.). Propyl iodide (37.4 g.) was added with stirring, and the mixture was stirred for 1 hour at room temperature and then under reflux for a further 19 hours. The mixture was concentrated to about 75 ml. and poured into water (300 ml.). The precipitated solid was filtered off and stirred with 2N sodium hydroxide solution (100 ml.). The insoluble solid was filtered off and washed with water to give crude 5-methyl-2-propoxybenzamide (37.5 g.), m.p. 112°-115° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[CH3:10][C:11]1([CH3:21])[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:13]=2[O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](=[O:7])[O:20][C:19]1[C:13]2[O:12][C:11]([CH3:21])([CH3:10])[CH2:15][C:14]=2[CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: CN(C(=O)Cl)C(=O)CCl
Reactant: CC1(C)Cc2cccc(O)c2O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 79.4 %

Procedure:
A mixture of 1.0 g (0.006 m) of N-chloroacetyl-N-methylcarbamoyl chloride and 1.0 g (0.006 m) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol in 15 cc dry toluene was stirred under nitrogen and 0.61 g (0.006 m) of triethylamine was added dropwise over a period of 10 mts. The mixture was stirred for an additional period of 2 hrs., filtered through a bed of celite and then the solvent was stripped off under reduced pressure to yield 1.39 g (yield 77%) of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chloroacetyl-N-methylcarbamate, a light yellow oil. NMR (CDCl3): δ 7.3-6.6 (mn,3H); 4.75(s,2H); 3.40 (s,3H); 3.05 (s,2H) and 1.45 (s,6H). IR (CHCl3): ν1760 and 1725 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[OH-].[NH4+:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH2:11])=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Cl)cc1F
Temperature: 165 °C
Yield: 73 %

Procedure:
To a stainless steel high pressure reactor was added 5-chloro-2,3-difluoropyridine (18.0 g) and ammonium hydroxide (65 mL). The reaction was heated to 165° C. for three hours. The reaction mixture was then cooled to room temperature and diluted with water (100 mL). The resultant solid was filtered, dried, re-dissolved in CH2Cl2, and passed through a silica gel plug to afford 12.8 g (73%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](S(C)(=O)=O)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[OH-:20].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][NH:13][C:14](=[O:20])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1cc(Cl)ccc1C2
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1[nH]nc2n1C=Cc1cc(Cl)ccc1C2
Temperature: 95 °C

Procedure:
To 2.3 g of 8-chloro-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine in 20 ml of dioxane was added 10 ml of 2N-potassium hydroxide and the mixture was heated on a water bath at 95° C. for 30 minutes. The solvent was evaporated off and water was added to the residue. The mixture was made acidic with 2N-HCl and the resultant crystalline precipitate was recovered by filtration and dried. By the above procedure was obtained 8-chloro-2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from chloroform-methanol yielded colorless platelets, m.p. 281°-283° C.