Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A 5 ml NMP solution of 352 mg of 4-morpholinoaniline was mixed with 0.95 ml of 4 M hydrogen chloride/1,4-dioxane solution and 400 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, and then the precipitate was collected by filtration. The collected solid was mixed with saturated sodium bicarbonate aqueous solution and extracted with a mixed solution of THF-ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was crystallized by adding methanol and then recrystallized (methanol-THF) to obtain 264 mg of 4-benzylamino-2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidine -5-carboxamide as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[H][H]>CO.[Pd]>[F:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2cnccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c2cnccc12
Yield: 40.2 %

Procedure:
To a nitrogen flushed solution of 8-fluoro-5-nitroisoquinoline (Description 42; 1.33 g, 6.9 mmol) in methanol (100 ml) was added 10% palladium on carbon (500 mg) and the resulting mixture stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purifted by MPLC (Biotage Flash™ 40) eluting with 2% MeOH in dichloromethane to give the title compound (450 mg, 40%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>C1(C)C(C)=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:11]([CH3:13])=[CH:10][C:9](=[O:14])[O:5]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)oc2cc(O)ccc12
Temperature: 120 °C

Procedure:
To a 2 liter flask, a reaction mixture of 55 g (0.5 mole) resorcinol, 71.5 g (1.3 mole) ethyl acetoacetate, 200 g xylene, and 10 g Amberlyst 15 (Rohm and Haas) ion exchange resin catalyst was charged. With heating to a strong reflux at 110-130° C., a Von Pechman condensation reaction was carried out between resorcinol and ethyl acetoacetate to yield 7-hydroxy-4-methyl coumarine product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Cl>O>[CH2:6]([O:5][C:1](=[O:8])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:7]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
250 g of potassium-tert.-butylate were suspended in a solution of 480 cc of diethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide, followed by the gradual dropwise addition of 100 g pinacolone at 45° C/normal pressure. On completion of the addition, the mixture was stirred for 1 hour at 45° C and, after cooling, alcohol, water and finally hydrochloric acid carefully added one after the other to the reaction mixture. The reaction mixture was then treated and purified in the same way as described in 1 above. The yield was 67% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].S(C)C>ClCCl.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of TiCl4 (1M in dichloromethane, 36 ml, 36 mmol) in dichloromethane (30 ml) at 0° C. was added Ti(OiPr)4 (10.8 ml, 36 mmol). The mixture was then stirred at room temperature for 10 min. To a solution of benzyl (S)-1-((1S,2R)-2-acetamido-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (23.25 g, 60 mmol) in dichloromethane (600 ml) was added tert-butylamine (30 ml, 300 mmol) at room temperature, followed by the addition of the TiCl4/Ti(OiPr)4 solution at −50° C. The reaction was allowed to warm slowly to room temperature. The reaction was finished after 2 h (The reaction was monitored on HPLC by quenching an HPLC sample with NaBH4 in methanol). The solution was cooled to 10° C. and BH3.SMe2 (1M in dichloromethane, 66 ml, 66 mmol) was added. The mixture was stirred at room temperature for 5 then quenched with Na2CO3 aqueous solution (300 ml). The precipitate was filtered off. The two layers were separated and the aqueous layer was extracted with dichloromethane (600 ml). The combined dichloromethane layers were extracted with 1N HCl twice (150 ml and 15 ml). (The product and the undesired trans isomer were both in the acidic aqueous phase.) The combined acidic aqueous layers were neutralized with 12 M aqueous solution of NH4OH (12 ml) to pH-8 and extracted with dichloromethane twice (600 ml, 450 ml). (The product was in organic phase, while the trans isomer was still in aqueous layer.) The combined organic layers were washed with NH4Cl aqueous solution 3 times (3×200 ml) until there was no trans isomer left in organic layer. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by crystallization in EtOAc/Hexane(200 ml/800 ml) to give the desired benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (20.80 g, 78% yield) as a white solid with 99.5% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 7.27-7.46 (m, 6H), 5.03 (m, 2H), 4.14 (m, 1 H), 4.07 (q, J=8.80 Hz, 1H), 3.83 (m, 1H), 3.36 (m, 2H), 2.91 (s, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.78 (s, 3H), 1.41-1.74 (m, 7H), 1.04 (s, 9H). m/z: 445.54 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13](Br)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21]1([CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([C:30]2([OH:33])[CH2:29][CH2:28][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:32][CH2:31]2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1Br
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a solution of tert-butyl(3-bromopyridin-2-yl)carbamate (4 g) in THF (dry) (20 mL) was added dropwise n-butyllithium (1.6 M in hexane) (20.1 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 1 hr to give a yellow suspension. A solution of 4-phenylcyclohexanone (3.06 g) in THF (dry) (30 mL) was added dropwise at −78° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (560 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]C(O)=O.[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][N:13]2[CH2:3][CH2:2][Cl:1]
Reactant: Oc1ccc(Br)c2cccnc12
Reactant: O=C(O)CCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)c2c1N(CCCl)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask, 3-chloropropanoic acid (8.44 g, 89.3 mmol, 20 eq.) was added to 5-bromoquinolin-8-ol (1 g, 4.46 mmol, 1 eq.) in 15 mL THF at 0° C. NaBH4 (759 mg, 20 mmol, 4.5 eq.) was added portionwise in 50 minutes at 0° C. The reaction was stirred at 0° C. for 30 minutes then heated to 80° C. for 2 hours. The reaction was cooled down. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated to give 5-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinolin-8-ol crude. LCMS-ESI+ (m/z): [M+H]+ calcd for C11H14BrClNO: 291.58. found: 292.0.
Reaction SMILES: CC#N.C(=O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:8]#[CH:9].C([Mg]Cl)(C)C.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[N:10]1([CH2:7][C:8]#[C:9][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C#CCN1CCOCC1
Reactant: CON(C)C(C)=O
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a cooled (˜40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+m/e 168.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:27]1([N:33]=[C:34]=[S:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:35])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(N)cc3)C2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CC#N
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(NC(=S)Nc4ccccc4)cc3)C2)cc1

Procedure:
3.4 g of 5-(4-aminophenyl)-3-(4-methoxyphenyl)-1-phenyl-2-pyrazoline and 1.5 g of phenyl isothiocyanate were reacted with each other in acetonitrile, and the product was reprecipitated from dimethylformamidemethanol to obtain 2.7 g of the desired end compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1>CCOC(C)=O.C(O)(=O)C.[Pd]>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])cnc3n2CC2CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2nc3cc(N)cnc3n2CC2CC2)cc1
Reaction time: 72 h
Yield: 95 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine (1.35 g, 3.84 mmol) in EtOAc (20 mL) and acetic acid (1 mL) at room temperature was added Pd/C (308 mg, 10% grade). The mixture was placed in a Parr apparatus under 35 psi H2. The mixture was shaken for 72 hours. The reaction was filtered over Celite. The filtrate was taken up into 1 M NaOH aqueous solution (25 mL) and EtOAc (50 mL) and the phases separated. The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The process gave 1.18 g of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-amine (95% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine), with purity>95% by HPLC analysis. The residue was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 0.35 (m, 2H), 0.46 (m, 2H), 1.11 (m, 1H), 1.39 (t, J=6.8 Hz, 3H), 3.26 (br s, 2H), 3.98 (m, 4H), 4.25 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 7.34 (d, J=2.3 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 323.
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH2:19]Cl)[CH3:14].Cl>CN(C)C=O>[C:8]([C:2]([Cl:1])([CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH3:26])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:9])[CH3:10]
Reactant: CCOc1ccc(CCl)cc1OCC
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)(Cc1ccc(OCC)c(OCC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
In 100 ml of dry dimethylformamide is dissolved 9.6 g of ethyl 2-chloroacetoacetate, and under ice cooling, 2.32 g of 60% sodium hydride in oil is added. The mixture is stirred at room temperature for 30 minutes. To this mixture are added 12.5 g of 3,4-diethoxybenzyl chloride and 30 ml of dry dimethylformamide, and the mixture is stirred at 70° C. for 2 hours. The mixture is then poured into a mixture of 200 g ice and 50 ml 6N-HCl and extracted with ether. The ethereal layer is washed with water, dried over MgSO4 and distilled to remove the ether. Column chromatography is carried out on the oily residue with 200 g of silica gel, elution being carried out with a 1:4 mixture of ether and n-hexane. The above procedure provides 14.2 g (71.4%) of ethyl 2-acetyl-2-chloro-3-(3,4-diethoxyphenyl)propionate as oil.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N[C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]([CH3:18])[CH3:17])[C:8]=1[C:9]#[N:10].[OH-].[Na+]>CCO>[CH:16]([NH:15][C:11]1[C:8]2[C:9]([NH2:10])=[N:5][S:1](=[O:3])(=[O:2])[NH:4][C:7]=2[CH:14]=[CH:13][CH:12]=1)([CH3:18])[CH3:17]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Nc1cccc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Nc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Yield: 14.6 %

Procedure:
A solution of 2-amino-6-(isopropylamino)benzonitrile sulfamide (Example 90a) (0.14 g, 0.54 mmol) and NaOH (2 N, 0.54 mL) in EtOH (3 mL) was stirred at 90° C. under nitrogen for 0.5 hour. The reaction mixture was cooled to room temperature, and concentrated under vacuum. H2O (1 mL) was added and the reaction mixture was neutralized to pH˜3 with 10% AcOH. The resultant precipitate was extracted with EtOAc, and after evaporation of solvents the residue was purified by preparative thin layer chromatography using a DCM/EtOAc (4:1) solution as eluant, to give N5-isopropyl-1H-benzo[c][1,2,6]thiadiazine-4,5-diamine-2,2-dioxide (0.02 g). 1H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J=6.4 Hz, 6H), 1.84 (bs, 1H), 5.24 (bs, NH), 6.22-6.19 (m, 2H, NH), 7.09 (t, J=8.0 Hz, 1H), 7.48 (bs, 2H). MS 255 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[N:31][CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M89) (0.29 g, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 76%).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1>CO>[Br:11][C:9]1[CH:10]=[C:5]([O:2][CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 2.20 ml, 10.0 mmol) was added dropwise to a stirred solution of 1-fluoro-3-chloro-5-bromobenzene (1.00 g, 4.77 mmol) in methanol (28 ml) at room temperature under a nitrogen atmosphere. The mixture was heated under reflux for 3 days and then cooled to room temperature. The mixture was evaporated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with water (2×20 ml) dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with cyclohexane to provide the title compound as a colourless oil (302 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Cl)cc1C=O
Yield: 98.2 %

Procedure:
4.3 g of 5-chlorosalicylaldehyde, together with 7.8 g of methyl iodide and 5.7 g of potassium carbonate, in 100 ml of acetone are heated to reflux (1 hour). After filtration, the filtrate is concentrated. 4.6 g of the title compound are obtained as an oil.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)(OC(C)(C)C)=O.[CH2:32]([C:34]1[NH:38]N=[N:36][N:35]=1)[CH3:33]>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:36]=[N:35][C:34]([CH2:32][CH3:33])=[N:38]3)[CH:10]=[CH:11]2)=[C:19]([Cl:23])[N:18]=1
Reactant: CCc1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1

Procedure:
The title compound is prepared analogously to di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (AA3) by replacing di-t-butyliminodicarboxylate with 5-ethyltetrazole. MS (ES+) m/e 351.2 (MH+)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][N:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:40]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: CC(C)(C)c1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(C(C)(C)C)cc5)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
In a nitrogen purged sealed tube, 8-chloro-3-methoxy-1,5-naphthyridine (0.053 g, 0.271 mmol) was dissolved in DMF (2.00 mL). 4-(4-(4-Tert-butylphenyl)phthalazin-1-ylamino)phenol (0.100 g, 0.271 mmol) and cesium carbonate (0.176 g, 0.541 mol) were added, and the mixture in the tube was stirred at 90° C. for 17 h. Upon cooling to RT, the mixture was concentrated in vacuo, and purified by silica gel chromatography using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2 to yield 4-(4-tert-butylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as off-white solid. MS [M+H]=528.1; Calc'd 527.6 for C33H29N5O2.
Reaction SMILES: Cl[CH:2]([CH:6]1OCCO1)[C:3](=[O:5])[CH3:4].Cl.[C:12]([NH2:15])(=[NH:14])[CH3:13].C([O-])(=O)C.[Na+]>C(O)(C)(C)C>[C:3]([C:2]1[N:14]=[C:12]([CH3:13])[NH:15][CH:6]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)C1OCCO1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)c1c[nH]c(C)n1

Procedure:
A mixture of 1.64 g (10 mmole) 2-(1-chloro-2-oxopropyl)dioxolane, 1.89 g (20 mmole) acetamidine hydrochloride, 2.46 g (30 mmole) sodium acetate and 20 ml t-butanol is heated at reflux for 24 hours and the product isolated as in Part A.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][N:6]=1.[Cl-].[NH4+:17]>[Fe].C(O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:10]([NH2:17])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Product: Nc1cccnc1OCC(F)(F)F
Yield: 23.1 %

Procedure:
2-(2,2,2-Trifluoroethoxy)-5-nitropyridine (5.0 grams), powdered iron (15 grams), and ammonium chloride (25 grams) were refluxed in 3A ethanol until TLC detected no starting material (about 4 hours). The reaction mixture was filtered, washed with water, and solvents removed, yielding 1.0 gram of the product as a thin brownish liquid. NMR confirmed the identity of the product.