Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.N1CCCCC1.C(O)=O.[CH3:23][C:24](=[O:29])[CH2:25][C:26](=[O:28])[CH3:27]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:25]([C:24](=[O:29])[CH3:23])[C:26](=[O:28])[CH3:27])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: O=CO
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)c(Cl)c1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 2.5 g of 3-chloro-4-methylsulfonylbenzaldehyde, 0.13 ml of piperidine and 0.05 ml of formic acid in 70 ml of 2-propanol was added 2.6 ml of 2,4-pentanedione with stirring at 20° C. The solution was stirred overnight at 20° C. The product was filtrated and washed with 2-propanol, yield 2.1 g (60%), mp. 140-142° C. 1H-NMR (DMSO-d6,400 MHz): 2.28 (s, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.40 (s, 3 H, CH3), 7.60 (m, 1 H, Ar), 7.80 (m, 1 H, Ar), 7.77 (s, 1 H CH), 8.1 (m, 1 H, Ar).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([F:16])[CH:7]=1.O.[OH-].[Li+].CO>O1CCCC1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)c1ccc(C2OCCO2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C2OCCO2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of EXAMPLE 17C (2.0 g) in tetrahydrofuran (10 mL) and water (5 mL) was added a solution of lithium hydroxide monohydrate (1 g) in water (5 mL). Methanol was added until a homogeneous solution formed. The solution was stirred at ambient temperature for 4 hours and concentrated to 5 mL. This was acidified with 2N hydrochloric acid to pH 2 and partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give 1.5 g (79%) of the title compound. MS (DCI): m/z 213 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:32])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1C[CH2:46][CH2:45][CH2:44]1.C(I)C=C>CN(C=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH2:46][CH:45]=[CH2:44])[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:32])[CH:8]=1
Reactant: C=CCC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: C1CCOC1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(CC=C)(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reaction time: 0.03 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylbut-3-enyl)-thiazolo[5,4-b]pyridine (1.17 g, 2.62 mmol) in 20 mL DMF under argon was added sodium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (3.28 mL, 3.28 mmol). The reaction mixture became deep blue/purple. After 2 min, allyl iodide (0.362 mL, 3.93 mmol) was added and the reaction became light orange after 1 min. After 5 min total, the reaction mixture was quenched with sat'd aq. NH4Cl, EtOAc, and water. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, ISCO, 80 g, 0-40% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(4-phenylhepta-1,6-dien-4-yl)thiazolo[5,4-b]pyridine as a white foam. MS (ESI) m/z: Calculated: 486.2; Observed: 487.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[CH3:19][NH:20][CH2:21][CH2:22][OH:23].CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:20]([CH2:21][CH2:22][OH:23])[CH3:19])=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CNCCO
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(CCO)C(=O)c1cc2nccc(Cl)c2s1
Yield: 49.2 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (1.0 g, 4.68 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with 2-(methylamino)ethanol (0.414 ml, 5.15 mmole) and Et3N (0.718 ml, 5.15 mmole), in a manner as previously described for example 9d to give a pale brown solid (0.624 g, 49% yield). 1H NMR (400 MHz, CDCl3) σ8.61 (1H, d, J=4.8 Hz), 7.80 (1H, s), 7.33 (1H, d, J=4.8 Hz), 3.92 (2H, m), 3.76 (2H, t, J=5.1 Hz), 3.37 (3H, s), 3.19 (1H, s); ESIMS (MH+): 259.10.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[NH2:16][NH2:17].O>C(OCC)(=O)C>[C:1]([NH:16][NH2:17])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NNC(=O)c1ccccc1
Temperature: 78 °C
Yield: 66 %

Procedure:
Into a 200 mL three-neck flask was put 25 g (0.17 mol) of ethyl benzoate, 60 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and this mixture was stirred while being heated at 78° C. for 8 hours. After the reaction, the reaction solution was added to about 500 mL of water, and ethyl acetate was added to this aqueous solution. An organic layer was separated from an aqueous layer, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order. Magnesium sulfate was added to the organic layer, so that the organic layer was dried. This mixture was suction filtered, so that the magnesium sulfate was removed, whereby a filtrate was obtained. The obtained filtrate was concentrated to give a solid. The solid was recrystallized with a mixed solvent of ethanol and hexane, whereby 15 g of a white solid of benzohydrazide, which was the object of the synthesis, was obtained in a yield of 66% (synthesis scheme (b-1)).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[B:24](OC)([O:27]C)[O:25]C.Cl>C1COCC1.BrCCBr>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([B:24]([OH:27])[OH:25])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C

Procedure:
Magnesium turnings (1.84 g, 0.08 mol) were added to a stirred solution, at room temperature under dry nitrogen, of compound 31 (15.00 g, 0.040 mol) in dry THF (150 ml) containing 1,2-dibromoethane (2 drops). The reaction mixture was maintained under these conditions for 1 h and then heated under reflux for 1 h. The reaction mixture was cooled to -78° C. and a solution of trimethyl borate (5.75 g, 0.08 mol) in dry THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and then stirred for 1 h with 10% hydrochloric acid (100 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)N)(=[O:3])[CH3:2].Cl.[N+:15]([O-])([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>C(O)(=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([S:20]([NH2:15])(=[O:22])=[O:21])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=S=O
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(C(C)=O)cc(S(N)(=O)=O)c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3,5-diacetylaniline (3.00 grams) in a mixture of acetic acid (17 (mL) and hydrochloric acid (5.7mL) was added a solution of sodium nitrate (1.27 grams) in 2.1 mL of water. The solution was stirred for 20 minutes. 14 mL of acetic acid was saturated with sulfur dioxide gas, and this mixture was added to the reaction, followed by cuprous chloride (0.63 grams). Significant foaming occurred. The reaction mixture was stirred for one hour, diluted with water, and extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with water, and concentrated. The resulting oil was taken up in diethyl ether, and ammonia gas was bubbled through the solution. The resulting slurry was filtered, and the solid was taken up in acetone and filtered to remove ammonium chloride. Removal of the acetone in vacuo afforded 1.48 grams of the title compound, m.p. 179.2-180.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:12].Cl>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (405 mg) and 2-bromo-4'-hydroxyacetophenone (646 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature, giving a clear solution. A precipitate had formed after an hour. After 231/2 hours, 2N-hydrochloric acid (5 ml) was added to the suspension and the solid was collected. This was washed with ethanol to give the title pyrimidinone (679 mg,); m.p. 260° with decomposition; λmaxEtOH 224 nm (ε 17300), 282.5 nm (ε 15660), 353 nm (ε 4900).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.O>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C@:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:43]5[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=NC2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 100 °C

Procedure:
To a vial was added (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (50 mg, 0.122 mmol), potassium phosphate (78 mg, 0.365 mmol), 2-fluoropyridin-4-ylboronic acid (34.3 mg, 0.243 mmol), and 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (4.31 mg, 6.09 μmol), dioxane (609 μL) and water (203 μL). The reaction mixture was purged with N2 gas and heated at 100° C. in microwave reactor for 15 mins. It was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to give the crude material. The crude was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 25% to 40% to 80% DCM/MeOH (90/10) in DCM, to provide (R,E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. MS m/z=472.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1 H) 2.24-2.41 (m, 1 H) 3.39 (dt, J=11.25, 5.62 Hz, 2 H) 4.37-4.47 (m, 1 H) 4.47-4.61 (m, 1 H) 6.13 (br. s., 2 H) 7.41 (d, J=8.31 Hz, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.60 (dt, J=8.39, 1.87 Hz, 1 H) 7.67-7.75 (m, 2 H) 7.89-7.95 (m, 1 H) 8.03-8.16 (m, 2 H) 8.25 (dt, J=4.82, 1.50 Hz, 1 H) 8.38 (d, J=5.28 Hz, 1 H) 8.66-8.77 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Br)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](=[S:19])([O:16]CC)[NH2:15].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[NH:15][C:14](=[O:16])[S:19][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(N)=S
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)c1csc(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (7.6 g.), O-ethyl thiocarbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for 3 hours at 50° C. Ethyl acetate (50 ml.) was added to the reaction mixture and the resulting mixture was washed with water and with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystalline residue. The residue was washed with diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate (syn isomer) (2.35 g.).
Reaction SMILES: C([N:3](CC)CC)C.Cl.N=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:26]([CH:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][C:11]1=[NH:3])=[O:27]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: N=C1NN(c2ccccc2)C=CC1C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 64 %

Procedure:
9.6 g (94.9 millimoles) of triethylamine were added dropwise to 7.5 g (36.1 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride and 8.3 g (39.6 millimoles) of 3,5-dichlorobenzoyl chloride in 100 ml of methylene chloride at room temperature, while stirring. Stirring was continued at room temperature for a further 2 hours, after which the product ws filtered off under suction, washed first with water and then with acetone and recrystallized from toluene. 8.0 g (64% of theory) of 4-(3,5-dichlorobenzoyl)-imino-1,4-dihydro-1-phenylpyridazine were isolated as yellow crystals of melting point 242°-244° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:12]1[CH:13]=[C:14]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carboxylate (347 mg, 0.69 mmol, 1.00 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (10 mL) dropwise with stirring over 10 min and the resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.278 g (crude) of 3-(2-fluoro-4-phenoxyphenyl)-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as brown oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.C1COCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:33]=1[C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35]>C1COCC1>[Cl:48][C:45]1[CH:46]=[CH:47][C:32]([NH:31][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[O:12])=[C:33]([CH:44]=1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92 mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solution of iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DXF/THF (0.7 mL) was added over 10 min via syringe. The ice bath was removed at addition's end, and the mixture was allowed to warm to ambient temperature. After 1 h, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol) was added in one portion, and the slurry was heated to 70° C. in an oil bath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amine remained, so the volatiles w re removed under reduced pressure, and EtOAc (25 mL) and water (20 mL) were added. The organic layer was extracted with saturated NaHCO3 (2×20 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to 0.97 g of yellow solid which was found to be contaminated with 45 wt % DMF. Corrected yield was 0.53 g (83 % yield), and no further purification was performed:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[CH3:22][C@@H:23]1[CH2:28][NH:27][C@@H:26]([CH3:29])[CH2:25][NH:24]1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:24]2[CH2:25][C@@H:26]([CH3:29])[NH:27][CH2:28][C@@H:23]2[CH3:22])=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: Clc1nnc(Cl)c2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nnc(Cl)c3ccncc23)[C@@H](C)CN1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 1,4-dichloropyrido[3,4-d]pyridazine 3 (4.80 g, 24.0 mmol) and Hünig's Base (14.7 ml, 84.0 mmol) in NMP (10 ml) was added (2R,5S)-2,5-dimethylpiperazine (4.11 g, 36.0 mmol). The reaction was stirred at 100° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (10× volume) and extracted with dichloromethane (4×50 mL). Silica gel chromatography (gradient 0 to 2.5% MeOH in 30% EtOAc in CH2Cl2 with 2.5% TEA additive) provided 1.4 g of 1-chloro-4-(rac-2,5-trans-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine 43. 1H NMR (500 MHz, CDCl3) δ ppm 9.66 (s, 1H) 9.08 (d, J=5.6 Hz, 1H) 7.97 (d, J=5.6 Hz, 1H) 3.77 (tdd, J=11.8, 5.9, 3.4 Hz, 1H) 3.43 (dd, J=12.1, 2.6 Hz, 1H) 3.17-3.32 (m, 2H) 2.91 (dd, J=10.5, 2.0 Hz, 1H) 2.74 (dd, J=11.7, 10.3 Hz, 1H) 1.13 (d, J=6.1 Hz, 3H) 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1.[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:22])[C:9]3[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:8]=3[NH:7][C:6]=2[N:19]=1
Reactant: Cc1ccc2c(n1)Nc1cc(C)c(C)cc1NC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Nc1cc(C)c(C)cc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 38 gm (0.15 mol) of 6,11-dihydro-2,8,9-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 300 ml of dimethyl formamide and 8.4 gm (0.18 mol) of 50% sodium hydride in mineral oil was stirred at room temperature in a nitrogen atmosphere for 30 minutes. Then, a solution of 31.4 gm (0.22 mol) of methyl iodide in 50 ml of dimethyl formamide was added dropwise, and the mixture was heated on an oil bath at 100° C. for 2 hours while stirring. The mixture was then evaporated in vacuo, ice was added to the oily residue, and the mixture was stirred until the residue crystallized. The crystals were collected by suction filtration and recrystallized from n-propanol, yielding 65% of theory of the compound named in the heading, which had a melting point of 217°-219° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[CH:12][C:13](=[O:17])[N:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=O.C(=O)(O)[O-].[Na+].NC1N=CN=C2C=1N=C(C1C=CC=C(F)C=1)N2C1C=CC(=O)N(C)C=1>C(OCC)(=O)C.CN1C(=O)CCC1>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=1)[N:9]2[C:10]1[CH:11]=[CH:12][C:13](=[O:17])[N:14]([CH3:16])[CH:15]=1
Reactant: Cn1cc(Nc2ncnc(Cl)c2N)ccc1=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cn1cc(-n2c(-c3cccc(F)c3)nc3c(N)ncnc32)ccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1cc(-n2c(-c3cccc(F)c3)nc3c(Cl)ncnc32)ccc1=O
Temperature: 40 °C
Yield: 66.7 %

Procedure:
5-(5-Amino-6-chloropyrimidin-4-yl)amino-1-methyl-1,2-dihydro-2-pyridinone (1 g) and NMP (10 mL) were introduced into a flask and stirred at 40° C. 3-Fluorobenzoyl chloride (0.53 mL, 1.1 eq.) was added dropwise to this suspension, and after additional NMP (3.2 mL) was added thereto and stirred for about 1.5 hours, the reaction solution was elevated to 110° C. and stirred for 3 hours. Ethyl acetate (33 mL) and 10% aqueous sodiumbicarbonate solution (16.5 mL) were added to the reaction solution, and the organic layer was washed with brine (16.5 mL) and concentrated. The concentrate was dissolved by adding DME (16.5 mL) and stirring it at 55° C., and then crystallized by adding water (33 mL). The crystals were collected by filtration and dried at 50° C. for 4 hours, to give 0.94 g of 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone (two-steps, yield 66.7%) (6) 5-[6-Amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: O=C(OCCOCCl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to a dry solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide (50 ml). The reaction was exothermic, immediately precipitating, triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first remove a small amount of ethylene glycol monobenzoate then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.