Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]([CH2:16][CH3:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[CH3:18][N:2]([CH3:1])[CH:3]([CH2:16][CH3:17])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[OH:5]
Reactant: CCC(C(=O)c1ccc(NC(C)=O)cc1)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C(O)c1ccc(NC(C)=O)cc1)N(C)C
Temperature: 25 °C

Procedure:
Step-4: A solution of N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide (3.80 g, 15.30 mmol) in 40 mL MeOH was cooled in an ice bath under N2 and treated with NaBH4 (725 mg, 19.12 mmol), added in one portion. The reaction vessel was removed from the ice bath and stirred at rt over the weekend. The reaction was quenched with acetone, then concentrated in vacuo and partitioned between DCM and half-saturated NaHCO3. The aqueous phase was extracted four times with DCM and the organic extracts were combined and dried over Na2SO4. The solution was decanted and concentrated in vacuo. The solid residue was purified by silica gel column chromatography eluting with 10%-12% MeOH (2N NH3)/DCM to provide the syn-isomer of N-(4-(2-(dimethylamino)-1-hydroxybutyl)phenyl)acetamide as a white amorphous solid and the anti-isomer as a straw colored oil. MS ESI: m/z 251.17 [M+1+].
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[N:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=2)[O:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2cccc(OCc3ccccc3)c2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2-ylamine (55 mg, 0.462 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (252 μL, 1.81 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (58 mg, 22%).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[O-]CC.[Na+].[CH2:14](Cl)[CH:15]=[CH2:16]>C(O)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([P:3]([CH:14]=[CH:15][CH3:16])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CCCl
Reactant: CCCCOP([O-])CC
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC=CP(=O)(CC)OCCCC
Yield: 66 %

Procedure:
At room temperature, a three-neck flask equipped with stirrer and high-performance condenser is initially charged with 400 g of ethanol and this initial charge is devolatilized by stirring and passing nitrogen through it. Then, under nitrogen, 3.27 g (5 mmol) of bis(triphenylphosphine)nickel dichloride and 30 g (0.2 mol) of butyl ethylphosphonite (produced as in Example 2) are added followed by the dropwise addition of initially 14.5 g (0.25 mol) of sodium ethoxide in ethanol and thereafter 19.1 g (0.25 mol) of allyl chloride. Following a reaction time of 5 hours, the reaction solution is passed for purification through a column charged with Deloxan® THP II and the solvent is removed in vacuo. The product is purified by column chromatography to obtain 25.1 g (66% of theory) of butyl ethylpropenylphosphinate as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10].O1CCOCC1>CCOCC>[ClH:10].[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:8](=[NH:7])[NH2:9])[CH:6]=1
Reactant: N#CN
Reactant: Cc1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cnn(C(=N)N)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 4-Methyl-1H-pyrazole (4.9 g, 60 mmol) was added cyanamide (2.5 g, 60 mmol), HCl (5.6 mL, 62 mmol, 4 M in dioxane) and dioxane (60 mL). The reaction was heated to 110° C. and aged for 9 h. It was then aged at rt overnight. The mixture was diluted with Et2O and stirred for 10 min. The product was isolated by filtration and washed with Et2O to afford the title compound.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.Cl.[CH3:15][O:16][NH2:17].C1(C)C(C)=CC=CC=1>O>[CH3:15][O:16][N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: CON
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: CON1C(=O)Cc2ccccc2C1=O

Procedure:
A mixture of homophthalic acid (9.0 g., 0.05 mole) and methyoxyamine hydrochloride (4.25 g., 0.05 mole) in 125 ml. of xylene was refluxed for 90 minutes, with water collected in Dean Stark trap as it formed. The reaction mixture was cooled and concentrated by vacuum to one half its original volume, then diluted with ethylacetate, washed with water and dried over sodium sulfate. Recrystallization from isopropanol and ethanol, followed by drying at 100° C. for 4 hours yielded pale pink crystals of 2-methoxyisoquinoline-1,3 (2H, 4H)-dione, m.p. 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.S(Cl)(Cl)=O.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[NH2:30]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH:30][C:24]2[C:23]3[C:27](=[CH:28][CH:29]=[C:21]([CH2:20][C:19]4[CH:31]=[C:32]([F:34])[CH:33]=[C:17]([F:16])[CH:18]=4)[CH:22]=3)[NH:26][N:25]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1Cl
Yield: 34.6 %

Procedure:
2,6-dichloropyridine-3-carboxylic acid (480 mg, 2.5 mmol) and thionyl chloride (0.28 mL, 3.75 mmol) were heated in toluene dry (120 mL) and a few drops of dry DMF at 90° C. for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (15 mL) at 0° C. under nitrogen atmosphere. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (518 mg, 2 mmol) in dry pyridine (7 mL) was added to the cooled reaction mixture. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with aqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using DCM/EtOH 100:4 as the eluant, affording 300 mg of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=450.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[C:4](C)[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1.C[C:29]1[O:33]N=C(CCC(OC)=O)C=1>>[OH:33][CH2:29][CH:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:7][CH:6]=2)=[N:12][CH2:11]1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: COC(=O)CCc1cc(C)on1
Reactant: Cc1cc(O)ccc1C1=NCCO1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Yield: 27 %

Procedure:
5-{7-[4-(4,5-Dihydro-2-oxazolyl)-3-methylphenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =3-CH3, Y=(CH2)7, oxazole at 4-position] was prepared from 4,5-dihydro-2-(4-hydroxy-2-methylphenyl)oxazole and 5-(7-bromoheptyl)-3-methylisoxazole according to the procedure of Example 9, part (d) and was obtained in 27% yield as a colorless solid, m.p. 58°-59° C. when recrystallized from an isopropyl acetate-hexane mixture.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([NH:8][S:20]([CH2:19][CH2:18][CH2:17][Cl:16])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCl)NCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Benzylamine (1 eq.) was dissolved in anhydrous DCM (0.5 M) and Et3N (1.1 eq.) was added; after cooling at 0° C., 1-chloro-3-propanesulfonyl chloride was slowly added and the mixture was stirred at RT for 20 h. All volatiles were evaporated in vacuo and the residue taken up with Et2O; the precipitate was filtered off and the filtrate was concentrated; addition of PE afforded N-benzyl-3-chloropropane-1-sulfonamide as a white solid (87%). (ES+) m/z 248 (M+H+). Di-tert-butyl dicarbonate (1.5 eq.) was slowly added to an ice-cooled 0.45 M THF solution of N-benzyl-3-chloropropane-1-sulfonamide. DMAP (0.1 eq.) was then added and the reaction stirred overnight at RT. All volatiles were removed in vacuo and the crude diluted with EtOAc, washed with HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4, all volatiles were evaporated in vacuo and the residual material used in the next step without purification. (ES+) m/z 348, 350 (M+H+).
Reaction SMILES: [C:1]1([Na])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[C:10]1C=CC=CC=1.[C:16](=[O:18])=[O:17]>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.O>[C:1]1([CH2:10][C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Na]c1ccccc1
Reactant: O=C=O
Reactant: Clc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A toluene (2 g) solution containing 0.21 g of diisopropyl amine (2.07 mmol, 2 mol % (mol % on the basis of phenyl sodium, which is also used hereinafter in the same meaning)) was added to phenyl sodium, which had been prepared by reacting 5.0 g (0.217 mol) of sodium dispersion and 11.6 g (0.103 mol) of chlorobenzene in 50 g of toluene (phenyl sodium was formed at the yield of about 100%, hereinafter the same as the above), at room temperature (about 20° C.), and then the reaction mixture was stirred for 2 hours. As the reaction proceeded, slight generation of heat occurred and a dark violet-colored slurry turned to a greenish brown-colored slurry. After that, an excess amount of dry ice was cast into the resultant slurry, little by little, keeping the reaction temperature at the range of from -10° C. to 0° C., and then the slurry was subjected to hydrolysis with 30 ml of water. The resulting aqueous layer was fractionated, and then it was washed with 10 g of toluene. After that, the aqueous solution was subjected to acid crystallization with concentrated hydrochloric acid, to give 13.2 g of phenylacetic acid (0.097 mol, 94.2% (the yield based on chlorobenzene, which will be used hereinafter in the same meaning), m.p. 75 to 77° C.) as white crystals. At that time, almost no benzoic acid derived from phenyl sodium was detected. This fact indicates that phenyl sodium was almost quantitatively changed to benzyl sodium by the presence of the diisopropylamine catalyst.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:15]=O.[ClH:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>C(O)C>[ClH:17].[N:18]1([CH2:15][CH2:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: C=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)CCN2CCCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4'-acetylmethanesulfonanilide (21.5 g., 0.1 mole), 95% paraformaldehyde (10 g., 0.3 mole), pyrrolidine hydrochloride (10.8 g., 0.1 mole) in 150 ml. of ethanol containing 1 drop of concentrated hydrochloric acid is refluxed for a period of 4 hr. at steam bath temperature and then for an additional period of 8 hr. permitting the ethanol to evaporate. The resulting glassy residue is stirred with 300 ml. of hot acetone providing a crystalline material which is collected and crystallized from methanol-isopropyl alcohol to afford analytically pure 4'-[3-(1-PYRROLIDINYL)PROPIONYL]-METHANESULFONANILIDE HYDROCHLORIDE, m.p. 182.0°-183.0°C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2cccc(Br)n2)CC1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of 6-bromo-pyridine-2-carboxylic acid (100.00 mg, 0.50 mmol) in DCM (5.0 mL) was added 1-isopropylpiperazine (95.20 mg, 0.74 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 189.78 mg, 0.99 mmol), 1-hydroxybenzotriazole (HOBt; 133.78 mg, 0.99 mmol), and iPr2NEt (0.86 mL, 4.95 mmol). After 18 h at rt, the mixture was diluted with water and extracted with DCM. Purification by FCC provided the desired product (83.0 mg, 54%). MS (ESI): mass calcd. for C13H18BrN3O, 311.06; m/z found, 312.2 [M+H]+. 1H NMR (CDCl3): 7.69-7.59 (m, 2H), 7.56-7.52 (m, 1H), 3.84-3.76 (m, 2H), 2.79-2.68 (m, 1H), 2.62 (t, J=5.1 Hz, 2H), 2.53 (t, J=5.1 Hz, 2H), 1.06 (d, J=6.5 Hz, 6H). Assay 1 (Human H3): Ki=1400 nM.
Reaction SMILES: CCCC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=O.CC(C)([O-:21])C.[K+].Cl>O1CCCC1>[CH:10]12[CH2:17][CH:16]([C:15](=[O:21])[C:14]1=[O:13])[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1
Reactant: CCCCON=O
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCC
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(=O)C2CC1C1CCCC21
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A cooled (-20° C.) solution of 8-ketotricyclo[5.2.1.0]decane (7.51 g, 50 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen was treated with n-butyl nitrite (6.70 mL, 5.92 g, 57.3 mmol), then with solid potassium t-butoxide (11.22 g, 100 mmol) in portions at a rate to keep the pot temperature below -10° C. The red mixture was stirred at -10° C. for one h and at 5° C. for 3.5 h, then it was quenched by addition to ice water (125 mL). The mixture was treated with concentrated hydrochloric acid (11 mL, 132 mmol), then the aqueous solution was extracted with methylene chloride (150 mL, then 2×100 mL). The combined organic solution was washed with saturated aqueous sodium bicarbonate (2×100 mL), water (100 mL), dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 5% acetone/methylene chloride) to afford tricyclo[5.2.1.0 (2,6)]decan-8,9-dione, oxime (4.88 g, 54.5%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:12]([O-])=[O:13].N([O-])=[O:16].[Na+].N([O-])=O.[K+]>>[N:12]([CH2:2][C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[OH:16])=[O:3])=[O:13]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: O=NCC(=O)Nc1ccccc1O

Procedure:
According to this scheme 1a, the compounds of formula (Ia) are prepared by reaction of an appropriate 3-acetamidophenol compound (1) with a nitrite (2), such as a sodium nitrite (X=Na), a potassium nitrite (X=K), etc., at a temperature of −3° C. The nitroso acetamidophenol (3) thus obtained is subsequently reacted with 1,3-dihydroxynaphthalene (4) in a solvent such as butanol, by heating to a temperature of approximately 70° C., then adding concentrated sulfuric acid and continuing the heating to 90° C., and then cooling, so as to form the appropriate 9-acetamido-benzo[a]phenoxazin-5-one. The latter compound is subsequently hydrolyzed by heating with moderately concentrated sulfuric acid so as to give the 9-amino-benzo[a]phenoxazin-5-one (5). The last step is equivalent to that of scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[Cl:16].C(Cl)(=O)C([Cl:23])=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[Cl:16]
Reactant: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.[CH3:14]OC(OC)N(C)C.[NH:22]([C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23].Cl.[OH-].[Na+]>C(O)C.O>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:22]1[C:9](=[O:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][NH:23]1
Reactant: NNc1ncccn1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1c(-c2ccc(Cl)cc2)c[nH]n1-c1ncccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.4 %

Procedure:
19.9 g (0.1 mol) of ethyl 4-chloro-phenylacetate are heated with 23.8 g (0.2 mol) of dimethylformamide dimethyl acetal to 100° C. for 5 hours. All volatile components are then distilled off at this temperature in a vacuum from a water pump. The oily residue, which essentially consists of ethyl α-dimethylaminomethylene-4-chlorophenylacetate, is dissolved in 140 ml of ethanol without further purification, and 11 g (0.1 mol) of 2-hydrazinopyrimidine and 10 ml of concentrated hydrochloric acid are added. The mixture is heated under reflux for 5 hours and cooled to room temperature, and, after the addition of 9 g of concentrated sodium hydroxide solution, is stirred for 5 hours at room temperature. After it has been neutralized with dilute hydrochloric acid, the mixture is diluted with 1 l of water. The precipitated crystals are filtered off under suction, washed with water and dried in the air. 7.2 g (26.4% of theory) of 1-pyrimid-2-yl-4-(4 -chlorophenyl)-pyrazolin-5-one of melting point 190° to 191° C. (methanol) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C@@H:34]([NH2:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:35][C@H:34]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:23])[C:33]([CH3:38])([CH3:37])[CH3:32]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
In a round-bottomed flask 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) was dissolved in DMF (1.2 ml). (S)-3,3-Dimethylbutan-2-amine (0.25 ml, 1.84 mmol) was added followed by HATU (114 mg, 0.30 mmol) and the yellow solution was stirred at room temperature overnight. Water was added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 104 mg (73%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.COC1C=C(C=CC=1OC)CN>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]([CH:38]2[CH2:41][C:40](=[O:42])[CH2:39]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]([CH:38]2[CH2:41][C:40]([C:2]3[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=3)([OH:42])[CH2:39]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)cc1NC(=O)C(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)cc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (12.6 g, 69.0 mmol) in 245 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (27.6 ml, 69 mmol, 2.5 M in hexanes). After 15 min, a solution of N-[2-tert-butyl-5-(3-oxo-cyclobutyl)-2H-pyrazol-3-yl]-2,2,2-trifluoro-acetamide (4.0 g, 11.5 mmol in 200 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a Biotage® column, eluting with 25% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (4.6 g, 98% yield). LRMS m/z (APCI+) 407 (M+1).