Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC(C)C)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A mixture of ethyl {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (680 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and 1M aqueous sodium hydroxide solution (5 mL) was stirred at 50° C. for 30 min, and then cooled to room temperature. Water and 1M hydrochloric acid (5 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (600 mg, 94%) as a yellow amorphous solid. MS 456 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:30]([C:23]3[CH:22]=[N:21][N:25]4[CH:26]=[CH:27][CH:28]=[N:29][C:24]=34)=[O:31])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnn2cccnc12)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a solution of 1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Description 11) (300 mg, 0.967 mmol) in DMF (15 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (158 mg, 0.967 mmol), HOBT.H2O (148 mg, 0.967 mmol) and HBTU (368 mg, 0.967 mmol). Finally DIPEA (0.507 ml, 2.90 mmol) was added and the reaction mixture was stirred at rt for 20 hours. Solvent was removed by evaporation, the crude material partitioned between DCM (50 ml) and saturated sodium bicarbonate (50 ml), the DCM layer collected, washed with 2N HCl aq. (50 ml), dried (hydrophobic frit) and evaporated. The crude was purified by MDAP. MDAP fractions were evaporated and the crude material partitioned between DCM (20 ml) and sat. sodium bicarbonate solution (20 ml). The DCM layer was collected and dried (hydrophobic frit) and evaporated to give the title compound (308 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH:17]=2)=[C:13]([OH:15])[CH:14]=1)C1C=CC=CC=1.O1CCCC1.C(O)C>ClCCl.[Pd]>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=3[OH:15])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: Oc1cc(OCc2ccccc2)ccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A flask equipped with magnetic stirrer was charged with 5-(benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (14.5 g, 42.8 mmol) and tetrahydrofuran (50 ml) and ethanol (100 ml) and palladium (4.54 g, 10% on activated carbon) were added sequentially. The reaction vessel was then evacuated, placed under a hydrogen atmosphere and stirred vigorously for 24 hr. The reaction mixture was filtered through a celite plug, washing with ethyl acetate. The filtrate was concentrated in vacuo to give an off white solid. The crude solid was slurried in dichloromethane (200 ml), affording the title compound (10.2 g, 95%) as a white solid. m/z(ES+) 251(M+H+).
Reaction SMILES: Br[C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Br:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1sc2cnccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1c(-c2ccccc2)sc2cnccc12
Temperature: 100 °C
Yield: 34.7 %

Procedure:
A mixture of 2,3-dibromothieno[2,3-c]pyridine (500 mg, 1.71 mmol), phenylboronic acid (197 mg, 1.61 mmol), Pd(PPh3)4 (187 mg, 0.16 mmol), 2.0 M aqueous sodium carbonate (4 mL, 8 mmol) in DME (25 mL) was evacuated and refilled with nitrogen 3× and then heated in a microwave at 100° C. for 30 min. The reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate and purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 162 mg (35%) of the title compound as a white solid. 1H NMR (acetone-d6): δ 9.24 (s, 1 H), 8.65 (d, J=5.5 Hz, 1 H), 7.82 (dd, J=7.9, 1.5 Hz, 2 H), 7.76 (d, J=5.5 Hz, 1 H), 7.55-7.61 (m, 3 H); MS (ESI): 290.36, 292.34 [M+H]+; HPLC tR=1.25 min (HPLC: Analytical—2 min).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].[CH3:13][OH:14]>>[CH3:13][O:14][C:8]([CH:3]1[CH:2]([C:11]([OH:10])=[O:12])[CH:1]2[CH2:7][CH:4]1[CH:5]=[CH:6]2)=[O:9]
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Reactant: CO
Product: COC(=O)C1C2C=CC(C2)C1C(=O)O
Reaction time: 3 h

Procedure:
The same procedure as that of process (I) of Example 1 was conducted to obtain a 50% by weight methanol solution of (A1). In the same manner, to a 1 liter flask were added 24.00 g of 5-norbornene-2,3-dicarboxylic anhydride and 33.37 g of methanol, and the resulting mixture was stirred under reflux in a water bath kept at 90° C. Ninety minutes after initiation of the stirring, solid components disappeared, 3 hours after, the temperature was lowered to room temperature to obtain a 50% by weight methanol solution of 5-norbornene-2,3-dicarboxylic monomethyl ester.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:12]=2)[CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccccc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and phenylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 2.37 (s, 3H), 4.64 (s, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.41 (t, J=7.7 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.58 (m, 3H), 7.96 (d, J=7.3 Hz, 2H). Mass spectrum m/e 341 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:13]1[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)cn12
Product: Clc1ccc(-c2cc3nc(CN4CCOCC4)cn3c(Cl)n2)c(Cl)c1
Temperature: 0 °C

Procedure:
103 mg (0.267 mmol) of 7-(2,4-dichlorophenyl)-2-(morpholin-4-ylmethyl)imidazo[1,2-c]-pyrimidin-5-ol (Example 93A) are introduced in 5 ml (53.64 mmol) of phosphoryl chloride and heated at the reflux temperature for 3 h. The mixture is allowed to cool and is added cautiously to an ice/water mixture. The precipitate which separates out is filtered off. Drying under high vacuum results in 105 mg (99% of theory) of the product.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH:18]=[O:19]>O1CCOCC1>[CH3:14][N:13]1[C:8]([S:4][CH2:1][CH2:2][CH3:3])=[C:9]([CH:18]=[O:19])[C:10](=[O:17])[N:11]([CH3:16])[C:12]1=[O:15]
Reactant: CCCS
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCSc1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C

Procedure:
To a stirred solution of propane-1-thiol (2.30 mmol) in dry 1,4-dioxane (4 ml), NaH (2.30 mmol) was added under argon. To the mixture, a solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (2 mmol) in dry 1,4-dioxane (8 ml) was added at 5-8° C. in one portion. The mixture was stirred at room temperature until the starting material was consumed (monitored by TLC). Then the mixture was poured onto ice water (50 ml) and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with water and dried over anhydrous MgSO4. The solvent was evaporated in vacuo and the crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (1:1) as the eluent.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][N:6]([O:22][CH3:23])[C:7]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:5][N:6]([O:22][CH3:23])[C:7]([N:9]([CH2:3][CH:2]=[CH2:1])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])=[O:11])=[O:8]
Reactant: CON(C)C(=O)NC(=O)c1cnccc1C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)c1cnccc1C(F)(F)F)C(=O)N(C)OC
Reaction time: 2 h

Procedure:
Allyl bromide (0.10 ml) was added to a suspension of 1-methyl-1-methoxy-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.25 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide at 20° C., and stirred for 2 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulfate), evaporated and the residue purified by column chromatography on silica gel, eluting with n-hexane/ethyl acetate (2:1) to give 1-methyl-1-methoxy-3-allyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.26 g, Compound E-85).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)CNc1c(N)cnc2cccnc12
Temperature: 22 °C

Procedure:
A hydrogenation vessel was charged with N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (7.50 kg, 30.5 mol) and toluene (125.0 kg). A suspension of 3% platinum on carbon (0.44 kg, approximately 33% by weight (w/w) in water) in isopropanol (7.0 kg) was added to the vessel followed by a rinse with toluene (10.0 kg). The reaction mixture was then placed under hydrogen pressure (2.4×105 Pa, 2.4 bars) for six hours while stirring and maintaining the temperature at 22° C. The reaction mixture was then filtered, and the filter cake was washed with toluene (30.0 kg). The filtrate was concentrated under reduced pressure (1×104 Pa, 0.1 bar) at approximately 50° C. to provide a solution of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in toluene (75 L, approximately 10 mL/g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:23]([N:24]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])=[CH:22][C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.[NH3:38]>>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:22]=[C:23]([N:24]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[C:7]2=[N:6][C:5]=1[C:3]([NH2:38])=[O:2])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)c1nc2c(N3CCN(C)C3=O)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Solvent: O
Product: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(C(N)=O)nc23)C1=O
Temperature: 40 °C
Yield: 62 %

Procedure:
3-Benzyloxy-9-(3-methyl-2-oxo-imidazolidin-1-yl)-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (example 221, 1 g, 2.03 mmol) was mixed with ammonia water (28%, 50 ml) and the mixture was heated at 40° C. overnight. The precipitates were collected by filtration and dried in vacuo to give the titled compound (600 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24]([NH:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)(=[O:26])=[O:25]
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: COc1ccc(-c2csc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxy-phenyl)-thiazol-2-ylamine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic MEIHOD B to give a white-yellow solid (58.2 mg) with purity >90%. MS (pos) m/z 449.1, 451.1, 453.1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:21])[C:18]([CH3:20])=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:21])[C:18]([CH3:20])=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(C)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cn2c3cc(Br)ccc3c3cc(O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
9-bromo-2-methoxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (1.6 g) produced in Example 113 was suspended in anhydrous methylene chloride (120 ml), and a solution of boron tribromide in methylene chloride (1M, 28 ml) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (1.5 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@@H:9]2[O:31][C@H:30]([CH2:32][O:33]C(=O)C3C=CC=CC=3)[C@@H:20]([O:21]C(=O)C3C=CC=CC=3)[C@H:10]2[O:11]C(=O)C2C=CC=CC=2)[CH:4]=[CH:5][C:6](=[O:8])[N:7]=1.C[O-].[Na+]>CO>[CH3:1][C:2]1[N:3]([C@@H:9]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:20]([OH:21])[C@H:10]2[OH:11])[CH:4]=[CH:5][C:6](=[O:8])[N:7]=1
Reactant: Cc1nc(=O)ccn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(=O)ccn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of 2-methyl-1-(2′,3′5′-tri-O-benzoyl-β-D-ribofuranosyl)-pyrimidin-4-one (13.86 g, 25 mmol) in methanol (150 ml) was added 4.37 N sodium methoxide solution in MeOH (2.5 mmol, 0.1 eq.). The solution was stirred overnight at room temperature and then evaporated. The residue was partitioned between water (100 ml) and dichloromethane (2×150 ml). The aqueous layer was neutralized with Dowex 50H+-form and evaporated. The orange oily residue was crystallized from ethanol/acetone 3:1 to give the title compound (2.37 g, 39%). 1H-NMR (CDCl3): δ8.1 (d, 1H, H6); 6.0 (d, 1H, H5); 5.65 (m, 2H, H1′, 2′-OH); 5.25, 5.2 (d,t, 2H, 3′-OH, 5′-OH); 2.45 (s, 3H, CH3)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[CH:23][N:22]=[CH:21]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([C:24]5[O:20][CH:21]=[N:22][CH:23]=5)[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(-c2cnco2)c1
Product: Fc1cnc(Nc2cccc(-c3cnco3)c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 3-(1,3-oxazol-5-yl)aniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.25 min.; purity: 81%, MS (m/e): 406 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](OC=C)(=O)[CH3:8].[CH2:13]([C:15]1([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)[CH2:18][O:17][CH2:16]1)[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([C:15]1([CH2:19][O:20][CH:21]2[CH2:22][CH2:23][CH:24]([O:27][CH:7]=[CH2:8])[CH2:25][CH2:26]2)[CH2:18][O:17][CH2:16]1)[CH3:14]
Reactant: C=COC(C)=O
Reactant: CCC1(COC2CCC(O)CC2)COC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COC1CCC(OCC2(CC)COC2)CC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Independently, a mixture (100 ml) of sodium carbonate (0.06 mol) with toluene was raised in temperature to 95° C. While maintaining the temperature at 95° C., 4.2 g of vinyl acetate was added dropwise, and 15 minutes later, di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.5 mmol) was added. Next, 4-(3-ethyloxetan-3-yl-methoxy)cyclohexanol (0.05 mol) was added dropwise over 2 hours, followed by performing a reaction in a nitrogen atmosphere while adding 12.6 g of vinyl acetate dropwise and maintaining the reaction temperature at 95° C. After the completion of the dropwise addition and subsequent stirring for 1 hour, the reaction mixture was analyzed by gas chromatography and found that there was formed 3-ethyl-3-(4-vinyloxycyclohexyloxymethyl)oxetane represented by following formula in a yield of 92%. This was subjected to a 1H-NMR (CDCl3) measurement and found that signals specific to vinyl group were observed at 6.5 ppm, 4.2 ppm, and 4.04 ppm, as in Synthesis Example 1.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[C:18]([O:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>CO.N1C=CC=CC=1>[C:18]([O:22][N:23]=[C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)[CH3:2])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NOC(C)(C)C)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of N-(5-acetyl-pyrazin-2-yl)-2,2-dimethyl-propionamide (800.0 mg, 3.62 mmol) in methanol (9 mL) and pyridine (9 mL) was treated with O-(tert-butyl)hydroxylamine hydrochloride (681.1 mg, 5.42 mmol). The resulting reaction mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/9 ethyl acetate/hexanes) afforded N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (1.04 g, 98%) as a white solid: mp 123–124° C.; EI-HRMS m/e calcd for C15H24N4O2 (M+) 292.1899, found 292.1901.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Br[C:18]1[CH:23]=[CH:22][N:21]=[N:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:20]1[CH:19]=[CH:18][C:23]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:22][N:21]=1
Reactant: Brc1ccnnc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccnnc2)cn1
Temperature: 96 °C

Procedure:
To a reaction tube were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1.00 mmol), 4-bromopyridazine (159 mg, 1.00 mmol), Pd(PPh3)4 (57.7 mg, 0.05 mmol) and K3PO4 (424 mg, 2.00 mmol). The tube was subjected to vacuum and back filled with argon. Dioxane (3.0 ml) and water (0.3 ml) were added and the mixture was heated at 96° C. overnight. After cooled to room temperature, the reaction mixture was filtered through celite (washed with ethyl acetate) and concentrated by evaporation. Subsequent silica gel column chromatography with 5% methanol in DCM as eluent gave 5-(pyridazin-4-yl)pyridin-2-amine 134-1 as brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]3[C:23]([CH:26]=[O:27])=[CH:24][CH:25]=[C:14]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]3[C:23]([CH2:26][OH:27])=[CH:24][CH:25]=[C:14]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (1.94 g, 5.40 mmol) in methanol (40 mL) was cooled to 0° C. Sodium borohydride (409 mg, 10.8 mmol) was added in one portion and the cooling bath was removed. After stirring for 1 h at room temperature, the reaction was diluted with saturated aqueous NaHCO3 (50 mL) and DCM (150 mL). The organic layer was separated and the aqueous layer was extracted twice more with DCM (150 mL). The organic layers were combined, dried, filtered and concentrated to give (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methanol (1.66 g) as a white solid. The crude material was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:25]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc3ccccc3c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-naphthalenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.2 mg) with purity >90%. LCMS (pos) m/z 377.2.