Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:19])[C:3]=1[C:4]([OH:6])=O.[F:20][C:21]1[CH:22]=[C:23]([C:27]2([CH2:33][CH2:34][N:35]3[CH:40]4[CH2:41][CH2:42][CH:36]3[CH2:37][CH:38]([N:43]3[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=5[N:45]=[C:44]3[CH3:52])[CH2:39]4)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C(N2CCC(C3C=CC=C(F)C=3)(CCN3C4CCC3CC(N3C5C=CC=CC=5N=C3C)C4)CC2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[Cl:1][C:2]1[C:3]([C:4]([N:30]2[CH2:29][CH2:28][C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=3)([CH2:33][CH2:34][N:35]3[CH:36]4[CH2:42][CH2:41][CH:40]3[CH2:39][CH:38]([N:43]3[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=5[N:45]=[C:44]3[CH3:52])[CH2:37]4)[CH2:32][CH2:31]2)=[O:6])=[C:7]([Cl:19])[CH:8]=[CH:9][C:10]=1[S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2c(Cl)ccc(S(=O)(=O)NC(C)(C)C)c2Cl)CC1
Yield: 17 %

Procedure:
Prepared from a mixture of 2,6-dichloro-3-{[(1,1-dimethylethyl)amino]sulfonyl}benzoic acid 884-5a, 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880). The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 2,4-dichloro-N-(1,1-dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide 5 as a white solid (21 mg, 17% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 250°-252° dec on recrystallization from ethanol.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH3:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34]>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:35][CH2:36][NH:37][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[NH:10][C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:27])[N:6]([CH2:24][CH2:25][CH3:26])[C:7]=3[N:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CN(C)CCN
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CCC)c1=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 13 %

Procedure:
A mixture of 4-(1,3-dipropyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (3.93 g, 0.01 moles) and N,N-dimethylformamide (100 ml) is prepared, cooled to 0° C., treated with thionyl chloride (2.4 g, 0.02 moles), and permitted to warm to ambient temperature with vigorous stirring. The resulting slurry is cooled to 0° C., treated with a solution of unsym dimethylethylenediamine (8.8 g, 0.10 mole) in N,N-dimethylformamide (11 ml) added in one portion, and allowed to warm to ambient temperature. The resulting solution is concentrated on a rotary evaporator. The residue is suspended in water, filtered, recrystallized from ethanol, and dried at 78° to yield 0.60 grams of N-[2-(dimethylamino)ethyl]-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide, mp, 270°-272° C.(d).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[N:5][CH:4]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1>>[CH:8]1([N:7]2[C:3]([CH2:2][S:20][C:18]3[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=3)=[CH:4][N:5]=[CH:6]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: ClCc1cncn1C1CCCC1
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2cncn2C2CCCC2)n1
Yield: 50 %

Procedure:
This example was synthesized from 5-(chloromethyl)-1-cyclopentyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109 to provide 2-{[(1-cyclopentyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (700 mg, 50% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (m, 2H), 1.79 (m, 4H), 2.10 (m, 2H), 2.21 (s, 3H), 4.48 (s, 2H), 4.54 (m, 1H), 6.02 (br, 1H), 6.88 (s, 1H), 7.73 (s, 1H); M+291.
Reaction SMILES: IC1C=NC(N)=C2OC(C3C4C(=CN=CC=4)N(C)N=3)=CC=12.I[C:23]1[CH:28]=[N:27][C:26]([NH2:29])=[C:25]2[O:30][C:31]([C:33]3[N:34]([CH3:42])[N:35]=[C:36]4[C:41]=3[CH:40]=[CH:39][N:38]=[CH:37]4)=[CH:32][C:24]=12.CC1(C)C(C)(C)OB([C:51]2[CH:52]=[N:53][N:54]([CH:56]3[CH2:61][CH2:60][N:59]([C:62](=[O:64])[CH3:63])[CH2:58][CH2:57]3)[CH:55]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:51]2[CH:52]=[N:53][N:54]([CH:56]3[CH2:57][CH2:58][N:59]([C:62](=[O:64])[CH3:63])[CH2:60][CH2:61]3)[CH:55]=2)=[C:24]2[CH:32]=[C:31]([C:33]3[N:34]([CH3:42])[N:35]=[C:36]4[C:41]=3[CH:40]=[CH:39][N:38]=[CH:37]4)[O:30][C:25]=12
Reactant: Cn1nc2cnccc2c1-c1cc2c(I)cnc(N)c2o1
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cn1nc(-c2cc3c(I)cnc(N)c3o2)c2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c6ccncc6nn5C)cc34)cn2)CC1
Temperature: 80 °C
Yield: 16.1 %

Procedure:
A 2:1 mixture of 4-iodo-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-7-amine and 4-iodo-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-7-amine (0.042 g, 0.102 mmol) and 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (0.041 g, 0.13 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.8 mL). The mixture was degassed with nitrogen for 10 min. To this mixture was added potassium carbonate (0.0530 g, 0.383 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane adduct (0.0104 g, 0.0128 mmol), and the mixture was heated to 80° C. for 5 h. Purification of the residue by MDP afforded 0.0143 g (29%) of 1-(4-{4-[7-amino-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)pethanone as a yellow gum (Ex. 363), and 0.0075 g (30%) 1-(4-{4-[7-amino-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone as a yellow gum (Ex. 364). 1-(4-{4-[7-amino-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone: 1H NMR (400 MHz, CD3OD): δ 9.77 (s, 1 H), 9.11 (d, J=5.8 Hz, 1 H), 8.60 (d, J=6.3 Hz, 1 H), 8.35 (s, 1 H), 8.03 (d, J=0.5 Hz, 1 H), 7.97 (s, 1 H), 7.89 (s, 1 H), 4.76-4.67 (m, 1 H), 4.61 (tt, J=4.1, 11.4 Hz, 1 H), 4.51 (s, 3 H), 4.18-4.09 (m, 1 H), 3.44-3.35 (m, 1 H), 2.90 (dt, J=2.5, 13.0 Hz, 1 H), 2.33-2.21 (m, 2 H), 2.20 (s, 3 H), 2.18-2.10 (m, 1 H), 2.10-1.98 (m, 1 H); MS (ESI): 457.37 [M+H]+; HPLC tR=2.23 min. 1-(4-{4-[7-amino-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone: 1H NMR (400 MHz, CD3OD): δ 9.85 (s, 1 H), 8.90 (d, J=6.6 Hz, 1 H), 8.39 (d, J=6.8 Hz, 1 H), 8.35 (s, 1 H), 8.07 (s, 1 H), 7.97 (s, 1 H), 7.91 (s, 1 H), 4.83 (s, 3 H), 4.73-4.65 (m, 1 H), 4.59 (tt, J=4.2, 11.4 Hz, 1 H), 4.16-4.07 (m, 1 H), 3.41-3.32 (m, 1 H), 2.88 (dt, J=2.5, 12.9 Hz, 1 H), 2.29-2.18 (m, 2 H), 2.17 (s, 3 H), 2.16-2.08 (m, 1 H), 2.08-1.95 (m, 1 H); MS (ESI): 457.37 [M+H]+; HPLC tR=2.14 min.
Reaction SMILES: [CH:1]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]3[C:14](O[C:17](=[O:18])[C:10]=3[CH:9]=2)=[O:15])=[CH:5][C:4]2[C:19](O[C:22](=[O:23])[C:3]=2[CH:2]=1)=[O:20].[CH2:24]([NH2:27])[CH:25]=[CH2:26].O>C(O)(=O)C>[CH2:24]([N:27]1[C:19](=[O:20])[C:4]2=[CH:5][C:6]([O:7][C:8]3[CH:9]=[C:10]4[C:17](=[O:18])[N:27]([CH2:24][CH:25]=[CH2:26])[C:14](=[O:15])[C:11]4=[CH:12][CH:13]=3)=[CH:1][CH:2]=[C:3]2[C:22]1=[O:23])[CH:25]=[CH2:26]
Reactant: C=CCN
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Solvent: O
Solvent: CC(=O)O
Product: C=CCN1C(=O)c2ccc(Oc3ccc4c(c3)C(=O)N(CC=C)C4=O)cc2C1=O
Temperature: 115 °C

Procedure:
N,N′-Bis(2-Propenyl)-4,4′-Oxydiphthalimide [ODPA-Bis (N-Allyl)] was synthesized in the following manner. A reaction flask was charged with 4,4′-oxydiphthalic dianhydride (21.7 g, 70 mmoles) in glacial acetic acid solvent (120 ml). Allyl amine (7.98 g, 140 mmoles) was added slowly to the flask while the reaction mixture temperature was controlled at 18° to 22° C. with external cooling. After addition was complete, the reaction mixture was heated to reflux (ca. 115° C.) for 90 min and the solution gradually turned to clear from cloudy. After cooling, the product mixture was poured into water (450 to 500 ml), The resulting mixture was then brought to boiling briefly. After cooling, product precipitated out of solution and was collected by filtration, washed several times with water, and finally with methanol. Product was then dried in a vacuum oven (150 mm Hg, room temperature). The white solid product was obtained in 76%.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[C:9]3[C:10]4([C:30]5[C:21](=[CH:22][C:23]6[O:28][CH2:27][CH2:26][O:25][C:24]=6[CH:29]=5)[O:20][CH2:19]4)[C:11](=[O:18])[N:12]([CH3:17])[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:7])CCC1.Cl[CH2:32]Cl.C(OCC)C>>[CH3:32][N:5]([CH3:1])[C:6]([C:8]1[C:9]2[C:10]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11](=[O:18])[N:12]([CH3:17])[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)NC3CCC3)cccc21
Reactant: ClCCl
Solvent: CCOCC
Product: CN(C)C(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Yield: 37 %

Procedure:
Phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (0.30 g, 0.70 mmol), cyclobutylamine hydrochloride (0.23 g, 2.1 mmol), potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0 mL) were added to a microwave reaction vessel. The reaction was heated at 110° C. for 1 h in a microwave reactor, allowed to cool to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 100% gradient of ethyl acetate in hexanes followed by recrystallization from dichloromethane/diethyl ether to afford N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.045 g, 17%) as a colorless solid: mp 128-129° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.41-7.33 (m, 1H), 7.26-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.51 (s, 1H), 6.20 (s, 1H), 5.46 (d, J=6.65 Hz, 1H), 4.96-4.81 (m, 2H), 4.35-4.01 (m, 5H), 3.25 (s, 3H), 2.27-2.09 (m, 2H), 1.70-1.40 (m, 4H); MS (ES+) m/z 407.0 (M+1). N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.12 g, 37%) was isolated as a byproduct from the synthesis of N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide, obtained as colorless solid: mp 218-221° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.8, 7.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.44 (s, 1H), 6.22 (s, 1H), 5.05 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.8 Hz, 1H), 4.20-4.04 (m, 4H), 3.28 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)ccc2N1CCCCl
Yield: 104.6 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol), Cs2CO3 (0.769 g, 2.36 mmol) and 3-chloro-1-iodopropane (0.354 g, 1.73 mmol) were mixed according to GP5 giving the crude title compound (0.40 g); 1H NMR (CDCl3) δ 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2 H), 2.18-2.11 (m, 2H).
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:20])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH3:19])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH2:17]([C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:20])[NH2:1])[CH:16]=[CH:15][CH:14]=1)[CH2:18][CH3:19]
Reactant: CCCc1cccc(NCC(=O)OC)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cccc(N(N)CC(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Glycine (Intermediate 32, 10 g, 48 mmol) was dissolved in acetic acid (50 ml) and water (5 ml). The solution was cooled to 0° C. and sodium nitrite (3.67 g, 53 mmol) in water (10 ml) was added such that the temperature did not rise above 5° C. The yellow solution turned red then brown, and was stirred at 0° C. for 1 h. The mixture was cooled to -5° C. and zinc powder (12.6 g, 193 mmol) was added very slowly such that the temperature did not rise above 0° C. The mixture was stirred at 0° C. for 5 h then poured into water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined, dried (Na2SO4) organic extracts were concentrated in vacuo to give a dark yellow oil. The crude material was purified by chromatography on silica (500 g) eluted with chloroform-ethanol 98:2 to give the title compound (Intermediate 33, 1.4 g, 13%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16][CH:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]=O>C(O)=O>[CH2:1]([N:8]([CH3:25])[CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16][CH:10]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CNC2COC3C(OCc4ccccc4)COC23)cc1
Solvent: O=CO
Product: CN(Cc1ccccc1)C1COC2C(OCc3ccccc3)COC21
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of N-benzyl-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (9.88 g, 30.36 mmol) in HCOOH (19 mL) was added formalin (2.96 g, 36.43 mmol). After addition, the reaction mixture was stirred at 110° C. overnight and concentrated in vacuo. The residue was adjusted to pH=8 with a saturated Na2CO3 solution and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water (100 mL×3) followed by brine (100 mL), then dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (4.77 g, 46.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[OH:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.90 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (1.48 g, 6.61 mmol). The resulting clear solution was stirred for 16 hours at room temperature. Overnight a white precipitate had formed that was filtered off. The filtrate was evaporated to a white solid, which was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (536 mg, 57%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:24])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N+:19]([O-:40])([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CC[N+]1([O-])CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (22.2 mg, 0.05 mmol) in DCM (10 mL) and MeOH (1 mL) was added MCPBA (11.2 mg, 0.07 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, the combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was purified by RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-1-ethylpiperidine-1-oxide; 1HNMR (MeOD-d4) δ7.91 (s, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 3.28 (m, 4H), 2.91 (m, 1H), 2.32 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.83 (s, 2H), 1.64 (d, 2H), 1.31 (t, 3H); ESMS m/z 460.2 (M+H+).
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[CH:2]12.[N-:14]=[N+:15]=[N-:16].[Na+].O>O1CCOCC1>[N:14]([C@H:3]1[C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]1=2)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)Oc2ccccc2C2OC21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccccc2[C@@H](N=[N+]=[N-])[C@@H]1O
Yield: 82 %

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (3.00g.) and sodium azide (1.23g.; and excess) were refluxed in dioxane (25 ml.) and water (5 ml.) mixture for 24 hours. Dilution with water and extraction via diethyl ether gave trans-4-azido-3,4-dihydro-2,2-dimethyl-2H-benzo[b]-pyran-3-ol (3.06g.) as needles from 60°-80° petroleum ether m.p. 70°-71°. To a solution of the hydroxy azide (2.90g.) in acetone (50 ml.) containing concentrated hydrochloric acid (10 ml.) was added with stirring and in portions, zinc dust (10 g.). Stirring was continued until gas evolution ceased. The zinc was filtered and washed with acetone. The combined washings and filtrate with water and extracted with diethyl ether. Basification of the aqueous layer and isolation via diethyl ether gave trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol (2.70 g.), re-crystallised from ethanol m.p. 138°. Treatment with anhydrous hydrochloric acid as in Example 1 yielded trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride, m.p. 223°-225°.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:17])[CH:13]=[CH:14][C:15]#[N:16].[OH-].[Na+]>ClCCCl>[C:15]([C:14](=[CH:13][N:12]([CH3:17])[CH3:11])[CH:3]=[O:4])#[N:16]
Reactant: CN(C)C=O
Reactant: CN(C)C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN(C)C=C(C#N)C=O
Temperature: 25 °C

Procedure:
36 ml. (0.465 mole) Of N,N-dimethylformamide were stirred at 0° and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0°). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25°), a clear solution resulted which was cooled to -7° with an ice/salt bath. A solution of 30 ml. (0.293 mole) of β-dimethylaminoacrylonitrile in 90 ml. of 1,2-dichloroethane was added dropwise keeping the temperature between -4° to -7°. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 15°-20°. The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, m.p. 143°-144°. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, m.p. 143°-144°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:31]=[CH:30][N:29]=[CH:28][C:21]=5[C:22]5[N:23]([CH:25]=[N:26][N:27]=5)[N:24]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](NN)(=O)C>>[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:31]=[CH:30][N:29]=[CH:28][C:21]=5[C:22]5[N:23]([C:25]([CH3:32])=[N:26][N:27]=5)[N:24]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nn3cnnc3c2cn1
Reactant: CC(=O)NN
Product: Cc1nnc2c3cnccc3c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nn12

Procedure:
The compound of Example 82 was obtained as a pale yellow solid in the same manner as in Example 2 and Example 79 or according to a method similar to it or according to a combination of the method with an ordinary method, but using 4-chloro-1-(4-methoxyphenyl)-pyrido[3,4-d]pyridazine obtained in Example 79 and acetohydrazide in place of formylhydrazide.