Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].CCN(C(C)C)C(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41]([S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:43][C:37]=2[S:36][CH2:35]1>C(Cl)Cl>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@@H:3]([CH2:2][NH:1][S:44]([C:41]3[CH:42]=[CH:43][C:37]4[S:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=4[CH:40]=3)(=[O:46])=[O:45])[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(F)c(CCN3C[C@H](CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (225 mg, 0.703 mmol) in DIPEA (188 μL, 1.05 mmol) and DCM (7 mL) at 0° C. was added 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (210 mg, 0.845 mmol) in one portion. The solution stirred for 0.5 h and was concentrated. The resulting residue was purified by column chromatography (silica, 2-4% MeOH in DCM (1% NH OH)) yielding the title compound (290 mg, 75%) as a white foam: LC/MS (ES) m/e 548 (M+H); H NMR (CD OD, 400 Hz) δ 8.65 (s, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.45-7.48 (m, 2H), 7.20 (d, J=9.1 Hz, 1H), 4.28-4.31 (m, 1H), 4.14 (s, 3H), 3.55 (s, 2H), 3.42-3.46 (m, 2H), 3.21-3.23 (m, 1H), 3.05-3.15 (m, 1H), 2.91-3.05 (m, 2H), 2.86-2.90 (m, 2H), 2.51-2.62 (m, 2H), 2.33-2.4 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]([F:14])([F:13])[F:12].[C:15]([CH2:17][CH2:18][N:19]([CH:24]=O)[CH2:20]C(O)=O)#[N:16]>C(OC(=O)C)(=O)C>[C:15]([CH2:17][CH2:18][N:19]1[CH:24]=[C:10]([C:11]([F:14])([F:12])[F:13])[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:20]1)#[N:16]
Reactant: N#CCCN(C=O)CC(=O)O
Reactant: FC(F)(F)C#Cc1cccc(Cl)c1Cl
Solvent: CC(=O)OC(C)=O
Product: N#CCCn1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1

Procedure:
23.9 g of 2,3-dichloro-(3,3,3-trifluoropropyn-1-yl)-benzene and 15.6 g of N-(2-cyanoethyl)-N-formylglycine are dissolved in 100 ml of acetic anhydride, and the solution is refluxed for 24 h. The mixture is concentrated by evaporation under reduced pressure; the residue is then taken up in toluene, and purified by chromatography through silica gel. The solvent is evaporated off, and from the eluate is obtained 1-(2-cyanoethyl)-3-(2,3-dichlorophenyl)-4-trifluoromethylpyrrole, m.p. 83°-85° C. from ether/hexane (compound No. 3.28).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH:28]=[CH:29][N:30]=[C:23]3[CH2:22][O:21][C:20]=2[C:19]=1[C:31]([O:33]C)=[O:32])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH:28]=[CH:29][N:30]=[C:23]3[CH2:22][O:21][C:20]=2[C:19]=1[C:31]([OH:33])=[O:32])(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1nccn1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1nccn1-2
Yield: 67.8 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (Intermediate 24, 0.138 g) and lithium hydroxide monohydrate (0.421 g) in dioxane (8 mL) and water (2 mL) was irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and concentrated in vacuo. The residue was triturated with a solution of methanol in DCM (15%) and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30%. The resultant gum was triturated with ethyl acetate and the solid was collected by filtration to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylic acid (0.091 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.[NH2:10][NH2:11]>C(O)(C)C>[F:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Fc1cccc(F)n1
Solvent: CC(C)O
Solvent: O
Product: NNc1cccc(F)n1
Yield: 76.8 %

Procedure:
2,6-Difluoropyridine (25 g), isopropyl alcohol (100 ml) and hydrazine hydrate (40 ml) were mixed and refluxed with heating for 3 hours. The isopropyl alcohol was evaporated under reduced pressure, and the residue was added with water. The deposited crystals were collected by filtration, washed with water and dried to obtain 6-fluoro-2-hydrazinopyridine (21.2 g, yield: 76.8%). Coloration was observed during drying, and accordingly, the product was used for the next reaction immediately after the drying.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=[C:12]4[C:28]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[CH:31]=[CH:30][N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[C:12]4[C:28]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[CH:31]=[CH:30][N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1cc(C2CC2)nc(-c2c[nH]c3ccc(-c4nnc(C5CC5)o4)cc23)n1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
2-Cyclopropyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (78.6 mg, 0.158 mmol) in a 5 mL glass microwave tube, was suspended in dioxane (1.5 mL). The suspension was treated with NaOH 1.000 n (2 mL, 2.000 mmol) (Fluka Analytical). The tube was sealed and the contents were stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 10 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (0-10% MeOH in DCM) to give 2-cyclopropyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazole (19.2 mg, 0.056 mmol, 35.4%) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 344.0 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 11.99 (br. s., 1H), 9.10 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.28 (s, 1H), 7.77-7.84 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.20 (d, J=5.1 Hz, 1H), 2.29-2.38 (m, 1H), 2.09-2.20 (m, 1H), 1.12-1.33 (m, 8H).
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.C(N1CCN(C2C=CC(N)=C(C)C=2)CC1)C.C(N1CCNCC1)C.CC1C=CC(N2CCOCC2)=CC=1N.[CH2:79]([N:81]1[CH2:86][CH2:85][N:84]([C:87]2[CH:92]=[CH:91][C:90]([NH:93][C:94]([N:96]3[C:100]4[N:101]=[C:102]([N:130]5[CH2:135][CH2:134][O:133][CH2:132][CH2:131]5)[N:103]=[C:104]([C:105]5[CH:106]=[N:107][C:108]([N:111](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:109][CH:110]=5)[C:99]=4[CH2:98][CH2:97]3)=[O:95])=[C:89]([CH3:136])[CH:88]=2)[CH2:83][CH2:82]1)[CH3:80]>>[CH2:79]([N:81]1[CH2:86][CH2:85][N:84]([C:87]2[CH:92]=[CH:91][C:90]([NH:93][C:94]([N:96]3[C:100]4[N:101]=[C:102]([N:130]5[CH2:131][CH2:132][O:133][CH2:134][CH2:135]5)[N:103]=[C:104]([C:105]5[CH:110]=[N:109][C:108]([NH2:111])=[N:107][CH:106]=5)[C:99]=4[CH2:98][CH2:97]3)=[O:95])=[C:89]([CH3:136])[CH:88]=2)[CH2:83][CH2:82]1)[CH3:80]
Reactant: CCN1CCN(c2ccc(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(C)c2)CC1
Agent: CCN1CCN(c2ccc(N)c(C)c2)CC1
Agent: CCN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(c2ccc(NC(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c(C)c2)CC1
Yield: 76 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg), and 4-(4-ethyl-piperazin-1-yl)-2-methyl-phenylamine (67 mg) obtained using 1-ethyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-240, instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazin-1-yl)-2-methyl-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-242) (110 mg, 76%).
Reaction SMILES: [CH3:1]C1CC(C=O)CC=C1.C[CH:11]1[CH2:16][CH:15]([CH:17]2[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH2:14][CH:13]=[CH:12]1>>[CH3:1][C:12]1[CH2:11][CH2:16][CH:15]([CH:17]2[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH2:14][CH:13]=1
Reactant: CC1C=CCC(C2OC(=O)NC2=O)C1
Reactant: CC1C=CCC(C=O)C1
Product: CC1=CCC(C2OC(=O)NC2=O)CC1

Procedure:
By the same three step procedures of the preceding Examples, 5-methyl-3-cyclohexene-1-carbaldehyde is inverted to 5-(5-methyl-3-cyclohexen-1-yl)oxazolidine-2,4-dione.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1)(=O)=O.N#N.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)(O)[O-].[Na+]>C1COCC1.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>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C1
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: N#N
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)nc2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (400 mg, 0.882 mmol) in THF (10 mL) was purged with N2 for 5 min and then was added potassium carbonate (610 mg, 4.41 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (233 mg, 1.059 mmol), Pd(PPh3)4 (10.20 mg, 8.82 μmol) and water (0.1 mL). The reaction mixture was heated and stirred at 70° C. overnight. The reaction mixture was poured to saturated sodium bicarbonate solution and extracted with ethyl ether. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/DCM) to yield the desired product (180 mg, 54.6%). LCMS (m/z): 262.2 (MH+), 0.598 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[CH3:21][N:22]1[CH:26]=[C:25](I)[CH:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=1
Reactant: Cn1cc(I)cn1
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
A solution of 2-(2-methoxy-4-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (635 mg, 1.79 mmol) and 1-methyl-4-iodo-1H-pyrazole (745 mg, 3.58 mmol) in ethanol (11 mL) and toluene (26 mL) was purged with argon for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (73.0 mg, 0.89 mmol) was added and the mixture was heated to 80° C., then 2M aqueous sodium carbonate solution (14 mL) was added and stirring at 80° C. was continued for further 24 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. Column chromatography (20 g silica, dichloromethane) afforded the title compound (245 mg, 58%) as a yellow solid. MS ISP (m/e): 234.0 [(M+H)+]. 1H NMR (DMSO, 300 MHz): δ (ppm)=8.35 (s, 1H), 8.08 (s, 1H), 7.85 (m, 3H), 4.03 (s, 3H), 3.90 (s, 3H). Mp 132-134° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](B1OC(C)(C)C(C)(C)O1)=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:36]2[N:56]=[CH:57][C:58](I)=[C:35]2[N:34]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:45])[CH3:46])[N:36]2[N:56]=[CH:57][C:58]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:35]2[N:34]=1
Reactant: CC1(C)OB(c2cnc3ccc(F)cc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (3.65 mmol, 996.4 mg), K3PO4 (9.12 mmol, 1933.6 mg), and PdCl2(dppf).CH2Cl2 (0.30 mmol, 248 mg) was added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.04 mmol, 1684.3 mg) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 80° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=3.34 Min (5 min run, UV254nm). Mass calculated for, M+ 573.2, observed LC/MS m/z 574.2 (M+H).
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([CH3:12])=[CH:5][C:4]=1[CH:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2.N1CCCCC1>C(Cl)Cl>[CH:14]12[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH:13]1[C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2])[CH2:22]2
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(C)cc1C1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 1.05 mmol) in CH2Cl2 (5 mL) was added piperidine (1.0 mL). The solution was stirred at room temperature for 1 h, adsorbed onto silica gel under reduced pressure and purified by flash chromatography on silica gel (0-15%, EtOAc-Hexanes) to provide 2-admantyl-4-methyl-5-nitrophenol (231 mg, 77%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CC(C)=[O:34].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:34])=[O:8])=[CH:11][CH:12]=2)[CH2:20][CH2:21]1)([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(C(=O)O)cc2)CC1
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of 20-4 (230 mg, 0.51 mmol) in acetone (5 mL) at 0° C. was added Jones Reagent dropwise until the color changed from green to orange. The excess Jones Reagent was quenched with isopropanol (1 mL) followed by stirring for 15 min. The reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated to give 20-5 as a yellowish oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][Cl:17])[CH:9]=[CH:8][N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:17][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12]
Reactant: CC(=O)OCc1nccc(OCCCCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(OCCCCl)ccnc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of 2.7 g (10.4 mmol) of the oil from stage b) in 25 ml of methanol is treated with 1.5 g (20.8 mmol) of potassium carbonate and stirred at room temperature for 4 h. The salts are then filtered off and the filtrate is concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia=19:1:0.4). 1.3 g (57%) of the title compound are isolated as a colorless oil which partially crystallizes after standing for a relatively long time. This product is employed directly for the further reaction (Example 15) without additional purification.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[C:3]1[C:27]#[N:28].P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:2]1[C:3]([C:27]#[N:28])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccccc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of crude 6-oxo-4-(4-phenoxyphenyl)-2-phenyl-1,6-dihydropyrimidine-5-carbonitrile and phosphorus oxychloride (4 mL) was stirred at 90° C. for 1 h, concentrated, dissolved in dichloromethane (10 mL) and water (20 mL) and carefully neutralized with solid potassium carbonate until CO2 bubbling stopped. The mixture was extracted with dichloromethane (3×5 mL). The combined extracts were dried (MgSO4) and concentrated to give crude 4-chloro-6-(4-phenoxyphenyl)-2-phenylpyrimidine-5-carbonitrile as tan solid. The crude material was taken to next reaction without purification. MS (ES+) m/z: 384 (M+H); LC retention time: 5.190 min (analytical HPLC Method 13 except with 2 min hold at 100% B).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:31])([CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[CH3:23])=[CH:15][C:10]=1[NH:11]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O>[NH2:11][C:10]1[CH:15]=[C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:23])([CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[CH3:31])[CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(C(O)CNC(C)(C)CCn2ccnc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CCn1ccnc1)NCC(O)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
A mixture of 15 gm of 2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-acetanilide (m.p. of the dioxalate 160°-163° C.), 18.5 gm of KOH, 80 ml of alcohol and 15 ml of water was refluxed for 24 hours, and the resulting 1-(3-amino-4-benzyloxy-phenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol was isolated as the trioxalate (m.p. 95°-100° C.). Aqueous ammonia were used to liberate the base which was reacted with potassium cyanate to form 1-{2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl}-urea (m.p. 142°-143° C.). Catalytic hydrogenation of 5.1 gm of this compound in 100 ml of methanol with palladium charcoal as the catalyst yielded 3.5 gm of 1-{2'-hydroxy-5'-[1-hydroxy-2-[-4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl}-urea, whose sulfate of the formula ##STR76## had a melting point of 243°-244° C. The yield was 70% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Product: CCC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and propionyl chloride (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 370.1807, Calcd for M+: 370.1805.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH:21]([CH3:27])[C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:12]1([NH:11][C:4]2[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH:21]([CH3:27])[C:22](=[O:26])[NH:23]4)=[CH:18][CH:17]=3)[N:3]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CC2)c2occc2n1
Reactant: CC1Cc2ccc(N)cc2NC1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1Cc2ccc(Nc3nc(NC4CC4)c4occc4n3)cc2NC1=O
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A flask was charged with 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.38 g, 1.8 mmol, Example #3, Step C), 7-amino-3-methyl-3,4-dihydroquinolin-2(1H)-one (0.30 g, 1.7 mmol), K2CO3 (0.38 g, 2.7 mmol), Pd2dba3 (0.17 g, 0.18 mmol) and X-Phos (0.17 g, 0.36 mmol) in 1,4-dioxane (20 mL). The flask was evacuated and purged with N2 (3×), and the mixture was heated to about 100° C. overnight. The mixture was cooled to rt and concentrated under reduced pressure to a residue. The residue was purified by preparative TLC (1.0 mm plate), eluting with DCM/MeOH (12:1). The product obtained was further purified by preparative HPLC (Table 2, Method r) to give 7-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-3,4-dihydroquinolin-2(1H)-one (0.15 g, 24%): LC/MS (Table 2, Method g) Rt=1.04 min; MS m/z: 177 (M+H)+. Syk IC50=A