Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.S(Cl)(Cl)=O.Cl.[N:19]1C=C[CH:22]=[CH:21][CH:20]=1>N#N.CCCCCC.C(O)(=O)C>[CH2:20]([NH:19][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)=[O:10])[C:21]#[CH:22]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: N#N
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: C#CCNC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Terephthalic acid mono methyl ester (0.775 g) was dissolved in dry pyridine (10 ml) in a N2 atmosphere. The solution was cooled in an ice-water bath, and thionyl chloride (0.44 ml) was added dropwise. The mixture was warmed to room temperature and was stirred for 1 h to give a pale brown suspension. The mixture was re-cooled in an ice-water bath, and a suspension of proparglyamine hydrochloride (413 mg) in pyridine was added rapidly. The mixture was warmed to room temperature and was stirred for 18 h to give a dark solution. The solvent was evaporated in vacuo to give a dark brown gum, which was dissolved in Ea/hexane/acetic acid (1:1:1% v/v) and flash chromatographed using the same solvent system to give a yellow sludge, which was triturated with ER to give the title compound as a white solid, (0.544 g), m.p. 151.5°-153°.
Reaction SMILES: I[Si](C)(C)C.C[O:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>ClCCl>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]=[O:7])=[CH:15][CH:14]=1
Reactant: CO/C=C/c1ccc(-c2cnccn2)cc1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
Iodotrimethylsilane (0.46 mL, 3.30 mmol) was added dropwise to a suspension of the product from step A (175 mg, 0.82 mmol) and solid NaHCO3 (100 mg, 1.18 mmol) in dichloromethane (5 mL) at rt. The reaction mixture was stirred at rt for 18 h, carefully quenched with sat. aq. NaHCO3, extracted with dichloromethane, dried with Na2SO4, and concentrated in vacuo to give 110 mg (68%) of the title compound. The product was >95% pure as judged by its 1H NMR spectrum, and was used immediately in the next step without further purification. MS 199 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[S:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:35]3([OH:38])[CH2:36][CH2:37][S:32][CH2:33][CH2:34]3)=[N:10][CH:9]=2)[CH:5]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: O=C1CCSCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1.50 g, 4.46 mmol) in THF (10 mL) was added dropwise to a solution of lithium diisopropylamide (7.43 ml, 13.38 mmol) in THF (15 mL) at −78° C. and the resulting mixture was stirred at −78° C. for 30 minutes. Tetrahydrothiopyran-4-one (0.57 g, 4.91 mmol) in THF (5 mL) was then added, the dry ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was quenched with aqueous saturated NH4Cl solution, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, gradient elution 0 to 30% EtOAc in toluene) afforded 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]tetrahydro-2H-thiopyran-4-ol (1.21 g, 2.67 mmol, 60% yield) as a yellow foam. MS ESI: [M+H]+ m/z 453.0.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH:30]([N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1)([CH3:32])[CH3:29]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A suspension of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (59.8 mg, 0.152 mmol) in 1,2-dichloroethane was treated with acetone (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred for one hour at ambient temperatures, under nitrogen, treated with sodium triacetoxyborohydride (66.3 mg, 0.313 mmol), stirred for 4 hours, diluted with chloroform and washed sequentially with 1.0 N sodium hydroxide and brine, treated with methanol to aid in solubility, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.2% ammonium hydroxide/2.0% methanol in chloroform to afford 5-(1-isopropyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a very light yellow foam, 45.4 mg (68.6% yield). The foam was dispersed in methanol and chloroform, treated with isopropanolic HCL and concentrated in vacuo at 84° C. for 14 hours to give the title product as a light brown foam, 42.1 mg, Mass spectrum (+APPI, [M+H]+) m/z 436. 1HNMR (500 MHz, DMSO-d6): δ14.22 (d, 1H, J=4.76 Hz), 10.39-11.06 (m*, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.55-8.59 (m, 1H), 8.27 (d, 1H, J=8.18 Hz), 8.04 (d, 1H, J=7.93 Hz), 7.71-7.75 (m, 1H), 7.56-7.64 (m, 3H), 7.25-7.28 (m, 1H), 7.09-7.15 (m, 1H), 5.19-5.22 (m, 1H), 3.39-3.87 (m*, 4H), 3.20-3.25 (m*, 1H), 2.02-2.53 (m, 2H), 1.24-1.28 ppm (m, 6H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])/[CH:31]=[CH:32]/C)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.NC1N=CN=C2N(C3CCCN(S(C=C)(=O)=O)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCCN(C(=O)C#C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCN(C(=O)C=C)CC3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@@H]3CCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@H]3CCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@@H]3CCCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@H]3CCCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCCN(C(=O)/C=C/CN(C)C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH:31]=[CH2:32])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: C/C=C/C(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C#CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C=CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Agent: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Product: C=CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Procedure:
(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 12); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Product: CCCC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Yield: 131.9 %

Procedure:
4-Methoxyaniline (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (57 g) were heated together on a rotary evaporator (bath temp 100°) for 1 hour to give ethyl 2-butyryl-3-(4-methoxyphenylamino)acrylate (78 g) as an orange oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]2[C:9](=[O:12])[NH:10][N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:4]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([F:49])([F:48])[F:47])=[N:44][CH:45]=1>CCOC(C)=O>[CH3:1][NH:2][C:3]1[N:8]2[C:9](=[O:12])[N:10]([CH2:39][C:40]3[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][CH:41]=3)[N:11]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:4]=1
Reactant: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of crude 5-(methylamino)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, DMF (0.5 mL), and potassium carbonate (38 mg, 0.28 mmol) was added 5-chloromethyl-2-(trifluoromethyl)pyridine (18 mg, 0.09 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was then diluted with EtOAc, washed with water and saturated aqueous NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by preparative reverse phase HPLC to obtain 25 mg (51% over two steps) of the title compound as a light yellow solid. HPLC/MS: retention time=4.40 min, [M+H]30 =545.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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>[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:4]2[CH:5]=[C:6]([Cl:32])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
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: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.52 g, 0.8 mmol), 4-methoxycarbonylphenylboronic acid (0.174 g, 0.966 mmol), sodium carbonate (0.256 g, 2.41 mmol) in THF (20 mL) and water (6 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.046 g, 0.04 mmol) and raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.49 g (96%) of the titled product. MS (m/z): 633 (M+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:12])[N:10]=2)[CH:7]=1
Reactant: O=c1[nH]nc2ccc(I)cn12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1nc2ccc(I)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-iodo[1,2,4]triazolo[4,3-α]pyridin-3(2H)-one (Intermediate 13, 360 mg, 1.379 mmol) in anhydrous dimethylformamide (DMF, 4 mL) was added sequentially cesium carbonate (1.35 g, 4.14 mmol) and iodomethane (0.52 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, and the precipitated solids were removed by filtration. The filtrate was washed with saturated aqueous brine, dried (magnesium sulfate), and concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 3% methanol/dichloromethane) to afford the title compound. LC/MS 257.8 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:10][C:11]([N:13]([CH2:29][C:30]([O:32]C)=O)[C@@H:14]([CH2:24][O:25][CH2:26][O:27][CH3:28])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:12])[CH:8]=[CH2:9].Cl.[Cl-].[Na+]>C1COCC1>[CH3:28][O:27][CH2:26][O:25][CH2:24][C@H:14]1[CH2:15][CH:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:30](=[O:32])[CH2:29][N:13]1[C:11]([O:10][CH2:7][CH:8]=[CH2:9])=[O:12]
Reactant: C=CCOC(=O)N(CC(=O)OC)[C@H](CCC(=O)OC(C)(C)C)COCOC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(=O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 54.7 %

Procedure:
To a suspension of potassium tert-butoxide (299 mg, 2.66 mmol) in THF (26 ml) was added tert-butyl (4R)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino}-5-(methoxymethoxy)pentanoate (0.52 g, 1.33 mmol) in THF (2.5 ml) and the mixture was stirred for 1 minutes. After cooling to 0° C., the reaction mixture was poured into diluted hydrochloric acid. The solution was adjusted to pH about 3 and after adding a saturated aqueous sodium chloride solution, the solution was extracted with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (15 g) chromatography (Hexane/ethyl acetate: 3/1) to give 1-allyl 4-tert-butyl (2R)-2-[(methoxymethoxy)methyl]-5-oxo-1,4-piperidinedicarboxylate (0.26 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:25](O)=[O:26])=[O:21].CCN=C=NCCCN(C)C.CCN(CC)CC>ClCCl>[CH:32]([O:31][C:30]1[CH:29]=[CH:28][C:24]([C:25]([N:17]2[CH2:18][CH2:19][C:14]3([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[O:13]3)[CH2:15][CH2:16]2)=[O:26])=[CH:23][C:22]=1[CH:20]=[O:21])([CH3:34])[CH3:33]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C=O
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (250 mg, 0.76 mmol), 3-formyl-4-isopropoxy-benzoic acid (160 mg, 0.76 mmol), EDCI (160 mg, 0.84 mmol), and Et3N (430 μL, 3.1 mmol) were combined in dichloromethane (7.1 mL) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a 1 M HCl (×2), a saturated aqueous solution of NaHCO3 (×2) and a saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in dichloromethane) to yield 2-isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde (117 mg, 34%) as a light yellow solid. ESI-MS m/z calc. 445.2, found 446.3 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[NH:3][S:4](=[O:14])(=[O:13])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]1[CH2:21][CH2:20]N[CH2:18][CH2:17]1>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([N:1]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: NC1=Nc2ccc(Cl)cc2S(=O)(=O)N1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Temperature: 185 °C
Yield: 68.7 %

Procedure:
A mixture of 3.0 g of 3-amino-7-chloro-2H-1,2,4-benzothiadiazine 1,1-dioxide and 2.5 g of 1-methylpiperazine is heated at 185° C. in a sealed tube for 8 hours. After removal of the remaining 1-methylpiperazine by distillation under reduced pressure, the residual solid is recrystallized from a mixture of dimethylformamide and water to give 2.8 g of the desired product, m.p. above 300° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH:7]=[CH:8][Sn:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[C@@H:3]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].[CH:31](N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][O:29][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:3]1[C@H:4]([CH:7]=[CH:8][Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Wang resin bound trans-7-[2-Oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid. A dichloromethane (5 mL) solution of trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid of Step E (6.35 g, 12.05 mmol, 3 eq) was added to the Wang resin (5.66 g, 4.02 mmol, 1 eq) along with diisopropylethylamine (6.23 g, 48.20 mmol, 12 eq). The mixture was allowed to swell for 1 hour, and EDC (2.31 g, 12.05 mmol, 3 eq) was added followed by 4-dimethylaminopyridine (catalytic amount about 20 mg). The mixture was stirred at room temperature overnight. The resin was filtered, washed with dichloromethane (20 mL×2), repeatedly swollen with dichloromethane (20 mL) and shrunk with methanol (20 mL). The resin was washed with diethyl ether (20 mL×3) and dried on a filter funnel attached to a water aspirator for 30 minutes. Further drying under high vacuum for 5 hours provided the title compound as a free-flowing yellow resin.
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH3:18])=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.[C:34]([Zn]C#N)#[N:35].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC(N(C)C)=O.CCOC(C)=O.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].[Zn]>[NH2:24][C:11]1[C:12]([N:17]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH3:18])=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[C:2]([C:34]#[N:35])=[CH:7][N:6]=2)[CH:10]=1
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: N#C[Zn]C#N
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: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Temperature: 95 °C
Yield: 52.5 %

Procedure:
N4-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N1-(2-dimethylaminoethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 33, 120 mg, 0.26 mmol), dicyanozinc (18.11 mg, 0.15 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (24.50 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.5 mg, 0.03 mmol) and zinc powder (1.681 mg, 0.03 mmol) were suspended in degassed DMA (1.1 mL) and sealed into a microwave tube. The mixture was then heated to 95° C. for 1 h in a microwave. The cooled mixture was then diluted with EtOAc (50 mL) and washed with sat. NaHCO3 (20 mL), water (20 mL), and sat. brine (10 mL). The organic solution was then concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (36 mg, 31%) as a yellow gum; 1H NMR: (CDCl3) 2.41 (6H, s), 2.60 (2H, s), 2.72 (3H, s), 3.07 (2H, t), 3.86 (3H, s), 6.72 (1H, s), 7.02 (1H, t), 7.41-7.53 (1H, m), 7.80 (2H, d), 8.60 (2H, d), 8.70 (1H, d), 9.09 (1H, s); m/z: ES+ MH+ 458.30.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:27]([O:31][CH2:32]Cl)([CH2:29][CH3:30])[CH3:28]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:32][O:31][CH:27]([CH2:29][CH3:30])[CH3:28])[C:19](=[O:24])[N:18]([CH2:25][CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(C)OCCl
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)OCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC)c1=O
Reaction time: 1 h

Procedure:
2.45 g (18.0 mmol) of potassium carbonate were added at 60° C. to a suspension of 3.0 g (11.0 mmol) of 7-benzyl-3-ethylxanthine (prepared according to Example 5a) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.77 g (14.0 mmol) of sec-butoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 5 hours. 0.7 g (5.5 mmol) of sec-butoxymethyl chloride was then added again and the mixture was stirred for a further 3 hours. 12 ml of water and 5 ml of methanol were then added and the mixture was stirred at 50° C. for 2 hours. A further 60 ml of water were then added, the mixture was extracted three times using 200 ml of methyl tert-butyl ether each time, and the combined organic phases were washed with 200 ml of water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2).