Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20](OCC)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:11][CH:10]=1.C(O)C>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Temperature: 92.5 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Piperidine (1.84 g, 21.63 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 0.6 g, 2.16 mmol) in a ethanol (10 ml) in a tube at 25° C. under nitrogen atmosphere. The tube was agitated for about 15 minutes under nitrogen and was sealed. The reaction mixture was heated at 90-95° C. for 15 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml). The mixture was washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.50 g, 73.0%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]4[CH2:25][O:24]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2.[CH3:28][S:29]([O-:31])=[O:30].[Na+]>CS(C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2
Reactant: CS(=O)[O-]
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(OCC5CO5)c(C)c34)ccc2[nH]1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCC(O)CS(C)(=O)=O)c(C)c34)ccc2[nH]1
Yield: 45.4 %

Procedure:
A mixture of Example 2 (10 mg, 0.027 mmol) and sodium methanesulfinate (120 mg, 85%, 1.0 mmol) in DMSO was heated at 105° C. for 1 hr. The mixture was concentrated and purified by chromatography on silica gel eluting with 5% methanol in ethyl acetate to provide the title compound (5.5 mg, 45%) as a white solid. MS: (M+H)+=449.3
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCc1cccc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(CC)n1)C(=O)OCC
Temperature: 100 °C

Procedure:
The crude product from Example 3b was combined with 2-ethoxymethylene-malonic acid diethyl ester (6.6 mL, 0.032 mol) and the mixture heated under a N2 atmosphere in an oil bath at 100° C. for 2 h. Purified by flash chromatography on silica gel eluting with EtOAc/hexane giving the title compound (7.16 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11]C2CCC(C(O)=O)CC2)=[CH:6][CH:5]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([NH:11][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]([F:34])([F:35])[F:22])=[CH:30][CH:29]=2)=[O:33])[CH:7]2[CH2:8][CH2:9][CH:4]([C:3]([OH:21])=[O:2])[CH2:5][CH2:6]2)=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CNC2CCC(C(=O)O)CC2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCC(C(=O)O)CC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The above 4-[(4-carboxycyclohexylamino)methyl]benzoic acid methyl ester (1 g, 3.4 mmol) was dissolved in acetonitrile (25 mL) and 4-trifluoromethoxyphenylisocyanate (0.73 g, 3.4 mmol) was added. Stirring overnight at 50° C. followed by cooling to 25° C. formed a precipitate, which was removed by filtration. The filtrate was concentrated in vacuo and the product purified by chromatography using silica as stationary phase and a mixture of ethyl acetate, methanol and acetic acid as eluent (15:1:0.1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 89 %

Procedure:
224 mg Of octene-1, 329 mg of triethoxysilane and 400 mg of toluene were placed in a glass reaction tube and 0.004 ml of acetic acid was then added to the tube. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of the octene-1 was 96% and n-octyltriethoxysilane was produced at a yield of 89%.
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8](N)=[N:9][CH:10]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:7]([O:12][CH3:13])=[N:6][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:10][N:9]=2)[N:20]=1
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>O1CCCC1>[SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.17 h

Procedure:
2.24 g of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]-pyrimidine-2-carboxylate were suspended in 350 ml of tetrahydrofuran and treated at 2° within 15 minutes with 40 ml of a 1M diisobutylaluminium hydride/hexane solution. The reaction mixture was stirred at 2° for 10 minutes and subsequently treated with ice. The reaction mixture was concentrated extensively, the residue was taken up in 30 ml of water, and the solution was acidified to pH 1.2 with concentrated hydrochloric acid. The solid was collected by filtration and dried in a high vacuum. There was obtained 7-mercapto-5-methyl-s-tria-zolo[1,5-a]pyrimidine-2-methanol of melting point 233° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:11](=[O:23])[C:10]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile (Step 1) (2.76 g, 9.13 mmol) was suspended in acetonitrile (50 mL) and cooled in an ice-bath. N-bromosuccinimide (1.71 g, 9.54 mmol) was added. Once the addition was complete the cooling bath was removed. After stirring for 45 minutes the reaction was diluted with acetonitrile and solids were collected by filtration to give a white solid (3.13 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=8.5 Hz, 2H), 7.84 (d, J=7.9 Hz, 1H), 7.66 (d, J=8.5, 2H), 7.50-7.37 (m, 5H), 6.63 (d, J=7.9 Hz, 1H), 5.41 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:11][N:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C.[CH2:29]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:29]([C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:19][CH2:18][CH2:17][C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][NH:11][C:7]=2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NCCc1c(-c2cccs2)n[nH]c1-c1cnccn1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cnccn2)cc1
Reaction time: 3 h
Yield: 30580.7 %

Procedure:
A mixture of the 2-(5-Pyrazin-2-yl-3-thiophen-2-yl-1H-pyrazol-4-yl)-ethylamine 1D (7 mg, 25.8 μmol), diisopropylethylamine (9.0 μl, 51.6 μmol) and 4-n-pentylbenzenesulfonyl chloride (7.0 mg, 28.3 μmol) in dichloromethane (1 mL) was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product dissolved in methanol (2 ml) and was purified by prep-HPLC. Removal of the solvent in vacuo provided the title compound (3.8 g mg, 41% yield). MS m/e 481; HPLC retention time 3.54 min (Method A).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[N:14][C:12]=2[N:13]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:32](=[O:34])[CH3:33])[CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccnc(N)c3)nc2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccn1
Temperature: 70 °C

Procedure:
To a 0.1 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (example lcz) (1 equiv) in pyridine was added acetic anhydride (3 equiv). A reflux condenser was attached to the reaction vessel which was then heated to 70° C. for 2 days. Upon completion, the reaction was purified, in its crude for by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccc(CCBr)cc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccc(Cl)cc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-4-chlorobenzene and isolated as white solid. MS (m/e): 421.3 (MH+).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1>CC(O)C.CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]5[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=5)[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)c1
Yield: 35 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 14 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 35% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)(=O)=O.[NH:40]1[CH:44]=[CH:43][C:42](B(O)O)=[N:41]1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>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>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][NH:27][C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:42]3[NH:41][N:40]=[CH:44][CH:43]=3)=[CH:8][CH:9]=2)[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[CH:23]([CH3:24])[CH3:25])=[O:37]
Reactant: OB(O)c1cc[nH]n1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccn1
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: [Cl-]
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3ccn[nH]3)cc2n1Cc1ccccn1

Procedure:
Following General Procedure BB, 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 29 mg, 0.05 mmol), was reacted with 1H-pyrazole boronic acid (9 mg, 0.08 mmol), LiCl (7 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (3 mg, 0.003 mmol) to yield the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1ccnc(Sc2ccc(CO)cc2)c1
Product: CC(=O)c1ccc(OCc2ccc(Sc3cc(C#N)ccn3)cc2)c(C)c1O
Yield: 69.4 %

Procedure:
Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.10 g, 4.54 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (754 mg, 4.54 mmol) affords the title compound (1.23 g, 69%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17].C[N+]1([O-])CCOCC1>CC#N>[CH3:17][C:3]1([CH3:18])[C:2](=[O:1])[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of phenylmethyl (4R)-4-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate (1.4088 g, 5.651 mmol) in MeCN (50 mL) was added N-methylmorpholine-N-oxide (0.861 g, 7.350 mmol) and tetra-N-propylammonium perruthenate (0.099 g, 0.282 mmol). The solution was stirred for 90 min, concentrated in vacuo, and purified directly by silica gel chromatography (20% EtOAc in hexanes) to give phenylmethyl 3,3-dimethyl-4-oxo-1-pyrrolidinecarboxylate (1.1321 g, 79%) as a colorless oil. LCMS: (M+Na)+: 270.4.
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][C:27](=O)[CH2:26][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C@@H:27]2[CH2:26][CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[N:13][C:14]([O:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:29][CH2:28]2)[CH2:34][CH2:33]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone (Intermediate Al) (0.90 g, 0.0022 mol), N-methylpiperazine (0.676 g, 0.0067 mol) and acetic acid (0.405 g, 0.0067 mol) in 1,2-dichloroethane (40 mL) was stirred for 10 min and sodium triacetoxyborohydride (0.62 g, 0.0029 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.30 g, 0.0014 mol) was added. The mixture was stirred for another 48 hours, the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer further extracted with dichloromethane twice (50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (89:10:1) as a mobile phase to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AJ): TLC (dichloromethane/triethylamine 9:1) Rf 0.29 and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: TLC (dichloromethane/triethylamine=9:1) Rf 0.14.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:24][O:25][C:26]1[C:34]2[C:33]([NH2:35])=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]([CH2:36][C:37]2[CH:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=2)[N:27]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O.C(Cl)Cl.CN(C=O)C>[CH3:24][O:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH:35][C:15]([C:12]2[N:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]3=[N:14][CH:13]=2)=[O:17])[N:28]([CH2:36][C:37]2[CH:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=2)[N:27]=1
Reactant: COc1nn(Cc2ccc(C)nc2)c2cccc(N)c12
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(OC)nn4Cc3ccc(C)nc3)cnc2c1
Reaction time: 8 h
Yield: 0 %

Procedure:
A suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Example 1, Steps A-D; 0.014 g, 0.059 mmol) and 2M oxalyl chloride in DCM solution (0.033 mL, 0.065 mmol) were suspended in DCM (1 mL) with a catalytic amount of DMF. 3-Methoxy-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (0.016 g, 0.059 mmol) in DCM (1 mL) was added, followed by diisopropylethylamine (0.012 mL, 0.071 mmol). The mixture was stirred overnight and then was in water-DCM, the organic layer was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (3% MeOH in DCM) to give N-(3-methoxy-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.014 mg, 49% yield) as a beige solid. MS (APCI) m/z=487 (M+H).
Reaction SMILES: C([NH:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:16])[NH:12]2)=[CH:7][CH:6]=1)(=O)C.[ClH:17]>>[ClH:17].[NH2:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:16])[NH:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2ccc(=O)[nH]c2c1C
Agent: Cl
Product: Cc1c(N)ccc2ccc(=O)[nH]c12
Temperature: 5570 °C

Procedure:
To 5 g of 7-acetylamino-8-methylcarbostyril was added 60 ml of 20% hydrochloric acid, and the mixture was heated at 11020 to 120° C. on an oil bath with stirring. After heating for 4 hours, the solvent was removed by evaporation under pressure, then the residue obtained was washed with hot-methanol, dried, next recrystallized from methanol-water to obtain 5.25 g of 7-amino-8-methylcarbostyril hydrochloride. Light yellow needle-like crystals. Melting point: 290°-293° C. (decomposed).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH3:6][CH:7]([CH3:21])[C:8](=O)[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=S.C(N(CC)CC)C.O>C(#N)C>[CH2:13]([O:12][C:10]1[CH:9]=[C:8]([CH:7]([CH3:21])[CH3:6])[N:4]([CH2:3][CH2:2][OH:1])[N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C(=O)CC(=S)OCc1ccccc1
Reactant: NNCCO
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(OCc2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
2-Hydroxyethylhydrazine (1.90 g) was added to a solution of O-Benzyl 4-methyl-3-oxothiopentanoate (5.90 g) and triethylamine (5.05 g) in acetonitrile (60 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give the title compound (5.90 g).