Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:25])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][O:15][C:16](=[O:25])[NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4COC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using benzyl-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:19][CH2:18][C:15]2[CH:16]=[N:17][C:12]([C:11]([F:21])([F:10])[F:20])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OCc1ccc(C(F)(F)F)nc1
Reactant: COc1cc(Br)ccn1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccc(C(F)(F)F)nc2)ccn1
Yield: 72.4 %

Procedure:
4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), Cut (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C[C:36]#[N:37])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:36]#[N:37])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)OCC1(c2ccc3ccccc3c2)CCCC1
Reactant: N#CCC1(c2cc(Cl)ccc2Cl)CCCC1
Product: N#CCC1(c2ccc3ccccc3c2)CCCC1
Yield: 72.67 %

Procedure:
(1-Naphthalen-2-yl-cyclopentyl)-acetonitrile (215) (9.0 g, 72.67%) was synthesized as a brown solid from methanesulfonic acid 1-naphthalen-2-yl-cyclopentylmethyl ester 214) (16.0 g, 52.63 mmol) following the procedure described for [1-(2,5-dichlorophenyl)-cyclopentyl]-acetonitrile (202).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[CH3:26]>>[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 77 %

Procedure:
The Suzuki coupling of (5)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-ethylphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 77% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.58 Hz, 3 H) 1.49 (s, 9 H) 1.79-1.95 (m, 3 H) 1.95-2.05 (m, 1 H) 2.82 (q, J=7.58 Hz, 2 H) 3.34-3.44 (m, 3 H) 3.44-3.53 (m, 1 H) 4.15 (br. s., 1 H) 6.08 (d, J=6.82 Hz, 1 H) 7.23-7.31 (m, 3 H) 7.32-7.38 (m, 1 H) 7.51 (dd, J=7.20, 1.39 Hz, 1 H) 7.91 (s, 1 H) 8.20 (d, J=6.32 Hz, 1 H); LRMS (ESI) m/e 422.0 [(M+H)+, calcd for C24H31N5O2 421.0].
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([N:7]([CH3:8])[CH3:6])=[O:43])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
TSTU (108 mg, 0.36 mmol) was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (115 mg, 0.36 mmol, as described in Example 3.00) and DIPEA (0.069 mL, 0.40 mmol) suspended in DCM (1 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. Dimethylamine (0.180 ml, 0.36 mmol) was then added and stirring was maintained for an additional 30 min. The mixture was pou red onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to afford 8-(1-hydroxyethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (123 mg, 0.355 mmol, 99%) as a off-white solid. Mass Spectrum: M+H+ 347.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][CH3:38])[C:32]([C:39](O)=[O:40])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][CH3:38])[C:32]([C:39]([NH:1][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:5]=[CH:6][CH:7]=3)=[O:40])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(N)c1
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1

Procedure:
By using tert-butyl (2-((3-aminophenyl)amino)-2-oxoethyl)carbamate (B1) and 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5), tert-butyl (2-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-2-oxoethyl)carbamate (D8) was obtained in the same manner as that of Example 12, (1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=O)[NH:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CC(C)=O.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[CH3:1][C:2]1[N:3]=[C:4]2[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:5]2[CH:6]=1
Reactant: Cc1c[nH]c(Cc2ccccc2NC(=O)N2CCN(C)CC2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cn2c(n1)Cc1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 1-[2-(4-methyl-2-imidazolylmethyl)phenylcarbamoyl]-4-methylpiperazine, 86 ml of phosphorous oxychloride and 7.24 g of phosphorous pentachloride is stirred at room temperature for 4 hours and evaporated to dryness. The residue is suspended in 186 ml of methylene chloride and 55.2 ml of triethylamine is added dropwise at 0° over a period of 15 minutes. The mixture is stirred at room temperature overnight, poured into cold water, basified with 10% aqueous potassium carbonate and extracted with methylene chloride. The methylene chloride extracts are re-extracted with 2N hydrochloric acid. The acidic extracts are basified with 2N aqueous sodium hydroxide and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness. The residue is chromatographed from 180 g of silica gel using methylene chloride-methanol-ammonium hydroxide (300:50:1) as eluant to give a foamy material which is dissolved in acetone and treated with an equivalent amount of maleic acid to give on dilution with ether the 2-methyl-5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine mono-maleate, m.p. 195°-197°.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)(CCCC)CCCC)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cnccn1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
To a solution of 4-bromo-5-nitrothiophene-3-carbonitrile (312 mg, 1.34 mmol) in dioxane (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (154 mg, 0.133 mmol) and tributylstannylpyrazine (794 mg, 2.15 mmol). This was heated by microwave irradiation to 140° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography to afford the titled compound (166 mg, 53%): Rf=0.33 (20% EtOAc/hexanes; silica); HPLC method [4], retention time=1.45 min; MS(ESI) 233.0 (MH+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21](OC)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C(OC)(C)(C)C>[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: NC1CC1
Reactant: COC(=O)c1onc(C(=O)NC(C)(C)C)c1C(=O)OC
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1c(C(=O)NC(C)(C)C)noc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.75 g (I3.1 mmol) of cyclopropylamine was added dropwise at 20° C., with cooling, to a solution of 2.5 g (8.8 mmol) of dimethyl 3-tert-butylaminocarbonylisoxazole-4,5-dicarboxylate in 50 ml of dry methanol, and the mixture was stirred at room temperature for 20 hours. The solvents were stripped off under reduced pressure, and the residue was taken up in methyl tert-butyl ether and extracted with dilute HCl and once with water. The organic phase was then dried over magnesium sulfate, and the solution was evaporated. The resulting methyl3-tert-butylaminocarbonyl-5-cyclopropylaminocarbonylisoxazole-4-carboxylate was purified by column chromatography (SiO2 ; cyclohexane/ethyl acetate 4:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21](Br)=[CH:22][C:7]2=3)[N:6]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][C:7]2=3)[N:6]=1
Reactant: COc1ccc2c(c1)CCc1ccc(Br)cc1C21N=C(N)N(C)C1=O
Reactant: OB(O)c1ccccc1
Product: COc1ccc2c(c1)CCc1ccc(-c3ccccc3)cc1C21N=C(N)N(C)C1=O

Procedure:
Using essentially the same procedure described in Example 3 and employing 2′-amino-2-methoxy-1′-methyl-7-bromo-10,11-dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol]-5′(1′H)-one and phenylboronic acid, the title compound was obtained as an off-white powder, mp 167-171° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH2:21][OH:22])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[C:19]([CH:21]=[O:22])[N:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Nc2nccc(-c3nc(CO)cs3)n2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Cc1cc(C)cc(Nc2nccc(-c3nc(C=O)cs3)n2)c1
Reaction time: 1 h

Procedure:
To a solution of 7a (100 mg, 0.320 mmol) and 163 uL of t-butanol in 2 mL of DCM was added 163 mg of Dess_Martin periodinane reagent. The reaction mixture was stirred for 1 h after which it was quenched with sodium thiosulfate (1 mL). It was stirred until the two phase became clear. The organic layer was dried (Na2SO4) and concentrated in vacuo to give 35 mg (38%) the crude aldehyde 9a that was used directly for the next step. 1H NMR (CDCl3) δ 10.1 (s, 1H), 8.3 (d, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.2 (s, 2H), 6.8 (s, 1H), 2.3 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][NH2:13])=[CH:4][CH:3]=1.[C:14]([C:19]1[C:20](=[O:32])[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][C:24]=1[OH:25])(=O)[CH2:15][CH2:16][CH3:17]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1
Reactant: NOCCC#Cc1ccc(F)cc1
Reactant: CCCC(=O)C1=C(O)CC(C2CCOCC2)CC1=O
Solvent: CO
Product: CCCC(=NOCCC#Cc1ccc(F)cc1)C1=C(O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.7 g (15 mmol) of 4-(4-fluorophenyl)-but-3-ynoxyamine were added to a solution of 4 g (15 mmol) of 2-butyryl-3-hydroxy-5-tetrahydropyran-4-ylcyclohex-2-enone in 60 ml of dry methanol. After the mixture had been stirred for 16 hours at room temperature, the methanol was removed under reduced pressure from a water pump. The crude product was purified by chromatography over silica gel (eluent: methylene chloride).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.[CH3:34][Si:35]([CH:38](O)[CH3:39])([CH3:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[O:19])=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1
Reactant: CC(O)[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.24 g (0.73 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7) in 10 ml of dry CH2Cl2 was added 0.09 g (0.74 mmol) of dimethylaminopyridine, 0.115 ml (0.80 mmol) of trimethylsilylethanol and 0.17 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. The reaction mixture was stirred at 25° C. for 5 hours, washed with sat. aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=N)C1C=CC=CC=1.C(OC([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)=O)(C)(C)C.[CH:33]1([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([C:48](O)=[O:49])=[CH:47][C:42]=3[N:41]=[C:40]2[C:51]2[CH:55]=[CH:54][O:53][CH:52]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(C(F)(F)F)=O>>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH:2]([NH:1][C:48]([C:46]2[CH:45]=[CH:44][C:43]3[N:39]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:40]([C:51]4[CH:55]=[CH:54][O:53][CH:52]=4)=[N:41][C:42]=3[CH:47]=2)=[O:49])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: NCc1ccccn1
Agent: N=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1ccc(O)cc1)c1ccccn1)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
2-(Aminomethyl)pyridine was converted to its benzaldehyde imine (benzaldehyde in DCM with 4A molecular sieves) and alkylated with 4-tert-butoxycarbonyloxy-benzyl chloride following an adaptation of the procedure described by Y. Wang et al. (Synth. Commun. 1992, 22, 265). The resulting racemic amine was coupled to the carboxylic acid of example 2 under the usual conditions, and deprotected with TFA to give the tide compound of example 38 after purification by preparative C18 reversed-phase HPLC.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].CCCCCC.CC(=O)OCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:21]=2[C:22]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:23])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: Cc1ccc(C(=O)NCc2cccs2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2cccs2)c(SCCS(=O)(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
336 mg (3.0 mmol) of potassium tert-butoxide were added at 0° C. to a solution of 607 mg (3.0 mmol) of 2-(phenylsulfonyl)ethanethiol in DMF (10 ml). After stirring for 10 min at 0° C., 534 mg (2.0 mmol) of 2-chloro-6-methyl-N-(thiophen-2-ylmethyl)nicotinamide were added and the mixture was then heated for 16 h at 50° C. Dilution with EA and washing with brine were then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 556 mg (1.28 mmol, 64%) of 2-[2-(benzenesulfonyl)ethylthio]-6-methyl-N-(2-thienylmethyl)-nicotinamide. MS: m/z 433.1 [M+H]+
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([O:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH:22]=[CH:23][CH:24]=1)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C(c2cccc(OC(=O)C(C)(C)C)c2)=CC2CCC1C2
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add H2O (18 mg, 1 mmol) and TMSCl (75 mg, 0.69 mmol) to a solution of 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester (197 mg, 0.58 mmol) in 2-butanone (70 mL). Stir the reaction mixture at ambient temperature for 2 hours. Evaporate the mixture under vacuum to afford 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester hydrochloride as white solid (219 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J=16.4, 1H), 7.13-7.15 (d, J1=7.2, J2=0.8, 1H), 6.96-6.98 (m, 2H), 6.21-6.23 (d, J=6.8, 1H), 3.68-3.71 (d, J=12.0, 1H), 3.16-3.23 (t, J=25.6, 1H), 2.99-3.00 (m, 1H), 2.88-2.92 (d, J=14.8, 6H), 2.65 (m, 1H), 2.60 (m, 1H), 1.95-1.98 (m, 1H), 1.82-1.86 (m, 5H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(O)(=O)/C=C\C(O)=O>N1C=CC=CC=1.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:43][CH:42]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(N(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.15 mmol) in pyridine (5 ml) was added 4-(dimethylamino)benzoylchloride (420 mg, 2.28 mol) dropwise. The solution was stirred overnight, the solvent evaporated and the residue partitioned between dichloromethane and 2N NaOH solution. The aqueous layer was extracted with dichloromethane (×3). The organics were dried, filtered and evaporated to leave a solid which was triturated with EtOAc/Et2O (1:4) to leave a solid which was dissolved in EtOAc and treated with maleic acid (3 eqs.) to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (320 mg, 30%). 1H NMR (d6-DMSO)): δ H 9.05 (1H, s), 8.25 (1H, s), 8.18 (1H, d, J=8 Hz), 7.84 (2H, d, J=9.2 Hz), 7.29 (1H, s), 7.25 (1H, d, J=8 Hz), 6.78 (2H, d, J=8.8 Hz), 6.17 (6H, s), 4.71 (1H, m), 3.95 (3H, s), 3.01 (6H, s), 2.83-3.18 (9H, m), 2.68 (3H, s), 2.08 (6H, m), 1.56 (2H, m). HPLC (5.23 mins, 100%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][N:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc(COCC2CC2)cn1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.089 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.142 g) as a light yellow gum (0.152 g). MS (ESI−): 365.0 ([M−H]−)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:30])[CH2:32][CH2:33][OH:34])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: CNCCO
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN(C)CCO)c34)cc2Cl)cn1
Yield: 34 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-methylethanolamine to give the title compound in 34% yield; NMR Spectrum: 2.31 (s, 3H), 2.45 (s, 3H), 2.54 (t, 2H), 2.88 (t, 2H), 3.49 (t, 2H), 4.41 (t, 2H), 7.19 (d, 1H), 7.26 (br s, 2H), 7.72 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 470 (MH+).