Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.ClC(O[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>ClCCl>[CH2:38]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccnc(Cl)n3)cn2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3ccnc(Cl)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A solution of 4-(2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrid-5-yl)-2-chloropyrimidine (8.00 g, 21.30 mmol) in dichloromethane (60 ml) was treated with trifluoroacetic acid and the resulting mixture stirred at room temperature for 2 h, then evaporated and reconcentrated four times from dichloromethane. The residue was suspended in a mixture of dichloromethane (150 ml) and saturated aqueous sodium bicarbonate (150 ml) then treated portionwise with benzyl chloroformate (4.00 g, 23.44 mmol) in dichloromethane (5 ml). The resulting mixture was stirred rapidly for 18 h then the organic phase was separated, dried (MgSO4) and evaporated to give the crude product which was purified by recrystallisation (ethyl acetate-hexane) to afford the title compound (7.85 g) as an off-white solid m.p. 145-147°. δH (CDCl3) 3.65-3.77 (8H, m), 5.18 (2H, s), 6.73 (1H, d, J 9.1 Hz), 7.36 (5H, m), 7.52 (1H, d, J 5.4 Hz), 8.31 (1H, dd, J 2.3, 8.1 Hz), 8.54 (1H, d, J 5.4 Hz) and 8.86 (1H, d, J 2.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:43].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:21]=[C:20]([CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:43])=[O:30])=[CH:25][CH:24]=2)=[O:40])[CH2:10][CH2:9]1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl-amino]-cyclohexyl}-carbamic acid tert-butyl ester was dissolved in 15 ml of THF and 0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to THF solution at 10° C. during 10 min. The reaction mixture stirred over night at RT. Reaction progress was monitored by TLC. Reaction mixture was filtered through celite and washed with THF and thus obtained mother liquor was concentrated under vacuo. Product was crystallized with ethyl acetate to afford 0.25 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 6.75 (1H, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (1H, d).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6].S(Cl)([Cl:15])=O>N1C=CC=CC=1.ClC(Cl)Cl>[Cl:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cn1cccc1C(=O)NCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cccc1C(=O)NCCCl
Reaction time: 8 h

Procedure:
To a stirred solution of 40 parts of N-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide in 450 parts of trichloromethane is added one drop of pyridine. Then there are added dropwise, during a 30 minutes-period, 28.3 parts of sulfinyl chloride (slightly exothermic reaction: temp. rises from 15° to 25° C). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 15 parts of N-(2-chloroethyl)-1-methyl-1H-pyrrole-2-carboxamide.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40].[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[C:19]([NH2:43])[C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1nc2cnc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reaction time: 16 h

Procedure:
Part B of the general methods described for Examples 35-40 was followed using 2.00 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol to provide 2.33 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid. Parts C and D of the general methods described for Examples 35-40 were replaced by the following procedure. mCPBA (0.853 g, 2.97 mmol) was added in one portion to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline (1.00 g, 2.47 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes Ammonium hydroxide (17 mL) was then added, followed by p-toluenesulfonyl chloride (0.710 g, 3.70 mmol). The reaction was stirred for 16 hours and then diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic solutions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile to provide 0.680 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a reddish-brown, crystalline solid, mp 209-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH:32]([O:31][C:29]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:27][CH2:26]1)=[O:30])([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottom flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylamine(200 μl). DMF (3 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Isopropyl chloroformate (1.0M in toluene, 0.22 mL) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give 4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129). 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 1.9 (m, 2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 5.63 (m, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.63 (s, 1H). Exact mass calculated for C21H24FN5O5S: 477.15, found 478.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:6]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:7]=1)[O:4][CH3:5].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH:33]([Si](C)(C)C)[O:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CO>C1C=CC=CC=1.CCOCC.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>[CH3:1][O:2][CH:3]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:27]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][O:34][CH2:35][CH2:36][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:31][C:26]=3[O:25][CH3:24])=[CH:12][CH:13]=2)[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:7]=1)[O:4][CH3:5]
Reactant: COC(OC)c1nn(COCC[Si](C)(C)C)c2cc(I)ccc12
Reactant: CCOC(Oc1ccc(B(O)O)c(OC)c1)[Si](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: O
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(OCOCC[Si](C)(C)C)ccc1-c1ccc2c(C(OC)OC)nn(COCC[Si](C)(C)C)c2c1
Yield: 164.4 %

Procedure:
3-(1,1-Dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (1.06 g, 2.37 mmol), 2-methoxy-4-(trimethylsilanyl-ethoxymethoxy)-phenylboronic acid (0.99 g, 3.32 mmol), and sodium carbonate (352 mg, 1.4 mmol) were stirred in a mixture of benzene (15 mL), MeOH (3 mL), and water (1 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added, and the reaction stirred at reflux for 16 h. The reaction was allowed to cool and was diluted with ether (70 mL). Organics were washed with H2O and brine (30 mL each), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.12 g (82%) of 3-(1,1-dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a faintly yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.91 (d, 1H, J=8.4 Hz), 7.64 (s, 1H), 7.37 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H, J=8.4 Hz), 6.71-6.77 (m, 2H), 5.82 (s, 1H), 5.75 (s, 2H), 5.28 (s, 2H), 3.77-3.83 (m, 5H), 3.57 (t, 2H, J=8.4 Hz), 3.46 (s, 6H), 1.00 (t, 2H, J=8.4 Hz), 0.88 (t, 2H, J=8.4 Hz), 0.03 (s, 9H), −0.05 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCN(CC1)CC2.[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[C:26]([CH2:37][OH:38])=[CH:25]2.[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O.C(O)(=O)C>[N:10]1[C:2]([O:38][CH2:37][C:26]2[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[N:28][C:29]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:19])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CO
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Prepared according to procedure L A mixture of 6-chloropurine (110 mg, 0.71 mmol) and 1,4-diazabicyclo[2.2.2]octane (160 mg, 1.43 mmol) in DMSO (0.7 mL) was stirred at rt for 4 h and was then added via cannula to a mixture of (8-methyl-2-o-tolylquinolin-3-yl)methanol (94 mg, 0.36 mmol) and sodium hydride, 60% dispersion in mineral oil (57 mg, 1.43 mmol) in DMSO (1 mL) that had been stirred at rt for 15 min prior to the addition. The mixture was stirred at rt for 3.5 h, neutralized by the addition of glacial acetic acid, diluted with brine (15 mL), and extracted with EtOAc (3×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel (deactivated with 2M NH3 in MeOH), and purified by flash chromatography (Biotage® Si 25+M) eluting with 2 M NH3 in MeOH/CH2Cl2 (5%) to provide a white solid [PI3Kδ IC50=27 nM]. MS (APCI+) m/z=282.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.CN(C)C=O.[Na].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:4]=[CH:5][C:6]=1[OH:12])(=[O:11])[CH3:10]
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cn2ccnc2)ccc1O
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a mixture of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol), sodium dimethylformamide was added imidazole (0.75 g, 11.0 mmol). The mixture was stirred four hours and concentrated in vacuo. The residue was stirred under 50 mL ethanol, filtered, and the filtrate concentrated in vacuo to give a residue. The residue was stirred under 30 mL chloroform, filtered, and the filtrate concentrated in vacuo to give crude product. The crude product was purified by flash chromatography eluting with 5:95 methanol:chloroform to give a solid. The solid was recrystallized from n-butlychloride to give 0.71 g (33%) product as a yellow crystalline solid, mp 106°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:18][C:12]3[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:18][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
With the exclusion of moisture, 121 mg (0.50 mmol) of 6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 1 ml of phosphorus oxychloride are heated at boiling for 1.5 hours. The reaction mixture is poured into ice-water and extracted twice with ethyl acetate. The organic phases are washed three times with water and brine, dried with MgSO4 and concentrated by evaporation. Stirring of the residue in diethyl ether yields the title compound; m.p. 248-249OC; FAB-MS: (M+H)+ =260.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)CCC.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:22]1[C:18]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][N:20]=[CH:21]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(-c2cncs2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (1.000 g; 3.62 mmol), 5-(tributylstannyl)thiazole (1.355 g; 3.62 mmol), and PdCl2(PPh3)2 (254 mg; 0.36 mmol) in anh. THF (20 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(thiazol-5-yl)benzoate as a pale yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 233.94 g/mol.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH:4]=[CH2:5].[N+:7]([CH3:10])([O-:9])=[O:8].CN(C)C(N(C)C)=N.CS(Cl)(=O)=O>C1(C)C=CC=CC=1.C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>[N+:7](/[CH:10]=[CH:5]/[CH2:4][CH2:3][CH:2]=[CH2:1])([O-:9])=[O:8]
Reactant: C=CCCC=O
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C=CCC/C=C/[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In an oven-dried 1 L round-bottomed flask pent-4-enal (11.3 g, 134 mmol) was dissolved in toluene (300 mL) to give a colorless solution. After cooling to 0° C., nitromethane (72.4 mL, 1343 mmol) and 1,1,3,3-tetramethylguanidine (1.685 mL, 13.43 mmol) were added. After the mixture was stirred at 0° C. for 60 min, TLC showed a major product (4:1 hexane/ethyl acetate). Methanesulfonyl chloride (15.7 mL, 202 mmol) and triethylamine (28 mL, 202 mmol) were added. The cooling bath was removed and the mixture was stirred at r.t. for 1 h. After 1 h, a further 0.5 equiv. of methanesulfonyl chloride (5.2 mL) and triethylamine (9.3 mL) were added to the mixture and the reaction continued for another h. It was quenched with saturated sodium bicarbonate solution and diluted with diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under high vacuum to give a tan oil. The residue was purified by flash column chromatography up to 20% ethyl acetate/hexanes. The major uv-active fraction was pooled and concentrated to a light yellow oil (further dried under house vac over 3 days: 12.30 g, 72%): 1H NMR (4.00 MHz, CHLOROFORM-d) δ ppm 7.24 (ddd, J=13.74, 7.15, 6.96 Hz, 1H) 6.98 (d, J=13.55 Hz, 1H) 5.67-5.86 (m, 1H) 4.98-5.14 (m, 2H) 2.37 (q, J=7.03 Hz, 2H) 2.27 (q, J=6.94 Hz, 2H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 140.82-141.82 (m, 1C) 139.50 (d, J=10.02 Hz, 1C) 135.60 (d, J=10.02 Hz, 1C) 115.56-116.67 (m, 1C) 30.49-31.82 (m, 1C) 26.73-27.94 (m, 1C).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(I)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(I)cc2c1O

Procedure:
Analogously to Example D-43 d), 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester was allowed to react with 5 ml of POCl3 to afford 0.057 g of a pale white solid: Proton NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), 7.97 (m, 1H), 4.5 (t, J=7 Hz, 2H), 2.0-1.8 (m, 1.65-1.4 (m, 2H), 1.00 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:36]2[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]2)=[C:20]([CH3:25])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a mixture of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-(4-bromo-3-methylphenyl)propanoate (1.23 g, 3.03 mmol), 1,4-dioxane (8 mL), triethylamine (1.69 mL, 12.1 mmol), palladium acetate (17 mg, 76 μmol), O-(dicyclohexylphosphino)biphenyl (106 mg, 0.303 mmol) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.57 mmol) dropwise. The greenish reaction mixture was stirred at 80° C. for 30 min. The reaction was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate twice. The organic solutions were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H), 7.3 (m, 5H), 6.9 (m, 2H), 5.22 (d, 1H), 5.10 (m, 2H), 4.64 (m, 1H), 3.70 (s, 3H), 3.06 (m, 2H), 2.48 (s, 3H), 1.33 (s, 12H); MF=C25H32BNO6; LCMS found for C25H33BNO6 (M+H)+: m/z=454.
Reaction SMILES: P(Cl)(Cl)Cl.[P:5]([OH:8])([OH:7])[OH:6].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]=O>O>[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]([P:5]([OH:8])(=[O:6])[OH:7])[P:5]([OH:8])(=[O:7])[OH:6]
Reactant: O=CNc1nccs1
Reactant: OP(O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Reaction time: 1 h
Yield: 29.9 %

Procedure:
7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and the mixture is heated, while stirring, at 60° for 1 hour. 6.12 g of N-(thiazol-2-yl)formamide are added thereto and the mixture is heated for a further 6 hours at approximately 60°. The mixture is then stirred with 30 ml of water, filtered with suction, subsequently washed with aqueous methanol and dried under reduced pressure. 2.0 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275° (decomposition) are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH:20][C:21](=[O:31])[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:27][CH2:26][N:25]([C:22]([CH3:24])([CH3:23])[C:21]([NH:20][CH3:19])=[O:31])[CH2:30][CH2:29]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CNC(=O)C(C)(C)N1CCNCC1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and N-methyl-2-piperazin-1-yl-isobutyramide using General Procedure B-3 yielded 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide.
Reaction SMILES: [C:1]([C:3]([C:21]#[N:22])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][OH:20])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2].Cl[CH2:24][CH2:25][OH:26]>C(#N)C>[C:1]([C:3]([C:21]#[N:22])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:24][CH2:25][OH:26])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2]
Reactant: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCO)ccc2c1
Reactant: OCCCl
Solvent: CC#N
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCO)ccc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
0.40 g (1.4 mmol) of the fourth compound 4 is obtained to be dissolved in 8 mL of anhydrous acetonitrile. 0.35 g (4.3 mmol) of 2-chloro-ethanol is added to be heated with stirring at 80° C. for 17 hrs. After cooling, extraction is processed with dichloromethane. After being dried with anhydrous sodium sulfate, an organic phase is concentrated under reduced pressure to be separated and purified by liquid chromatography (SiO2, CHCl3:EtOAc=1:1). Thus, a product, 2-(1,1-dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methylamino}naphthalene 5 (hereinafter referred to as fifth compound 5), is obtained, which has a weight of 0.29 g and a yield of 60.0%.