Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C:6]([F:9])([F:8])[F:7])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([Br:30])[CH:24]=1>CN(C=O)C>[Br:30][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:23][CH:24]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
To a stirred solution of trifluoroethyl tosylate (1.5 g, 5.8 mmol) in DMF (20 mL) was added K2CO3 (4 g, 29.4 mmol) followed by addition of p-bromo phenol (1.1 g, 6.46 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 120° C. for 6 h. The volatiles were evaporated under reduced pressure; the residue was diluted with water (5 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with water, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 5% EtOAc/hexane to afford the desired product (0.8 g, 3.13 mmol, 53.3%) as semi solid. 1H NMR (200 MHz, CDCl3): □ 7.44-7.38 (m, 2H), 6.86-6.80 (m, 2H), 4.38-4.25 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:34]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]phenyl]propionic acid (2.10 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to rooms temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.09 g, 52%). HRMS calcd for C23H27NO5: 397.4711. Found: 397.4713. MA calcd for C23H27NO5: C, 69.50%; H, 6.85%; N, 3.52%. Found: C, 69.62%; H, 6.83%; N, 3.53%.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1.[C:25](Cl)(=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:26]([C:25]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1)=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
{circle around (1)}: A solvent comprising 1.1 g of triethylamine and 5 g of toluene was added dropwise to a mixture comprising 2.28 g of benzyl 4-hydroxybenzoate, 2.33 g of n-tridecanoic chloride and 15 g of toluene in 30 minutes while cooling it with ice. After finishing adding dropwise, the mixture was stirred at room temperature for 3 hours. After finishing the reaction, deposited salts were filtered off, and the filtrate was neutralized with ½ N hydrochloric acid and washed with water. Then, toluene was distilled off under reduced pressure, and the resultant residue was recrystallized from ethanol, whereby 3.52 g of benzyl 4-n-dodecylcarbonyloxybenzoate was obtained in the form of a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:45]1(C)C=CC=CC=1B(O)O>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:33][CH2:34][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:36][CH2:37]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH3:45])[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccc(C)cc1
Reactant: Cc1ccccc1B(O)O
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1C

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(4-methylphenyl)-1,3-thiazol-2-amine was used to convert o-tolylboronic acid (0.200 g, 1.47 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.8-11.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(2-methylphenyl)-1,3-thiazol-2-amine as an off-white solid (0.075 g, 0.123 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.83 min; MS (MH)+ 608.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH3:20][CH:19]([C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1)[CH3:21]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(CO)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Reaction time: 0.5 h
Yield: 438 %

Procedure:
A solution of 1N ZnCl2 in Et2O (182 mL, 182 mmol) was added to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (21.3 g, 152 mmol) and N-hydroxy-2-methylpropanimidamide (18.6 g, 182 mmol) in EtOAc (50 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 30 min, decanted, and was treated with concentrated HCl (45 mL) and ethanol 20 mL). The mixture was heated at reflux for 2 h. The mixture was evaporated to dryness, and the resulting residue was charged with water and the pH was adjusted to basic with K2CO3. The mixture was extracted with EtOAc and the material obtained was combined with 9 other batches prepared similarly and purified by silica gel chromatography to give 150 g of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH3:9].[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(N(C(C)C)CC)(C)C>C(#N)C>[I-:1].[CH3:9][N+:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: C[n+]1ccccc1Cl
Reactant: c1cn[nH]c1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[n+]1ccccc1-n1cccn1
Reaction time: 8 h

Procedure:
2-Chloro-1-methylpyridinium iodide (5.0 g), pyrazole (1.3 g) and diisopropylethylamine (2.5 g) were added to acetonitrile (50 ml) and the mixture refluxed for 3.5 hours. The acetonitrile was removed and the residue dissolved in hot ethanol. The solution was left in the refrigerator overnight. The product was collected by filtration Yield, 1.73 g; mp 129°-130° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv), 1-(pyridin-2-yl)piperazine (50 mg, 0.31 mmol, 2.00 equiv), and DIEA (100 mg, 0.78 mmol, 3.00 equiv) in DMF (10 mL) was placed in a 20-mL sealed tube under an inert atmosphere and stirred overnight at 100° C. in an oil bath and then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) yielded 68 mg (crude) of methyl 2-phenyl-3-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Solvent: ClCCl
Solvent: O
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-chloro-3-fluoro-pyridin-2-yl)-7-hydroxitetrahydroimidazo-[1,5-a]-pyridin-1,3-dione (isomer B, Example H10) in 80 ml dichloromethane is treated at −55° C. to −65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hour. The reaction mixture is then allowed to stir at 20° C. over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The combined extracts are washed with water, dried, filtered through a small silicagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(N(CC)CC)C.Cl[CH2:38][C:39]([NH2:41])=[O:40]>O.C(O)C>[C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:38][C:39](=[O:40])[NH2:41])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)CCl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CNCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 4.0 ml of water there was dissolved N-[N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline (406 mg, 0.0001 mole), after which triethylamine (364 mg, 0.0036 mole) was added, followed by slow, dropwise addition of a solution of 2-chloroacetamide (140.3 mg, 0.0015 mole) in 6.0 ml of ethanol. The reaction mixture was stirred at room temperature for 15 minutes, followed by refluxing with stirring for 15 hours. Thin layer chromatography indicated a nearly complete reaction, and the refluxing was continued for 2 more hours. The reaction mixture is allowed to cool and then concentrated under vacuum, flushed with benzene 3 times, then further concentrated under vacuum. The crude product was purified on a 2.5×240 cm LH-20 chromatographic column using a methanol system. Product-rich fractions were evaporated to dryness and freeze-dried to give N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -carbamoylmethyl-L-lysyl]-L-proline.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]([N:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][C:14]([CH2:27]SC)=[CH:15][CH:16]=2)[C:11]1=[O:30])([CH3:9])[CH3:8].O1CCOC[CH2:32]1.O>O>[CH:7]([N:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][C:14]([CH2:27][S:3]([CH3:32])(=[O:5])=[O:2])=[CH:15][CH:16]=2)[C:11]1=[O:30])([CH3:9])[CH3:8]
Reactant: CSCc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Reactant: C1COCCO1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(CS(C)(=O)=O)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
Oxone (0.43 g, 0.7 mmol) was added in one portion to a stirred solution of 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylsulfanylmethyl-2H-phthalazin-1-one (0.06 g, 0.17 mmol) in a 4:1 mixture of dioxane/water (1.2 ml) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with water (5 ml) and the solution was extracted with EtOAc (3×75 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.013 g, 20% yield) as a white solid. δH (400 MHz, DMSO) 9.23 (1H, s), 8.48 (1H, d), 8.38 (1H, d), 7.89 (1H, dd), 6.36 (1H, s), 5.33-5.20 (1H, m), 4.77 (2H, s), 2.96 (3H, s), 2.25 (3H, s), 1.33 (6H, d) Tr=1.58 min, m/z (ES+) (M+H)+ 376.24.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O>>[CH3:14][CH:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[OH:7])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccccc1O
Reactant: CCCCC(C)=O
Product: CCCCC(C)Nc1ccccc1O
Reaction time: 5.33 h

Procedure:
The same procedure as in Example 3 was repeated except for using 145 mL (121 g; 1.2 mol) of 2-hexanone in place of 100 mL of acetone, to conduct the reaction. As a result, it was confirmed that the rate of conversion of o-aminophenol was 93%, the selectivity to the N-monoalkylated compound (molar ratio of the monoalkylated compound to a sum of the mono- and di-alkylated compounds) was 41%, and the oxygen absorption initiation time as an index of determining an oxidation-inhibiting property thereof was 320 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:54][C:55]2[CH:56]=[C:57]([C:61]3[N:70]=[C:69]([NH:71][C:72]4[CH:73]=[C:74]5[C:78](=[CH:79][CH:80]=4)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]5)[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]=3)[CH:58]=[CH:59][CH:60]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CN1CCN(CC(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(4-methylpiperazin-1-yl)acetic acid (34 mg, 0.22 mmol), PyBOP® (11 mg, 0.22 mmol), DIEA (300 μL, 1.72 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:27][CH3:28])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]1([CH:35]=[CH:36]B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1(C)C=CC=CC=1.COCCOC.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>[CH3:28][O:27][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][C:17]=1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:36]=[CH:35]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:3]=1)[O:9]2
Reactant: OB(O)C=Cc1ccccc1
Reactant: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1cccc(Br)c1)O2
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: Cc1ccccc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1cccc(/C=C/c3ccccc3)c1)O2
Temperature: 90 °C
Yield: 16.5 %

Procedure:
A solution of Example 82 (0.046 g, 0.1 mmol) in EtOH/DME/toluene (1 mL, 2:1:1) was added to phenylvinylboronic acid (0.015 g, 0.1 mmol). A solution of Pd(PPh3)4 (0.006 g, 0.005 mmol) in DME (0.5 mL) and aqueous Na2CO3 (20 mg in 0.3 mL H2O, 0.2 mmol) were added. The reaction mixture was heated to 90° C. on a shaker for 15 min then concentrated, diluted with DMSO/MeOH (1:1, 1 mL) and purified by HPLC with 0.1% TFA, water, and CH3CN to provide the titled compound (8 mg, 17%). 1H NMR (500 MHz, CDCL3) δ 8.46 (d, J=8.4 Hz, 1H), 7.50 (m, 4H), 7.36 (dd, J=15.3, 7.8 Hz, 3H), 7.26 (m, 3H), 7.17 (t, J=8.1 Hz, 1H), 7.09 (s, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.65 (m, 2H), 6.24 (s, 1H), 6.01 (s, 1 H), 3.95 (s, 3H), 2.97 (s, 3H); MS (CI, +Q1MS) m/e 483.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.Br[C:16]1[N:21]=[C:20](C=O)[CH:19]=[CH:18][CH:17]=1.N1C[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:21]1([CH2:28][CH2:27][C:26]#[C:25][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:3]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Brc1cccc(CN2CCCCC2)n1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Product: C(#Cc1cccc(CN2CCCCC2)n1)CCN1CCCCC1
Yield: 83 %

Procedure:
2-Bromo-6-piperidin-1-ylmethyl-pyridine. The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.406 g, 2.18 mmol) and piperidine (0.186 g, 2.18 mmol). The crude product was purified (SiO2: 0-4% 2 M NH3 in MeOH/DCM) to provide the title compound (0.46 g, 83%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[C:14]([CH2:13][NH:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[O:18][N:17]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(-c2cc(CBr)on2)cc1
Reactant: CCOC(=O)CC(C)(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)no1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-amino-3-methylbutyrate hydrochloride (333 mg) in tetrahydrofuran (4.00 mL), a solution in tetrahydrofuran (2.00 mL) of the compound (100 mg) obtained in step (2) above and potassium carbonate (406 mg) were added and the mixture was stirred at 60° C. for three days. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure and the resulting residue was roughly purified by preparative HPLC. To the resulting roughly purified product, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-50:50) to give the titled compound as a colorless amorphous mass.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[N+:29]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O.CCO.[Pd]>[NH2:29][C:32]1[CH:33]=[N:34][N:35]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Pd]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Diisopropyl azodicarboxylate (3.60 mL, 18.3 mmol) was added dropwise to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (2.45 g, 12.2 mmol), 4-nitro-1H-pyrazole (1.38 g, 12.2 mmol) and PPh3 (4.79 g, 18.3 mmol) in THF (25 mL) at 0° C. The resulting mixture was maintained at this temperature for 10 minutes and then warmed to room temperature at which it was stirred for 6 days. The mixture was diluted with hexanes (80 mL) and EtOAc (20 mL) and stirred for 5 hours at room temperature before filtering, washing the filter cake with hexanes (50 mL) and concentrating the filtrate in vacuo. The resulting oil was purified by silica gel column chromatography (Biotage Isolera, 2×40 g SiO2 cartridges, 0-50% EtOAc in cyclohexane) to give a residue that was dissolved in EtOH (200 mL). 10% Pd/C (53% water; 0.500 g) was added and the resulting suspension stirred under an atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through Celite, washing with EtOAc (ca. 100 mL) and then the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in EtOAc (200 mL) and washed with water (2×100 mL) and then aqueous 2 M HCl (100 mL). The acidic layer was basified with aqueous 2 M NaOH to pH 13 and extracted with EtOAc (2×100 mL). The combined organic layers from the basified extraction were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A124 as a purple oil (1.39 g, 34%); 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=0.9 Hz, 1H), 7.02 (d, J=0.9 Hz, 1H), 4.20 (s, 2H), 4.11 (m, 1H), 2.95-2.76 (m, 4H), 2.11-2.02 (m, 2H), 1.83 (qd, J=12.3, 4.5 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:22][CH:23]=1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:22][CH:23]=1
Reactant: c1c[nH]nn1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C(c2ccc(Cl)cc2)n2ccnn2)cc1
Product: Clc1ccc(C(c2ccc(Cl)cc2)n2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the general procedure of Example 1B, 5.0 g of 1,2,3-triazole in 100 ml of dimethylformamide were treated first with 1.44 g of sodium hydride (60% in mineral oil), and then with 5.0 g of 4,4'-dichlorobenzhydryl chloride. The reactants were stirred overnight at about 25° C. and then heated for 1 hour on a steam bath. Chromatography of the residue after work-up provided 2.4 g of the undesired 2-[bis(4-chlorophenyl)methyl]-2H-1,2,3-triazole and 3.1 g of the desired title product, m.p. 124°-125° C.