Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[C@H:10]([CH3:14])[CH2:9]2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCN[C@H](C)C2)ccc1Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@H](C)C2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (R)-1-(4-Chloro-3-methoxyphenyl)-3-methylpiperazine and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7.5% MeOH in CH2Cl2) to provide 1-[(R)-4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.75 (d, 0.6H), 8.66 (dd, 0.4H), 8.57-8.54 (m, 1H), 7.29-7.18 (m, 4H), 6.44-6.39 (m, 2H), 5.42 (br. s, 2H), 4.82 (br. s, 0.3H), 4.45 (br. s, 0.3H), 4.33 (br. s, 0.3H), 3.88 (s, 1.2H), 3.87 (s, 1.8H), 3.83 (br. s, 0.3H), 3.73-3.67 (m, 1H), 3.54-3.52 (m, 1H), 3.38 (br. s, 1H), 3.17-3.13 (m, 1H), 2.99 (br. s, 1H), 2.80 (br. s, 1H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]CC3C=CC=CC=3)[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][C:6]=1[O:32][CH2:33][O:34][CH3:35])[CH3:2].C(OCC)(=O)C>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][C:6]=1[O:32][CH2:33][O:34][CH3:35])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
To a solution of 4-[4-(2-benzyloxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxymethoxy-benzoic acid ethyl ester (2.3 g) in a mixed solvent of ethyl acetate (20 mL) and methanol (20 mL) was added palladium-carbon powder under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure to give the title compound (1.4 g)
Reaction SMILES: [OH2:1].[C:2]1([CH:8]([CH3:10])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.[Na].[C:15]([OH:18])(=O)[CH3:16]>>[C:15]([CH2:10][C:8](=[O:1])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[C:16]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)c1ccccc1
Reactant: O
Reactant: CC(=O)O
Agent: [Na]
Solvent: CSC
Product: O=C(CC(=O)c1ccccc1)c1ccccc1

Procedure:
Into a two liter beaker equipped with a mechanical stirrer, 500 mL of water and 250 mL of cumene were added. A ph-stat (Metrohm titrator, model 716 DMS, Brinkmann Instruments) was set up to add acetic acid to pH 7. The sodium salt of DBM was added slowly to the beaker. The pH varied between 5 and 7.5; 14.7 mL of acetic acid was added. The two layers were transferred to a separation funnel, the aqueous layer was removed, and the organic layer was washed with aqueous sodium bicarbonate and then with water. The organic layer was then concentrated under vacuum in a rotary evaporator. The residue was crystallized from 90% isopropanol, affording DBM (53.58 g, 96% yield) having a purity of more than 99% (GC).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.[I:36]I.[NH4+].[Cl-]>C1COCC1>[I:36][C:9]1[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: II
Reactant: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(I)n2)s1
Temperature: -50 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of 4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole (2.20 g, 5.42 mmol) in THF (100 mL) was cooled to −78° C. nBuLi mL of a 1.6 M solution in hexanes, 6.2 mmol) was added dropwise (˜2 min) and the pale yellow solution was allowed to warm to −50° C. (over ˜1 h) and then re-cooled to −78° C. I2 (2.74 g, 10.4 mmol) was added and the mixture was allowed to warm to room temperature (over ˜4 h) and stirred overnight. Saturated aqueous NH4Cl (2 mL) was added and the mixture was concentrated to ˜10 mL. The mixture was diluted with EtOAc, H2O, saturated aqueous Na2S2O3 and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 5:95 then 15:85) to give 2-iodo-4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole 2 (1.72 g, 60%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.45 (s, 3H), 6.60-6.64 (m, 1H), 6.94 (s, 1H), 6.99 (d, J=3.5 Hz, 1H), 7.19-7.39 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ15.3, 90.6, 120.4, 122.3, 125.5, 125.6, 127.2, 128.1, 130.8, 134.2, 138.1, 138.2, 141.4, 146.8; HRMS (EI) m/z 532.0459 C27H21N2IS [M]+. requires 532.0465.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[C:19]4=[O:25])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[CH3:26]O.O[O:29][S:30]([O-:32])=O.[K+]>O.C(Cl)Cl>[CH3:26][S:30]([C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[C:19]4=[O:25])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1)(=[O:32])=[O:29]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(SC)n2)C1=O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(S(C)(=O)=O)n2)C1=O
Reaction time: 7 h

Procedure:
To a solution of 2-Methylthio-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (100 mg, 0.282 mmol) in 1:1 methanol:methylene chloride (7 ml) was added a mixture of Oxone® (520 mg, 0.846 mmol) in water (2 ml) at 0° C. The reaction mixture was stirred at it for 7 h, then diluted with methylene chloride. The mixture was separated; the aqueous layer was extracted with methylene chloride (3×50 ml). The combined methylene chloride layer was dried over magnesium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography eluting with 5% 2N ammonium in methanol:methylene chloride system provided 63 mg of the title compound. Mass spectrum (ESI): 387 (M+1).). 1H NMR (CDCl3): δ8.97 (d, J=5.7 Hz, 1H); 8.71 (s, 1H); 8.26 (d, J=9.1 Hz, 1H); 8.02 (dd, J1=8.9 Hz, J2=2.1 Hz, 1H); 7.85 (d, J=2.0 Hz, 1H); 7.74 (d, J=5.7 Hz, 1H); 3.93 (t, J=8.0 Hz, 2H); 3.56 (t, J=8.0 Hz, 2H); 3.45 (s, 3H); 3.42(q, J=7.3Hz, 2H); 1.23 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CO[CH:35]1[CH2:39][CH2:38][CH:37](OC)O1.OS(O)(=O)=O.NC1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.C1COCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[CH:35]=[CH:39][CH:38]=[CH:37]4)=[CH:3][CH:4]=3)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]2[CH3:32])=[O:31])=[CH:28][CH:27]=1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc(N)cc3)CC2C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Nc1ccccc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(-n4cccc4)cc3)C[C@@H]2C)cc1

Procedure:
N-(4-amino-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (22 mg, 0.05 mmol) was dissolved in MeOH:THF (1 mL each) and cooled to 10° C. 2,5-dimethoxy-tetrahydrofuran (1.25 equiv.) was dissolved in THF and catalytic H2SO4, and added drop wise to the aniline mixture. The mixture was poured into sat. NaHCO3 and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated, and the crude residue was purified by preparative HPLC to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[C@@H:48]([NH2:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:50][C@H:48]([C:44]2[S:43][CH:47]=[CH:46][N:45]=2)[CH3:49])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: C[C@H](N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4nccs4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (30 mg, yield 66%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[CH2:8]([S:15][C:16]1[N:20]=[C:19]([SH:21])[NH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O-].[Na+].O>CN(C)C=O.CCOCC>[CH2:8]([S:15][C:16]1[N:20]=[C:19]([S:21][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[NH:18][N:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(CBr)OC
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(CSc1nc(SCc2ccccc2)n[nH]1)OC
Temperature: 110 °C
Yield: 90.4 %

Procedure:
Bromoacetaldehyde dimethyl acetal (7.8 g) was added portionwise to 3-benzylthio-5-mercapto-1,2,4-triazole (10 g) and sodium methoxide (2.5 g) in dimethylformamide (60 ml) under nitrogen. The mixture was heated at about 110° C. for 5 hours. Addition to water and isolation through ether gave 12.6 g of desired product, mp 73°-76° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)CC)C.[N:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH2:61][NH2:62]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([NH:62][CH2:61][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][N:55]=4)=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NCc1ccccn1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (0.060 g, 0.17 mmol) was dissolved in dry DMF (1.7 mL), and then TSTU (0.064 g, 0.21 mmol) was added followed by triethylamine (0.059 mL, 0.43 mmol). The reaction was stirred for 15 min then 2-picolylamine (0.019 mL, 0.19 mmol) was added. The reaction was stirred at room temperature under argon over night. The crude product was purified by preparative LC. The fractions were combined and the acetonitrile was evaporated. DCM was added and the layers separated. The aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 37 mg (49%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Product: CC(Oc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1)C(=O)O

Procedure:
Prepared from (5-bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and ethyl 2-bromopropionate according to GP2 and GP3: LC/MS (an 10p8) Rt 2.51 min, m/z 415 [M+H]+; 1H NMR (CDCl3): δ 1.65 (d, J=6.8 Hz, 3H), 4.93 (q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 7.35-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.70-7.76 (m, 3H), 8.17 (s, 1H), 8.52 (s, 1H); 13C NMR (CDCl3): δ18.8, 75.2, 114.8, 116.7, 120.1, 124.4, 128.3, 130.0, 133.3, 136.2, 139.2, 143.3, 155.0, 173.1, 187.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Li+].[Li+].[Br-:35].[Li+].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][Br:35])[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [Br-]
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)CC(CCBr)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 91.9 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (6.3 g) in THF (50 mL) was treated with lithium carbonate (2.0 g) and lithium bromide (2.34 g). The mixture was heated at reflux temperature for 2 hours. The cooled reaction mixture was diluted the CH2Cl2 (100 mL) and washed with H2O (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil, (5.6 g).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8](=O)([O-])[O-].[K+].[K+].[CH:14]([C:16](C)=O)=[CH2:15]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:6][C:5]1[CH2:7][CH2:8][C:3](=[C:14]([CH3:16])[CH3:15])[C:2](=[O:1])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C=C(C)C
Reactant: C=CC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Product: CC1=CC(=O)C(=C(C)C)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A 688 ml (6.0 mol) portion of mesityl oxide was put into a one liter capacity four neck flask and mixed with 13.82 g (0.1 mol) of potassium carbonate and 2.28 g (10 mmol) of benzyltriethylammonium chloride, and the mixture was heated to 80° C. To this was added dropwise 166.48 ml (2.0 mol) of methyl vinyl ketone spending 1 hour while keeping at 80° C. After completion of the dropwise addition, this was stirred for 30 minutes and then the reaction solution was distilled under a reduced pressure to obtain 186 g of piperitenone. Yield 62%.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:31][CH2:30]5)=[N:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 86.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 2 of example 140) (85 mg, 0.14 mmol) was alkylated using (S)-2-methyloxirane (10 mg, 0.169 mmol), DIPEA (22 mg, 0.169 mmol) and ethanol (3 mL) to get 80 mg (86%) of the titled compound. MS: m/z=662.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:22]([NH:21][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:13]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(NC(=O)NCc2ccccc2)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccccc1)Nc1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.3 mL), was added N-(3-aminophenyl)-N′-benzylurea (220 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (30 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→85/15). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (97 mg) as pale-yellow powder crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:7]=1[F:22])[CH3:2].C(N(CC)CC)C.[CH2:40]([O:42][C:43](=[O:46])[CH2:44]Br)[CH3:41]>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:46])[CH2:20][CH2:21]2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(Oc2cc(OCC)cc(C(Nc3ccc(C#N)cc3)C(=O)OCC)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 300 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester in 10 ml THF was cooled to 0° C. and treated with 0.14 ml triethylamine and 0.90 ml bromoacetic acid ethyl ester. The reaction mixture was stirred at r.t. overnight, then evaporated. The residue was taken up in water and extracted with EtOAc. The organic layer was dried over MgSO4. The crude product was purified by chromatography on silica with cyclohexane/EtOAc 1:2 to give 215 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-3-(1-ethoxycarbonylmethyl-piperidin-4-yloxy)-2-fluoro-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 528.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[O:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1>>[O:33]1[CH2:34][CH:35]=[C:36]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][S:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=4)[CH2:37][CH2:38]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCOCC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method BB12 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A reaction vessel was charged with 11.1 g of 3,5-dichloro-4-(3-bromopropoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 3.31 g of benzoic acid, 3.90 g of potassium carbonate and 50 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 150 ml of diethyl ether. The ether layers were combined, and washed with water, dried over anhydrous magnesium chloride, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.6 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (95% yield).