Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:34]1(I)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)N1C=Cc2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 33.2 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (890 mg, 2.41 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (2.0 g, 14.5 mmol) and cyclopentyl iodide (0.84 mL, 7.24 mmol) dropwise. The reaction mixture was heated with stirring at 85° C. for 18 h. The solvent was evaporated and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (350 mg, 32% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[N:9]=[C:8]([C:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2N(C3C=CC(N)=C(OC)C=3)N=C(C3CCN(C(OC(C)(C)C)=O)CC3)C=2N=CN=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:9]=[C:8]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nn(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc23)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: COc1cc(-n2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nn(-c3ccc(N)cc3)c3c(N)ncnc23)CC1

Procedure:
The title compound was prepared from tert-butyl 4-[7-amino-1-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidine-3-yl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate in the same manner as described for the preparation of tert-butyl 4-[7-amino-1-(4-amino-3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-1-piperidinecarboxylate: RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 16.07 min; MS: MH+ 410.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:17]=3[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:10]1([N:14]2[CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:22]([O:25][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:21][C:18]=3[CH2:19][CH2:20]2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C

Procedure:
Ethyl 4-bromobutyrate (2 ml, 13.8 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (2.00 g, 9.2 mmol) and potassium carbonate (3.8 g, 27.6 mmol) in 2-butanone (50 ml). After stirring at reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography eluting with a mixture of methanol:dichloromethane (5:95) to afford the title compound (E167a). MS (ES+) m/e 332 [M+H]+
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CS(C)=O.CO>[CH2:16]([O:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OCc1ncccc1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: C=CCOc1cccnc1CO
Reaction time: 2 h

Procedure:
To a sodium methoxide, methanol mixture made from 1.43 g (62 mmole) sodium metal and 100 ml methanol was added 5.9 g (31 mmole) 3-hydroxy-2-hydroxymethylpyridine and the methanol removed in vacuo. The resulting residue was dissolved in 80 ml dimethylsulfoxide (DMSO) and 3.0 ml (34.7 mmole) allyl bromide in 20 ml DMSO was added over 20 minutes at room temperature. The mixture was stirred for two hours, the DMSO distilled in vacuo and the residue partitioned betwen chloroform/water. The aqueous phase was adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to give 3.48 g (68%) of the desired ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:32][C:31]3[C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[N:27][CH:28]=[C:29]([N:33]4[CH2:34][CH2:35][S:36][CH2:37][CH2:38]4)[CH:30]=3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(N2CCSCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCSCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (117 mg, 0.43 mmol), 2-morpholino-5-thiomorpholinopyridin-3-amine (120 mg, 0.43 mmol) and a 4.0M solution of HCl in dioxane (0.11 mL, 0.43 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 7-fluoro-3-methyl-N-(2-(4-morpholinyl)-5-(4-thiomorpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=4.1, 1.0 Hz), 7.85-7.96 (2H, m), 7.75-7.84 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.40 (1H, ddd, J=7.0, 4.9, 1.8 Hz), 7.28-7.32 (1H, m), 6.74 (1H, s), 6.19 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.31 (4H, ddd, J=4.9, 2.7, 2.5 Hz), 3.23 (4H, br. s.), 2.63 (4H, dt, J=5.1, 2.5 Hz), 2.38 (3H, s). Mass Spectrum (ESI) m/e=517.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.N1CCC(CNC(=O)OC(C)(C)C)CC1>>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Product: O=[N+]([O-])c1ccccc1

Procedure:
Nitrobenzene Int-15b was prepared by following similar procedures to those described in Step A of Example 2 using 4-bromo-1-fluoro-2-nitrobenzene and tert-butyl piperidin-4-ylmethylcarbamate as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](CN=[N+]=[N-])C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
A procedure similar to that used to prepare compound 161 was used except that (3S,5S)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 169 (2.50 g, 8.405 mmol) was used as a reactant to give 170 as an oil (1.648 g, 72%). MS (APCI) m/z 272 (M++1, 100%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1([C:13]([F:16])([F:15])[F:14])[O:7][C:6]([CH:9]=[CH2:10])([F:8])[C:5]([F:12])([F:11])[O:4]1.C([Al](Cl)Cl)C.[CH:24]#[N:25]>C1(C)C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[C:3]1([C:2]([F:1])([F:17])[F:18])[O:7][C:6]([CH2:9][CH2:10][C:24]#[N:25])([F:8])[C:5]([F:11])([F:12])[O:4]1
Reactant: C#N
Reactant: C=CC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F
Agent: CC[Al](Cl)Cl
Solvent: Cc1ccccc1
Product: N#CCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F
Temperature: 60 °C
Yield: 66 %

Procedure:
A mixture comprised of Ni[P(O-tolyl)3]4 (3.3 g, 2.2 mmole) and P(O-tolyl)3 (1.7 g, 4.8 mmole), 2,2-bis(trifluoromethyl)-4-vinyl-4,5,5-trifluoro-1,3-dioxolane (30 g, 0.103 mole), 25% EtAlCl2 in toluene (2.0 ml), and toluene (25 ml) was heated under nitrogen in an oil bath at 60° C. A 50% HCN in toluene solution was fed from an ISCO pump at a rate of 1.5 ml/hour for 4.5 hours and then 0.5 ml/hour overnight until the reaction was complete (GC determination). The mixture was allowed to cool and was purified by distillation to give 2,2- bis(trifluoromethyl)-4-(2-cyanoethyl)-4,5,5-trifluoro1,3-dioxolane as a clear, colorless liquid in 66% yield. Bp. 65°-68° C./7.0 mm. 1H-NMR (CDCl3): δ 2.72 (t, J=7.8 Hz, 2H), 2.50 (m, 2H); 19F NMR (CDCl3 ): -110.2 (m, 1F), -76.9, -77.6 (2m, 1F), -87.0, -87.7 (2d, J=9.3 Hz, 1F), -80.6 (m, 3F), -81.3 (m, 3F). Anal. Calc. for C8H4F9NO2 : C: 30.28, H: 1.27, F: 53.94; Found: 30.21, H: 1.34, F: 54.26. MS: [M]: Calc.: 317.0098; Found: 317.0081; MS (PCI): [M+H]: Calc.: 318.0177; Found: 318.0176. ##STR10##
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]#[C:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Cl>C(O)(=O)C.O1CCOCC1>[C:1]([NH:4][CH:5]([CH2:9][C:10]#[C:11][CH2:12][NH2:13])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CC#CCNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=O)NC(CC#CCN)C(=O)O

Procedure:
Ex-8g) 10 g of 2-Acetylamino-6-t-butyloxycarbonylamino-4-hexynoic acid is taken up in 50 mL of acetic acid and 25 mL of 4N HCl in dioxane and stirred for 2 h at 25° C. The reaction mixture is stripped to dryness to give 2-Acetylamino-6-amino-4-hexynoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10]([CH:16]=[N:17]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].ClC1C=CC=CN1C.CCN(CC)CC.Cl>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10]([C:16]#[N:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CC(C=NO)CN(Cc2ccccc2)C1
Agent: CN1C=CC=CC1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1CC(CO)CN(Cc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To 1-benzyl-5-(hydroxymethyl)piperidine-3-carbaldehyde oxime (3.3 g, 13.30 mmol) in CH2Cl2 (15 mL) at 23° C. was added 2-chloro-1-methylpyridine iodide (3.73 g, 14.62 mmol) in one portion and the resulting mixture stirred at 23° C. for 10 min. Et3N was then added and the reaction mixture stirred for 3 hours (color changed from light yellow to light brown). The solution was neutralized with HCl (5%), to approximately pH 6 and the organic material was extracted with CH2Cl2 (3×25 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford 3.06 g (95% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.37 (5 H, m), 3.51-3.60 (4 H, m), 3.11 (1 H, ddd, J=11.0, 1.9, 1.8 Hz), 2.98 (1 H, d, J=7.6 Hz), 2.73-2.82 (1 H, m), 2.12-2.22 (2 H, m), 1.80-1.92 (2 H, m), 1.45 (1 H, br s), 1.27-1.38 (1 H, m). LCMS (+ESI, M+H+) m/z: 231.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:14](=[O:23])[NH:15]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][NH:26][C:25]=1/[CH:24]=[C:13]1\[C:14](=[O:23])[NH:15][C:16]2[C:12]\1=[C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=2
Reactant: OB(O)c1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Yield: 81 %

Procedure:
Using Method S above, phenyl boronic acid (75.2 mg, 0.617 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 6) using DPPFPdCl2 (17 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.42 mL, 0.84 mmol) and DME (15 mL) at reflux for 18 h to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (yield: 120 mg, 80%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(NC(=O)N3CCOCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[C:45]3[C:40](=[C:41]([F:47])[CH:42]=[CH:43][C:44]=3[F:46])[O:39][CH2:38][CH:37]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C(OCC)(=O)C.O>[CH2:13]([O:20][CH2:21][CH2:22][C:23](=[O:25])[CH2:24][CH:37]1[CH:36]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C:45]2[C:40](=[C:41]([F:47])[CH:42]=[CH:43][C:44]=2[F:46])[O:39][CH2:38]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CCOCc1ccccc1
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCOCc1ccccc1)CC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (1.23 g, 12.2 mmole) was dissolved in 150 ml dry THF and the reaction was cooled to 0° C. n-Butyllithium (2.5 ml in Hexane, 4.5 ml, 11.2 mmole) was added and the reaction was stirred at 0° C. for 10 minutes. The reaction was cooled to −100° C. and 4-benzyloxy-2-butanone (1.83 g, 10.3 mmole) in 50 ml dry THF (pre-cooled to −78° C.) was added. The reaction was stirred for 30 minutes at −78° C. 4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (3.2 g, 9.36 mmole) in 20 ml THF (pre-cooled to −78° C.) was added. The reaction was stirred at −78° C. for 1 hour. 20 ml water was added at −78° C. to quench the reaction. After the reaction was warmed up to room temperature, 200 ml EtOAc was added. The organic layer was washed with brine (2×100 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 40/60 in 45 minute). Yield, 2.6 g, 53%. 1H NMR (CDCl3 400 MHz δ 7.82 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.20-7.35 (m, 5H), 7.05 (m, 1H), 6.47 (m, 1H), 4.89 (dd, J=11.7 and 2.9 Hz, 1H), 4.42 (s, 3H), 4.24 (dt, J=12.4 and 2.2 Hz, 1H), 3.65 (t, J=5.9 Hz, 2H), 3.31 (m, 1H), 2.33-2.67 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3[O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[CH:13]1[C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 81.1 %

Procedure:
A solution of 4-(4-nitrophenyl)dibenzo[b,d]furan (22 g) in EtOAc (800 mL) was hydrogenated in presence of Pd/C (10%, 4.2 g) for 12 h at rt under 2 Kg of pressure. The reaction mixture was filtered, and the filtrates were concentrated. The residue was crystallized from chloroform/PetEther (6/4) to give the title compound (16 g, 84%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.57 (d, 1H, J=8.6 Hz), 7.50 (m, 1H), 7.38 (m, 2H), 6.72 (d, 2H, J=8.4 Hz), 7.35 (s, 2H). M+(LC/MS(ESI)): 260.2
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[C:45]2[C:41]([CH:42]=[C:43]([C:47]([OH:49])=O)[NH:44]2)=[CH:40][CH:39]=1.[NH2:50][CH2:51][C:52]1[C:53]([F:69])=[C:54]([O:59][C:60]2[CH:61]=[C:62]([CH:65]=[C:66]([Cl:68])[CH:67]=2)[C:63]#[N:64])[C:55]([Cl:58])=[CH:56][CH:57]=1>CN(C=O)C>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][NH:50][C:47]([C:43]2[NH:44][C:45]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:37][CH2:36][CH2:35][OH:34])[CH:46]=3)=[O:49])=[C:53]([F:69])[C:54]=1[O:59][C:60]1[CH:61]=[C:62]([C:63]#[N:64])[CH:65]=[C:66]([Cl:68])[CH:67]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1cc2ccc(OCCO)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(OCCO)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
HATU (0.070 g, 0.186 mmol) and DIPEA (0.024 mL, 0.186 mmol) were added to a solution 6-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.041 g, 0.186 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.057 g, 0.186 mmol) in DMF. This solution was stirred 2 h at room temperature. The mixture was partitioned between water and EtOAc, the organic layer was separated, washed with a 15% solution of Na2CO3, dried over MgSO4 and filtered. The EtOAc was evaporated to yield a residue which upon trituration in EtOAc afforded the title compound (0.041 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (s, 1H), 8.88 (t, 1H), 7.80 (s, 1H), 7.43-7.53 (m, 4H), 7.37 (t, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 6.68 (d, 1H), 4.83 (t, 1H), 4.53 (d, 2H), 3.94 (t, 2H), 3.71 (q, 2H). MS m/z 512 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH:21]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][CH2:27]Cl)([CH3:23])[CH3:22]>CN(C)C=O>[CH:21]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][CH2:27][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)([CH3:23])[CH3:22]
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Reactant: CC(C)N(CCCCl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN(C(C)C)C(C)C)c1ccccc1N(C)C2=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 4.5 gm of 6,11-dihyrdo-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 60 ml of dimethyl formamide and 1.27 gm of 50% sodium hydride in mineral oil was stirred at 90° C. for 1 hour. Thereafter, 4.6 gm of 3-diisopropylamino-propyl chloride were added dropwise and the mixture was stirred at 120° C. for 2 hours. The reaction solution was then evaporated in vacuo, and the residue was dissolved in a mixture of ether and dilute ammonia. The organic phase was separated, dried over sodium sulfate and evaporated. The oily residue was distilled, and the fraction passing over between 189°-193° C. at 0.13 mm Hg was recrystallized from petroleum ether, yielding 31% of theory of the compound named in the heading, which had a melting point of 118°-119° C.
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[CH2:24]([O:26][C:27](=[O:31])[C:28](Cl)=[O:29])[CH3:25]>C(OCC)(=O)C.O>[CH2:24]([O:26][C:27](=[O:31])[C:28]([NH:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])=[CH:16][CH:15]=1)=[O:29])[CH3:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To 20 ml of tetrahydrofuran, were added 3.13 g of 4-t-butyl aniline, and 2.42 g of triethylamine, and the solution was iced. In the iced solution, 2.73 g of ethyl chloroglyoxylic acid was added dropwise to the resulting solution over 10 minutes, after which the solution was heated to room temperature, and stirred for about one hour. After completion of the reaction, 50 ml of water was added to the reacted solution, and extraction was carried out three times with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and solvent was evaporated under reduced pressure to obtain 4.97 g (99.7%) of ethyl-2-(4-t-butylphenylamino)-2-oxoacetate.
Reaction SMILES: [C:1]([C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:26]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOCC>[ClH:26].[CH:1](/[C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cnc2ccc(NCCCN3CCOCC3)nn12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCC/C=C\c1cnc2ccc(NCCCN3CCOCC3)nn12
Reaction time: 48 h
Yield: 18 %

Procedure:
3-(Hex-1-ynyl)-N-(3-morpholinopropyl)imidazo[1,2-b]pyridazin-6-amine (75 mg, 0.22 mmol) was dissolved in ethanol (4 mL) and Lindlar's catalyst (20 mg) added. After degassing with a nitrogen stream for 10 mins, the reaction was put under a balloon of hydrogen for 48 h. The solids were filtered off and the filtrate was concentrated. The obtained residue was purified by semi-prep HPLC to provide the free-base, which was subsequently converted to the HCl salt with 2N HCl in Et2O to provide the title compound (15 mg, 18%) as an orange solid; 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=9.6 Hz, 1H), 7.61 (d, J=4.9 Hz, 1H), 6.81-6.74 (m, 2H), 5.88 (dt, J=7.2, 16.2 Hz, 1H), 3.89 (m, 4H), 3.52 (t, J=6.5 Hz, 2H), 3.37-3.22 (m, 6H), 2.44-2.37 (m, 2H), 2.21-2.12 (m, 2H), 1.56-1.39 (m, 4H), 0.95 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 155.6, 135.0, 127.9, 124.8, 115.8, 114.5, 65.3, 56.8, 53.4, 39.6, 32.6, 30.8, 24.5, 23.6, 14.3 (2 quaternary aromatic carbons did not show); HPLC tR=13.1 min (Synergi), 91.7%; ES-MS: (M+H)=344 m/z.