Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][OH:17])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(OC(N=NC(OCC)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][O:17][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCO)s1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCOc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butyl acetate (285 mg, 0.88 mmol) obtained in Example 52(a) and 4-chlorophenol (136 mg, 1.06 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml), and then azodicarboxylic acid diethylester (230 mg, 1.32 mmol) and triphenylphosphine (346 mg, 1.32 mmol) were added thereto in an ice bath followed by stirring for 4 hours at room temperature. Into the reaction mixture was poured water, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-1:3) to give (2R)-acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butyl acetate (195 mg, 51% yield) as a yellow oil. This product was dissolved in 6 ml of a mixture solvent (tetrahydrofuran:methanol:water=1:1:1), and lithium hydroxide monohydrate (370 mg, 8.82 mmol) was added thereto followed by stirring for 6 hours at 50° C. The reaction solution was poured into water, extracted with dichloromethane, and after the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue (175 mg, 0.50 mmol) was dissolved in ethyl acetate (5 ml), and oxalic acid (45 mg, 0.50 mmol) was added thereto to precipitate crystals. The crystals were filtered off to afford the title compound (198 mg, 86% yield) as white crystals.
Reaction SMILES: [CH2:1](/[C:3](/[CH:10]([OH:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2].N1C=CC=CC=1.C1COCC1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:1](/[C:3](/[CH:10]([O:12][C:26](=[O:27])[CH2:25][Cl:24])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC/C(C(N)=O)=C(/CC)C(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC/C(C(N)=O)=C(/CC)C(C)OC(=O)CCl
Reaction time: 0.25 h
Yield: 98 %

Procedure:
27 (rac-Diethyl (2E)-4-hydroxypent-2-enamide) (1.05 g, 6.0 mmol), pyridine (969 μl, 12 mmol) and DMAP (147 mg, 0.60 mmol) are dissolved in toluene (30 ml) and THF (10 mL) and cooled to 0° C. Chloroacetylchloride (954 μl, 12 mol) in toluene (4 ml) is added dropwise under stirring at ≦2° C. over 15 min. The reaction mixture is stirred 2.5 h at 0° C. The resulting suspension is then poured onto H2O (50 ml) and extracted with tBuOMe (150 and 75 ml). The organic phases are washed with 1 M HCl (50 ml), H2O (50 ml), saturated NaHCO3 (50 ml) and brine (50 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is filtered with tBuOMe (50 ml) and tBuOMe:AcOEt 50:50 (300 ml) over SiO2 (15 g) and yields 34 (rac-Diethyl (2E)-4-(chloroacetoxy)pent-2-enamide) (1.46 g, 98%) as a yellow oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][O:21][C:22](=[O:64])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[CH2:55][CH2:56][N:57]=[N+]=[N-])=[CH:25][C:24]=1[O:60][CH:61]([CH3:63])[CH3:62].O>C1COCC1>[CH3:20][O:21][C:22](=[O:64])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:33]=2[CH2:55][CH2:56][NH2:57])=[CH:25][C:24]=1[O:60][CH:61]([CH3:62])[CH3:63]
Reactant: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
Ph3P (polymer support: 3 mmol Ph3P/gram) (0.100 g, 0.30 mmol) was added to a solution of the azide from Step 6 (0.100 g, 0.16 mmol) in THF (2 mL). Reaction was stirred at room temperature for 24 hours. Then water (0.5 mL) was added and reaction was stirred at room temperature overnight. Reaction solution was filtered and the filtrate was concentrated by rotary evaporation. The resulting residue was purified with silica gel prep plates and 2% MeOH in dichloromethane as eluent. Obtained 0.020 g of 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in 21% yield.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(Br)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(Br)C(=O)Cl
Yield: 63.5 %

Procedure:
To a solution of 20 g (90 mmol) 2-bromooctanoic acid in 100 mL toluene was added 13.2 mL (180 mmol) thionyl chloride. The solution was heated at reflux under nitrogen for 3 hours. The excess thionyl chloride and toluene were distilled at atmospheric pressure under N2. The yellow residue was purified by kugelrohr distillation (bp=60°-65° C./0.1 mm Hg) and 13.8 g (64%) of the 2-bromooctanoyl chloride as a colorless oil was isolated. 1H NMR (CDCl3)δ0.85-0.95 (m,3H,CH3), 1.24-1.57 (m,8H,CH2), 1.98-2.22 (m,2H,CH2CBr) 4.51 (t, J=7.10 Hz, 1H, CHBr); IR (CHCl3) 1788 (C=O) cm-1 ; microanalysis: calcd. for C8H14BrClO-39.78% C,5.84% H, 33.08% Br, 14.68% Cl, found-39.55% C,5.91% H, 33.17% Br, 14.84% Cl.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3c2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless foam.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:30])([F:31])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][C:17]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
2 ml (0.021 mol) of acetic anhydride and 0.9 ml (0.02 mol) of 98% strength nitric acid are successively added to 6 g (0.019 mol) of 5-acetamido-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole in 15 ml of glacial acetic acid at room temperature, and the mixture is stirred at room temperature for 15 hours. For working-up, the reaction mixture is added dropwise to 200 ml of ice-water, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 5.8 g (85% of theory) of 5-acetamido-4-nitro-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 129°-130° C. are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)CC>>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)CCN(C)Cc1ccccc1
Agent: CCC[Mg]Cl
Product: CCCC(=O)CCN(C)Cc1ccccc1

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-one, propylmagnesium chloride (2 M solution in diethyl ether) affords the title compound: mass spectrum (ion spray) m/z=220 (M+1): 1H NMR (CDCl3) δ 7.35-7.24 (m, 5H), 3.51 (s, 2H), 2.74-2.69 (m, 2H), 2.66-2.61 (m, 2H), 2.39 (t, 2H), 2.20 (s, 3H), 1.67-1.57 (m, 2H), 0.92(t, 3H).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC#N.CCN(CC)CC.[CH3:52][NH:53][S:54](Cl)(=[O:56])=[O:55]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[N:9][S:54](=[O:56])(=[O:55])[NH:53][CH3:52])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNS(=O)(=O)Cl
Reactant: N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CNS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Disolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH3CN, benzene or toluene and add Et3N (2 equivalents). Cool the solution to 0° C. and add N-methylsulfamoyl chloride (1.2 equivalents) [prepared as described in: J. A. Kloek and K. L. Leschinsky, J. Org. Chem., 41 (25) (1976), p. 4028-4029]. Stir the mixture at 0° C. to 25° C. for 3 h, extract, filter and evaporate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20](O)=[O:21]>O1CCCC1>[CH:13]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:20]=[O:21])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=2)=[CH:16][CH:15]=1)=[O:14]
Reactant: O=CO
Reactant: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=CNc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]

Procedure:
4-[(4-amino-3-nitrophenyl)oxy]benzaldehyde (1.4 g, 5.4 mmol), 10 mL of 96% formic acid and 25 mL of tetrahydrofuran were heated at reflux for approximately 18 hours. The reaction was concentrated and the residue was heated to reflux in 96% formic acid for six hours. The reaction mixture was concentrated to give {4-[(4-formylphenyl)oxy]-2-nitrophenyl}formamide. (M-1) 285.1, 2.22 min (LC/MS method A)
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][C:10]([C:12]1[C:20]2[S:19][C:18]([NH:21][C:22](=[O:26])[NH:23][CH2:24][CH3:25])=[N:17][C:16]=2[CH:15]=[C:14]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][C:36]([CH3:44])([C:39]([O:41]CC)=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH:13]=1)=[O:11])[CH3:8]>CS(C)=O>[CH2:7]([NH:9][C:10]([C:12]1[C:20]2[S:19][C:18]([NH:21][C:22](=[O:26])[NH:23][CH2:24][CH3:25])=[N:17][C:16]=2[CH:15]=[C:14]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:34][CH2:35][C:36]([CH3:44])([C:39]([OH:41])=[O:40])[CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(=O)NCC)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C(=O)NCC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Potassium tert butoxide (67 mg, 0.59 mmol) was added to a solution of ethyl 1-[5-[7-(ethylcarbamoyl)-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (78 mg, 0.147 mmol) in DMSO (1.5 mL). The mixture was stirred at ambient temperature for 2 h after which time LCMS indicated clean conversion to the acid. The mixture was filtered through cotton wool to remove solid particulates and purified by preparative HPLC. Compound 97 was obtained as a white solid, 44 mg, 75% yield. 1H NMR (DMSO-d6): δ 10.86 (1H, s), 8.88 (2H, s), 8.82 (1H, t, J=5.47 Hz), 8.12 (1H, d, J=1.57 Hz), 8.05 (1H, d, J=1.45 Hz), 7.14 (1H, t, J=5.61 Hz), 4.32 (2H, dt, J=13.66, 4.46 Hz), 3.24 (5H, p, J=6.88 Hz), 3.20-3.27 (2H, m), 2.06 (2H, dt, J=13.52, 3.72 Hz), 1.41 (2H, ddd, J=13.42, 10.06, 3.89 Hz), 1.24 (1H, s), 1.22 (3H, t, J=3.29 Hz), 1.21 (3H, s), 1.14 (3H, t, J=7.17 Hz). MS: 512 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:4].[NH2:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23].[I-].[Na+].C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: CCNC(=O)c1cccc(N)c1
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc(NCC(=O)NCCc2ccc(OC)c(OC)c2)c1
Reaction time: 4.5 h
Yield: 44.8 %

Procedure:
75 ml of dimethylformamide was added to a mixture of 15.0 g of 2-chloro-N-(2-(3,4-dimethoxyphenyl)ethyl)acetamide, 9.5 g of 3-amino-N-ethylbenzamide, 8.7 g of sodium iodide and 11.6 g of calcium carbonate, and the mixture was stirred for 4.5 hours at 55° to 60° C. After cooling, an insoluble material was removed by filtration and, the filtrate was concentrated in vacuo. The residue was extracted with 500 ml of chloroform, and the extract was washed successively with a 10% sodium sulfite aqueous solution and a saturated aqueous solution of sodium chloride. The washings were extracted with 500 ml of chloroform, and the extract was added to the chloroform solution. The combined chloroform solution was dried over sodium sulfate, and the solvent was distilled off. 120 ml of 10% hydrochloric acid was added to the residue, and the mixture was washed 6 times with 30 ml of dichloroethane. The aqueous solution was made alkaline by adding sodium carbonate to form an aggluten-like material. The material was extracted with 300 ml of dichloroethane, and the extract was washed with a saturated aqueous solution of sodium chloride. The washings were extracted with 200 ml of dichloroethane. The extract was added to the above dichloroethane solution, and the mixture was dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on 390 g of silica gel using a mixture of ethyl acetate and ethanol (10:1 by volume) for elution to obtain a fraction containing a product. The solvent of the fraction was distilled off and the residue was recrystallized from a mixture of methanol and diethyl ether to give 10.0 g of 3-((2-((2-(3,4-dimethoxyphenyl)ethyl)amino)-2-oxoethyl)amino)-N-ethylbenzamide as colorless needles with m.p. 99° to 101° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:36])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:28])=[C:23]([F:37])[CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:36])=[C:23]([F:37])[CH:22]=3)=[CH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)(C)OC3CCCCO3)c(F)c1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)OC4CCCCO4)c(F)c3)cc2c1
Yield: 65.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-vinyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (6 g, 9.1 mmol) in tetrahydrofuran (5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 15 mL, 15 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-vinyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (3 g, 63.8%) as a white solid: LC/MS m/e calcd for C30H35FN2O4 [M+H]+ 507.62, observed 507.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][OH:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=2)[CH2:4][O:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH:16]=[O:17])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=2)[CH2:4][O:3]1
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 66 h
Yield: 54.5 %

Procedure:
Thereafter, 253 mg of (4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol was dissolved in 10 ml of methylene chloride. Then, 2.5 g of activated manganese dioxide was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 66 hours. Thereafter, the reaction solution was filtered through celite, and the filtrate was concentrated under a reduced pressure, so as to obtain 137 mg of the subject compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:10]([CH:22]([CH:30]([CH3:32])[CH3:31])[C:23]([O:25]C(C)(C)C)=[O:24])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:10]([CH:22]([CH:30]([CH3:31])[CH3:32])[C:23]([OH:25])=[O:24])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
t-Butyl 2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.22 g; 0.48 mmol) was dissolved in CH2Cl2 (2 ml), and the reaction solution was cooled to 0° C. Then TFA (2 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. It was then concentrated in a rotary evaporator, and the residue was taken up with water and extracted with CH2Cl2 (3×). The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. 2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (0.18 g; 0.45 mmol) was obtained as a yellow oil. MS: 397.20 (M+H); Rt: 1.52 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].P(Cl)(Cl)([Cl:18])=O.CN(C=O)C>S(Cl)(Cl)=O>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Yield: 81 %

Procedure:
A mixture of 7-chloro-6-nitro-3,4-dihydroquinazolin-4-one (40 g, 0.18 mol), (J. Org. Chem. 1975, 40, 356), phosphorus oxychloride (50 ml) and DMF (1 ml) in thionyl chloride (300 ml) was heated at reflux for 4 hours. The reaction mixture was allowed to cool and the volatiles removed by evaporation and by azeotroping with toluene. The residue was basified with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride (4×100 ml). The extracts were combined, washed with brine and filtered through phase separating paper. The solvent was removed by evaporation and the residue triturated with ether/isohexane to give 4,7-dichloro-6-nitroquinazoline (35.2 g, 81%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([C:10]3[N:14]4[N:15]=[C:16]([NH:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=5)[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([C:10]3[N:14]4[N:15]=[C:16]([N:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=5)[CH3:37])[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccc3ncc(-c4cc5cc(OC)c(OC)cc5s4)n3n2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ccc3ncc(-c4cc5cc(OC)c(OC)cc5s4)n3n2)cc1OC
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 3-(5,6-dimethoxybenzo[b]thiophen-2-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (50 mg, 0.108 mmol, 1.0 equiv) in DMF (5.0 mL) was added NaH (13 mg, 0.324 mmol, 3.0 equiv) followed by iodomethane (0.07 mL, 0.541 mmol, 5.0 equiv). After 1 h, the reaction was quenched with saturated aqueous solution of ammonium chloride then extracted with ethyl acetate. Purification by column chromatography using 2% methanol in dichloromethane elution gave 30 mg of the brown solid, 58%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13](C(O)=O)[CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[ClH:19]>ClCCl.O1CCOCC1>[ClH:19].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N[C@H]2CCNC2)nc1
Reaction time: 8 h

Procedure:
The above nitro compound (6.16 g, 20.0 mmol) was suspended in dichloromethane (200 mL) and hydrogen chloride in dioxane (4M, 25 mL) was added. The mixture was stirred overnight and solvents were evaporated to give (S)-5-nitropyridine-2-yl-pyrrolidine-3-yl-amine hydrochloride as an off white solid (5.92 g).