Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:16]([O:15][C:11]([CH2:12][CH2:13][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(CC#N)cc1
Reaction time: 72 h

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatographed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenylacetonitrile; 2.8 g of this product is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatographed on silica gel with 7.5% methanol saturated with ammonia in methylene chloride as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-2-phenethylamine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (2-bromo-5-trifluoromethyl-phenyl)-methanol (2.216 g, 8.69 mmol) and N-methylmorpholine N-oxide (2.051 g, 17.38 mmol) in CH2Cl2 (44 mL) and MeCN (2.2 mL) was added tetrapropylammonium perruthenate (0.311 g, 0.87 mmol), and the reaction was stirred at room temperature for 20 minutes. Once no starting material was seen by analytical tlc, the mixture was concentrated and purified by silica gel chromatography to give 2-bromo-5-trifluoromethyl-benzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:5]4[CH:6]=[C:7]5[C:11](=[C:3]([CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:4]=4)[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]5)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CNS(C)(=O)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Methanesulfonyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-(methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 483.2. found 484.3 (M+1)+. Retention time of 1.84 minutes.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH3:18])[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].N(C1(CC)C(=O)N(C2CCCCC2)C(=O)NC1=O)=[N+]=[N-].[C:39]1(=O)[O:44][C:42](=[O:43])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>C(O)(=O)C>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([CH2:17][CH3:18])([N:1]3[C:42](=[O:43])[C:41]4=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]4[C:39]3=[O:44])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCC1(N=[N+]=[N-])C(=O)NC(=O)N(C2CCCCC2)C1=O
Solvent: CC(=O)O
Product: CCC1(N2C(=O)c3ccccc3C2=O)C(=O)NC(=O)N(C2CCCCC2)C1=O
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A mixture of about 500 mg (about 2 mmol) of 5-amino-1-cyclohexyl-5-ethylbarbituric acid available from 5-azido-1-cyclohexyl-5-ethylbarbituric acid as described in Guetschow, M. et al., Synthesis, 1999, 410-414 (incorporated herein by reference) and about 300 mg (about 2 mmol) of phthalic anhydride and about 20 mL of glacial acetic acid was refluxed for about 5 hours. The mixture was cooled to room temperature and the precipitate was filtered off. The precipitate was next washed with H2O and dried to give about 470 mg of 1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (a yield of about 61%). The 1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid had a melting point of about 248 to about 253° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH3:29])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25]N>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH3:29])[CH3:21])=[N:7][C:6]=2[N:8]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN(C)CC(C)(C)CN
Product: CN(C)CC(C)(C)CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
The title compound was prepared as described above in Example 20 by reacting 2.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 15 mL of N,N,2,2-tetramethyl-1,3-propanediamine.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: ClC[C@H]1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1C[C@@H](O)CCl

Procedure:
Alternatively, a mixture of 0.42 g (3.7 mmole) of 2-nitroimidazole, 85 mg (0.62 mmole) of anhydrous potassium carbonate, and 5 mL of (R)-(-)-epichlorohydrin is refluxed for 10 minutes then filtered while hot. The filtrate is concentrated and cooled to give a solid. Crystallization from ethanol and further processing as above gives 0.56 g of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(Cl)Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 1.5 mmol) in pyridine (15 ml) was stirred at room temperature for 30 mins. DCM (40 ml) and acetic anhydride (168 mg, 1.65 mmol) was then added to the mixture. And it was stirred at room temperature for overnight. The mixture was concentrated in vacuo and the residue was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 10%-30%, 20 min) to give the title compound (226 mg, 40.2%) as a light yellow solid. 1H NMR: DMSO 400 MHz. δ9.99 (s, 1H), 9.19 (s, 1H), 8.24 (d, J=12.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.12 (dd, J=10.0 Hz, 1H), 6.45 (s, 1H), 6.35 (dd, J=10.8 Hz, 1H), 5.95 (brs, 2H), 4.85 (s, 2H), 4.54 (s, 2H), 1.92 (s, 3H). ESI-MS m/z 374 (M−H, positive); HPLC purity: 90.13% (MaxPlot 190-370 nm), 96.33% (220 nm).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:33].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:3]1[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=1[C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1Cl
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (30.3 mg, 0.065 mmol), 4-methoxyphenylboronic acid (15.1 mg, 0.099 mmol), tricyclohexylphosphine (3.2 mg, 0.011 mmol), and tris(dibenzylideneacetone)dipalladium (0) (3.7 mg, 4 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 mL) and aq. 1.3M potassium phosphate tribasic (0.1 mL, 0.13 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-50% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a solid as 5,7-difluoro-N-(4′-methoxy-4-morpholinobiphenyl-2-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.9 Hz), 8.05 (4H, m), 7.46 (1H, ddd, J=7.4, 4.9, 1.2 Hz), 7.34 (2H, m), 7.30 (1H, m), 7.07 (1H, m), 6.93 (2H, m), 6.83 (1H, dd, J=8.5, 2.4 Hz), 6.57 (1H, d, J=2.3 Hz), 3.91 (4H, m), 3.82 (3H, s), 3.24 (4H, m), 2.03 (3H, s). Mass Spectrum (pos.) m/e: 539.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25](C(OCC2C=CC=CC=2)=O)[CH2:24][CH2:23]1)=[O:21]>O1CCCC1>[O:21]=[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1]
Reactant: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCNCC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 50 mL pressure bottle was charged with tetrahydrofuran (10 mL), the product from Example 24A (0.450 g, 0.904 mmol) and 20% Pd(OH)2—C, wet (0.090 g, 0.641 mmol). The reaction mixture was stirred at 50° C. under an atmosphere of 30 psi H2 for 15 minutes. The mixture was filtered through a nylon membrane and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; 2N NH4OH in CH3OH/CH2Cl2, 2:98, eluant) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.36-7.19 (m, 10H), 4.16 (s, 2H), 3.40-3.25 (m, 7H), 2.73 (t, J=6.5, 2H), 2.68-2.59 (m, 4H); MS (DCI+) m/z 364 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25].C1(NC2CCCCC2)CCCCC1>C(#N)C.CCOCC.[Cu]I>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#CCCCCOCCCCCCBr
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
A mixture of 2-bromoquinoline (3.00 g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77 g), BTPC (90 mg), copper (I) iodide (11 mg), and dicyclohexylamine (2.79 g) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with ether (90 ml), filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane:ether (4:1→2:1) gave the title compound as a brown oil (4.25 g), t.l.c. (hexane:ether 2:1) Rf 0.22.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([O:28]CC)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([OH:28])=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 79.5 %

Procedure:
Ethyl 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylate (3 g), 1N-aqueous sodium hydroxide solution (17.3 ml) and ethanol (30 ml) were combined, and the mixture was refluxed for 5 hours. After cooled to room temperature, the organic solvent was removed in vacuo. The aqueous solution was acidified (pH=4) with 1N-hydrochloric acid, and extracted with ethyl acetate (twice). The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was dissolved in pyridine (45 ml), and then acetyl chloride (1.48 ml) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 13 hours, and pyridine was removed in vacuo. Water was added to the residue, and acidified with 1N-hydrochloric acid. The precipitate was collected in vacuo. The solid was washed with water and ethyl ether to give 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (2.23 g) as an off-white solid.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8]([CH:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC)=[O:9])C.[CH3:22][C:23]([CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:24][CH:25]=O.[OH-].[K+].Cl>C(O)(C)C.CCCCCC.O.O1CCCC1>[CH3:21][C:11]([CH:12]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:10][C:8]([OH:7])=[O:9]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CC=O
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC(=O)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 30.3 g. of sodium ethoxide in 300 ml. of tetrahydrofuran was added 118 g. of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate. To the mixture was added 67 g. of 3,7,11-trimethyl-2,4,6,10-dodecatetraene-1-al under stirring, chilling with ice and shielding from the light. After 1 hour, the reaction liquid was poured into 1 liter of water, and 1 liter of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanol and water (2:1), and concentrated to give 99 g. of a concentrate. To a refluxing solution of 8.2 g. of potassium hydroxide and 80 ml. of isopropyl alcohol was added 21 g. of the concentrate under shielding from the light. After 15 minutes, the reaction liquid was poured into 300 ml. of ice-water, made acidic by addition of hydrochloric acid, and extracted with 300 ml. of diethyl ether. The extract was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was dissolved in 200 ml. of n-hexane and chilled to -20° C. to crystallize it. There was obtained 9.8 g. of the desired product as pale yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)(=O)=O.C(N(CC)CC)C.C([SiH](CC)CC)C.CN([CH:47]=[O:48])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:47]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH2:25])(=[O:27])=[O:26])=[CH:22][CH:23]=1)[N:13]=[CH:12]2)=[O:48]
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cccc(OS(=O)(=O)C(F)(F)F)c3n2)cc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Nc2ncc3cccc(C=O)c3n2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-sulfamoylphenylamino)quinazolin-8-yl trifluoromethanesulfonate (900 mg, 2 mmole), Pd(dppf)Cl2 (170 mg, 0.2 mmole), triethylamine (700 ul, 5 mmole) and triethylsilane (960 ul, 6 mmole) in DMF (20 ml) was placed in a stainless steel reactor. CO was bubbled into the mixture in the reactor. The reaction solution was stirred at 85° C. under CO (420 psi) for overnight. The reaction mixture was poured into 80 ml of saturated NaHCO3 and extracted with ethyl acetate (2×250 ml). The combined organic layers were washed with water (2×60 ml) and brine (60 ml), then dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography to give 4-(8-formylquinazolin-2-ylamino)benzenesulfonamide (274 mg, 0.83 mmole) as brown solid. ES/MS m/z 328.9 (MH+).
Reaction SMILES: N[C:2](N)=[O:3].[CH3:5][C:6]([SiH2:11]Cl)([CH2:9][CH3:10])[CH2:7][CH3:8]>CO>[CH3:5][C:6]([SiH2:11][O:3][CH3:2])([CH2:9][CH3:10])[CH2:7][CH3:8]
Reactant: NC(N)=O
Reactant: CCC(C)(CC)[SiH2]Cl
Solvent: CO
Product: CCC(C)(CC)[SiH2]OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 300 ml 3-necked flask equipped with a magnetic stirrer, a Dimroth condenser and a 50 ml dropping funnel were charged 50 ml of methanol and 4.5 g of urea. To this was added dropwise 7.3 g of 3-methyl-3-(chlorosilyl)pentane obtained above over 15 minutes. After completion of the addition, the resulting mixture was stirred at room temperature for 1 hour while monitoring the reaction by gas chromatography. After evaporation of methanol, the residue was extracted with 60 ml of hexane. The extraction was repeated 3 times. Then, hexane was distilled off and the residue was used for the following reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18](OCC4C=CC=CC=4)[C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[CH2:29]([O:36]C1C=CC=C2C=1C(CCN)=CN2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: NCCc1c[nH]c2cccc(OCc3ccccc3)c12
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cccc(OCc3ccccc3)c21
Agent: Cl
Product: CCOC(=O)C1=CNCCc2c1[nH]c1c(OCc3ccccc3)cccc21

Procedure:
10-benzyloxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-benzyloxytryptamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C:17]([O-:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][C:27]([NH2:29])=[NH:28])=[N:4][CH:3]=1.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][C:27]([NH2:29])=[NH:28])=[N:4][CH:3]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CC(=O)[O-])c3ccccc3)cc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(CC(=O)O)c3ccccc3)cc12

Procedure:
A solution of t-butyl DL-3-{[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]amino}-3-phenylpropanoate (153 mg, 0.33 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give DL-3-{[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]amino}-3-phenylpropanoic acid trifluoroacetate (132 mg, 0.25 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]2=[O:29])=[C:4]2[N:10]=[CH:9][N:8](CC3C=CC(OC)=CC=3)[C:5]2=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]2=[O:29])=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC1CC(=O)N(Cc2c(Br)cnc3c2ncn3Cc2ccc(OC)cc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CCCC1CC(=O)N(Cc2c(Br)cnc3[nH]cnc23)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution containing 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x213 (0.5 g, 0.1 mmol), anisole (0.4 ml) and concentrated H2SO4 (0.2 ml) in trifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C. for 2 h. The homogeneous reaction mixture is added dropwise at 0° C. to a mixture of a saturated aqueous solution of NaHCO3 (50 ml) and ethyl acetate (50 ml). The organic layer is separated. The aqueous one (pH ˜8) is subjected to additional extraction with chloroform containing 10% of tert-butanol. The combined organic layers are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 0.31 g of 1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one 99.