Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=O)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCC(=O)Nc2cccc(Cl)c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 2, react N-(3-chlorophenyl)-2-[[(3,4-dimethoxyphenyl)methyl]amino]acetamide (13.6 g, 40.1 mmol) with lithium aluminum hydride (3.1 g, 81 mmol) to obtain thetitle compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=O)[CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)NC1(c2ccc(Br)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC1(c2ccc(Br)cc2)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of N-[1-(4-bromophenyl)-cyclopropyl]-propionamide (Intermediate 117, 85.0 mg, 0.32 mmol) in THF (5 mL) at 0° C. was added BH3-Me2S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). The solution was heated to 55° C. for 17 hours, cooled to room temperature, saturated aqueous NaHCO3 was added and the resulting mixture was stirred for 2 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-30% EtOAc-hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[Cl:14][CH2:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[Cl:14][CH2:15][N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: O=C=Nc1nc2cc(F)ccc2s1
Reactant: O=CCNCCl
Solvent: c1ccccc1
Product: O=CCN(CCl)C(=O)Nc1nc2cc(F)ccc2s1
Reaction time: 1 h

Procedure:
5-Fluorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-chloromethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-fluorobenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[C:18]([O:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][C:24]=1Br)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:1]2[CH2:2][CH2:3][N:4]3[C:12]4[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]3[C:13]2=[O:15])=[CH:25][CH:26]=[CH:27][C:28]=1[Br:29])(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 105 °C
Yield: 31.1 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101k (720 mg, 3.78 mmol), 2,6-dibromobenzyl acetate 104g (2.33 g, 7.57 mmol), cesium carbonate (2.47 g, 7.57 mmol), N,N′-dimethylethylenediamine (333 mg, 3.78 mmol) and 1,4-dioxane (31 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (360 mg, 1.89 mmol) was added, and the reaction mixture was heated at 105° C. (oil bath temperature) for 3 days. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (200 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 31% yield (490 mg) of 2-bromo-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 109a.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[CH:7]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CN(Cc1ccnc(Br)c1)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(Cc1ccnc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(2-bromo-pyridin-4-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[2-(3-methanesulfonyl-phenyl)-pyridin-4-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 492.9 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccccc2)cc1OC
Temperature: 15 °C
Yield: 85.2 %

Procedure:
To a mixture of 3,4-dimethoxybenzylamine (24.0 g, 0.144 mol), tetrahydrofuran (192 mL) and triethylamine (15.5 g, 0.153 mol) was added dropwise benzoyl chloride (20.7 g, 0.147 mol) at −7-0° C. During addition dropwise, tetrahydrofuran (24 mL) was added thereto to stir the mixture. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (12 mL), and tetrahydrofuran (24 mL) was added again thereto. The reaction mixture was gradually warmed to about 15° C. The reaction was monitored by TLC (eluent: hexane/ethyl acetate (1:1)). To the reaction mixture was added water (48 mL) at 5-8° C., and then added ethyl acetate (144 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (48 mL×2). The combined organic layers were washed successively with 10% hydrochloric acid (48 mL), saturated aqueous sodium hydrogen carbonate solution (48 mL), water (48 mL) and saturated brine (48 mL), and dried over magnesium sulfate (12 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. To the concentrate (40 g) was added ethyl acetate (89 g), and the mixture was homogenized with warming at 50° C., and cooled to 11° C. The solid was collected by filtration, washed with cold ethyl acetate (15 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-3,4-dimethoxybenzylamine (33.3 g, 85.4%) as white crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12

Procedure:
{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetate (0.463 g, 0.991 mmol), potassium hydroxide (0.224 g, 3.99 mmol) in THF (5 mL) and water (5 mL) according to the procedure described in Step 4 of Example 5. The title compound was obtained as a light yellow solid (0.314 g, 78%), mp 169-171° C. Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.75 (s, 1H), 8.45 (d, 1H, J=1.5 Hz), 7.75-7.8 (m, 2H), 7.7 (d, 1H, J=8.5 Hz), 7.6 (dd, 1H, J=8.7 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25-7.35 (m, 5H), and 5.65 ppm (s, 2H).
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=1[C:13]#[N:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:11]([O:10][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: CCCCCCOc1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To dimethylformamide solution (91 ml) containing 2-chloro-5-nitrobenzonitrile (18.2 g) and n-hexanol (11.2 g) was added sodium hydride (60% content, 4.8 g) under ice-cooling and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give 2-n-hexyloxy-5-nitrobenzonitrile (16.2 g). Then, ammonium chloride (0.2 g) and iron powder (1.6 g) were added to a mixed solvent of water (6.3 ml) and ethanol (17 ml), and the mixture was heated to 65° C. Then, the obtained ethanol solution (4 ml) containing 5-nitro-2-n-hexyloxybenzonitrile (16.2 g) was added dropwise thereto, and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated and the solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (6.0 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[C:12]([NH2:13])=[C:11]([NH2:14])[N:10]=[CH:9][N:8]=1.C(=O)(O)[O-].[Na+].C(=O)=O.[OH:23][C:24]1[CH:25]=[C:26]([C:30]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=O)=O)[CH:27]=[CH:28][CH:29]=1>O>[OH:23][C:24]1[CH:25]=[C:26]([C:30]2[N:13]=[C:12]3[C:11](=[N:14][C:32]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)[N:10]=[CH:9][N:8]=[C:7]3[NH2:6])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncnc(N)c1N
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ncnc2nc(-c3cccc(O)c3)c(-c3cccc(O)c3)nc12
Temperature: 80 °C

Procedure:
2.23 g (10.0 mmol) of 4,5,6-triaminopyrimidine sulfate was added in small portions to a solution of 1.68 g (20.0 mmol) sodium bicarbonate in 50 mL of water with vigorous stirring. A brisk evolution of CO2 gas was observed. The resulting suspension was heated to 80° C. and 2.42 g (10 mmol) of 3,3′-dihydroxybenzil was added to the mixture. The reaction mixture was refluxed for 1 hour, during which time the starting materials completely dissolved and the product precipitated out as a light-yellow solid.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>ClCCl>[CH2:1]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reactant: CCCCCN=C=O
Solvent: ClCCl
Product: CCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
Pentylisocyanate (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.050 g, 0.15 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 h. After removal of dichloromethane, the residue was purified by column chromatography to yield the title compound as a light purple solid (24.5 mg, 35% yield). 1H NMR (300 MHz, CDCl3) δ 7.99, 7.71, 7.58, 7.33, 6.62, 6.28, 4.69, 3.91, 3.58, 3.43, 3.28, 3.18, 1.45, 1.27, 0.88. MS (ES+) m/z 464.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[N:5]=[C:4]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([F:12])[N:5]=[C:4]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCn1c(-c2cccc3ccccc23)nc(F)c1[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(F)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Crude 1-ethyl-4-fluoro-2-naphthalen-1-yl-5-trimethylsilanyl-1H-imidazole (5.49 g) is dissolved in THF (75 ml), and to the solution is added tetrabutylammonium fluoride hydrate (5.4 g, 20.6 mmol, 1.2 eq.). The resulting mixture is stirred at rt for 4 hr. The organic solvent is evaporated under reduced pressure, and the residue is dissolved in EtOAc (150 ml), washed with water and brine, and dried over Na2SO4. Concentration and purification through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) affords 1-ethyl-4-fluoro-2-naphthalen-1-yl-1H-imidazole. LCMS 241 (M+1).
Reaction SMILES: [C:1]([N:8]([CH3:34])[C@H:9]([C:31](O)=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:31](=[O:32])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCc1ccccc1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1

Procedure:
This compound is prepared using Procedure C. Nα-Boc-Nδ-Fmoc-Nα-methylornithine (100 mg) was coupled with benzylamine to afford titled compound (50 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.42 (s, 9H), 1.52 (m, 2H), 1.70 (m, 2H), 2.80 (s, 3H), 3.26 (m, 2H), 4.18 (m, 1H), 4.22 (m, 1H), 4.41 (m, 2H), 4.61 (m, 2H), 7.31 (m, 7H), 7.43 (m, 2H), 7.63 (m, 2H), and 7.81 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][CH:9]=[C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=4)[N:14]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:11]2[NH:10][CH:9]=[C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([Cl:28])=[O:20])=[CH:17][CH:16]=4)[N:14]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of finely ground 4-(6-Fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoic acid (1.1 g. 3.4 mmol) in dichloromethane (6 ml) was added oxalyl chloride (2.4 ml, 29 mmol) followed by a drop of dimethyl formamide. The mixture was stirred under nitrogen at 45° C. for 3 h. The solvent was removed in vacuum to yield 4-(6-Fluoro-3-oxo-3,5-dihydro-pyrazolo[4, 3-c]quinolin-2-yl]-benzoyl chloride (1.15 g, quantitative) as a pale yellow solid that was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:11]([C:12](O)=[S:13])=[C:10]([Cl:15])[N:9]=[C:8]([CH3:16])[N:7]=1.C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[O:45][C:46](=[O:50])[N:47]([CH3:49])[N:48]=2)[CH:39]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(OCC)(=O)C.O.C1COCC1.CN(C=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][N:37]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[O:45][C:46](=[O:50])[N:47]([CH3:49])[N:48]=2)[CH:39]=1)[C:12]([C:11]1[C:10]([Cl:15])=[N:9][C:8]([CH3:16])=[N:7][C:6]=1[Cl:5])=[S:13])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nc(Cl)c(C(O)=S)c(Cl)n1
Reactant: Cn1nc(-c2cccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)c2)oc1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(C(=S)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3nn(C)c(=O)o3)c2)c(Cl)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 163.7 %

Procedure:
Thionyl chloride (15.7 mL, 215 mmol) and DMF (1 mL) were added to 4,6-dichloro-2-methylthio-pyrimidine-5-carboxylic acid (5.15 g, 21.5 mmol) obtained in Reference Example 4, and the mixture was stirred at 80° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was dried for 12 hours under reduced pressure. The resulting residue was dissolved in THF (8 mL), and the mixture was stirred at room temperature for 1 hour after adding triethylamine (1.02 mL, 7.30 mmol), and a THF (10 mL) solution of (S)-1-tert-butoxycarbonyl-2-{N-[3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]aminomethyl}pyrrolidine (1.37 mmol, 3.65 mmol) obtained in Step 5. The mixture was further stirred at 60° C. for 5.5 hours, and then for 6 hours under reflux. Water and ethyl acetate were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)—N-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4,6-dichloro-N-[3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylthiopyrimidine-5-carboxamide (1.30 g, 60%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:20])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:22]1[N:23]=[C:24]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35]([O:42][CH3:43])[CH:34]=2)=[O:32])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CC(C)=O.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]>[NH2:20][C:22]1[N:23]=[C:24]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35]([O:42][CH3:43])[CH:34]=2)=[O:32])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1cc(C(=O)c2nc(N)c3ccccn23)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
8.67 g (26.61 mmol) of cesium carbonate and then 4.5 ml (26.82 mmol) of benzophenone imine are added, under a nitrogen atmosphere, to 5 g (13.29 mmol) of (1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitro-phenyl)methanone obtained in example 20 in 66 ml of N,N-dimethylformamide. After stirring for 30 minutes, 1.66 g (2.67 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and then 1.22 g (1.33 mmol) of tris(dibenzylideneacetone)dipalladium(0) are added. The reaction medium is heated for 3 hours and then concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane and water. The organic phase is separated by settling, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in 250 ml of tetrahydrofuran and 135 ml of a 2N aqueous hydrochloric acid solution are added. After stirring at ambient temperature for one hour, the reaction medium is concentrated under reduced pressure. The solid residue obtained is taken up in acetone, filtered off, washed with acetone and then with ethyl ether and dried. 3.43 g of a brown solid are collected. Melting point: 214° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.29-7.36 (2H, m), 7.96-8.04 (2H, m), 8.11 (1H, d), 8.16 (1H, s), 9.78 (1H, d)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:15][N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH:18]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:17]1)=[O:14].[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:15][N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH:18]([CH2:27][C:28]([OH:30])=[O:29])[CH2:17]1)=[O:14]
Reactant: COC(=O)CC1CN(CC(=O)NCCCCNc2ccccn2)CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1CN(CC(=O)NCCCCNc2ccccn2)CCc2ccccc21
Reaction time: 8 h

Procedure:
Methyl 2-(3-({N-(4-(2-pyridylamino)but-1-yl)carbamoyl}methyl)-1H,2H,4H,5H-benzo[d]azepin-1-yl)acetate was dissolved in MeOH (0.1M) followed by addition of 1N NaOH (5 eq). After stirring overnight, 1N HCl (5 eq) was added, and the solution was concentrated in vacuo. Flash chromatography (10% MeOH/CHCl3) afforded a colorless solid. EI-MS m/z 411 (M+H)+; 1H NMR (400 MHz; D2O): 7.50 (2H, m), 6.93 (4H, m), 6.62 (1H, d, J=8.9 Hz), 6.51 (1H, t, J=6.7 Hz), 3.23 (1H, m), 3.01 (6H, m), 2.75 (2H, br), 2.57 (4H, m), 2.38 (2H, m), 1.36 (4H, br).
Reaction SMILES: Br[C:2]1[C:3]([N:8]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:27])[CH2:10][C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH:16]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C(N)C2CCCCC2)CCCCC1.O>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:27]=[C:9]1[CH2:10][C:11]2([CH:12]=[CH:13][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16]2)[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:8]1[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
Bis(tri-t-butylphosphine) palladium(0) (9.0 mg, 0.018 mmol) was added to solution of benzyl 4-[2-((3-bromopyridin-2-yl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.10 g, 0.18 mmol) and dicyclohexylmethylamine (42 μL, 0.196 mmol) in dioxane (2 mL). After 5 min, the reaction mixture was heated to 50° C. After 1.5 h, additional bis(tri-t-butylphosphine) palladium(0) (9.0 mg, 0.018 mmol) was added. After 20 min, water was added and the mixture was extracted with ether (2×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (95% hexanes/ethyl acetate→40% hexanes/ethyl acetate) gave the title compound (68 mg). MS 480.2 (M+1).