Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:34])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][O:32][CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[O:32]1[CH:33]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:34])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)[CH:30]=[N:31]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Yield: 20.1 %

Procedure:
A solution of the compound (127 mg, 0.26 mmol) obtained in Example 74-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (20 mg, 20%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([CH2:25][C:26]([F:29])([F:28])[F:27])=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:23]#[N:24])=[N:13][N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:23]([C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:13]=1)=[NH:24]
Reactant: COc1cc(CC(F)(F)F)c(-c2ccc3c(C#N)nn(C4CCCCO4)c3c2)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OC)cc3CC(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 37, 1.737 g, 4.00 mmol) in methanol (40 mL) was added sodium methoxide (648 mg, 12.0 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the aqueous layer was extracted with further EtOAc (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as an oily solid (1.64 g) in an 88% yield.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(N)CCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CCC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole) and 4-amino-pentanoic acid (prepared from hydrolysis of 5-methyl-2-pyrrolidinone in 6 N HCl at reflux for 2 days, followed by lyophilization, 274 mg, 2.4 mmole) in 0.5 M sodium methoxide in methanol (4.6 ml) was refluxed for twenty hours before it was cooled to room temperature, concentrated and dissolved in water, extracted with dichloromethane. The remaining aqueous layer was acidified with 1N hydrochloric chloride, extracted with a mixture of dichloromethane and methanol. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and methanol to give the title compound as a white solid (43 mg). LC-MS ESI−: 404 (M−1)−.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])[CH2:29][CH2:28][CH2:27]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:2](=[O:1])[CH2:7]1)=[O:36])[CH2:29][CH2:28][CH2:27]2
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CC(C)[C@@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1)N1CCCc2cc(Cl)ccc21
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), (S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid (27 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=588.0; tR=3.37 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:15]=[CH2:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:10])[CH2:16][CH2:15]2
Reactant: CC(C)[C@@H](C(=O)Cl)c1ccc(F)cc1
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)[C@H]1C(=O)CCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 54.8 g (0.255 mol) of [R]-(-)-2-(p-fluorophenyl)-3-methylbutyryl chloride in 950 ml of methylene chloride was saturated at -10° with ethylene gas. The temperature was then reduced to -56° and 47.5 g (0.356 mol) of aluminum chloride in one portion were added. After 15 minutes, 10.0 g (0.075 mol) more of aluminum chloride were added thereto and the reaction mixture was left to warm slowly to -20°. Then, 500 ml of ice-water were cautiously added, and the organic phase was separated and washed with 3N hydrochloric acid and water. After drying and evaporating the solvent under reduced pressure, 59.6 g of [R]-(+)-6-fluoro-3,4-dihydro-1-isopropyl-2(1H)-naphtone were obtained as a light yellow oil; [α]D20 =+189.5° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[CH2:10][CH2:11][CH3:12])=[CH:8][CH:9]=1
Reactant: CCC[Mg]Br
Reactant: O=Cc1ccc(Cl)nc1
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)nc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a −10° C. solution of 6-chloronicotinaldehyde (553 mg, 3.91 mmol) in 3.5 mL THF was added n-propylmagnesium bromide (2.34 mL of a 2.0 M solution in THF, 4.69 mmol). The solution was stirred at −10° C. for 10 min, and was then allowed to warm to room temperature. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridin-3-yl)butan-1-ol (400 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.24-8.31 (m, 1H), 7.61-7.67 (m, 1H), 7.25-7.30 (m, 1H), 4.68-4.74 (m, 1H), 2.05-2.26 (br s, 1H), 1.69-1.82 (m, 1H), 1.57-1.68 (m, 1H), 1.19-1.49 (m, 2H), 0.91 (t, J=7.43 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:19](OC)(OC)(OC)[CH3:20]>CN(C=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:19]1[CH3:20]
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: COC(C)(OC)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(C)n(CC(OC)OC)c12
Yield: 73.7 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.0 g, 3.9 mmol) from Step C of Example 13 in DMF (30 mL) was added trimethyl orthoacetate (1.5 mL, 11.8 mmol) and the reaction was refluxed overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate, extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 90% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (0.8 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J=8.1, 1.2 Hz, 1H), 7.55 (dd, J=7.8, 1.2 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 4.56 (d, J=4.8 Hz, 2H), 4.44 (t, J=4.8 Hz, 1H), 3.90 (s, 3H), 3.21 (s, 6H), 2.58 (s, 3H); MS (ESI+) m/z 279 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]=[O:16].Cl>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:15][OH:16]
Reactant: c1ccc2sccc2c1
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Benzothiophene (5.0 g, 37.3 mmol) in anhydrous THF (100 ml) stirring at −20° C. was treated with n-butyllithium (34 ml, 1.6 M, 55.8 mmol) and stirred for 1 hour. The mixture was cooled to −78° C. and treated with paraformaldehyde (7.8 g, 261 mmol) in four portions. The mixture was allowed to slowly warm to room temperature with stirring overnight. The mixture was treated with 2N HCl (100 ml) and extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over NaSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was crystallized from DCM/hexanes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 4.94 (s, 2H) 7.23 (s, 1H) 7.33 (m, 3H) 7.74 (m, 1H); (ESI) m/z 165 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:6](N)[C:5]([CH3:9])=[CH:4][CH:3]=1.N(OCCCCC)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH:8]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(F)cc1N
Agent: CCCCCON=O
Product: Cc1ccc(F)cc1-c1ccncc1

Procedure:
5-Fluorotoluidine (Example1,B), pyridine and pentyl nitrite are warmed until a vigorous reaction with evolution of gas sets in. This is allowed to proceed without heating until it has subsided (20 minutes) and the mixture is boiled under reflux for another 100 minutes. The excess pyridine is removed under reduced pressure to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=2)[CH:16]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(F)c2)c1
Yield: 49.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-fluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-fluorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.035 g (50%) of the title compound as a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16][O:15][CH2:14]1.C(N(CC)CC)C>ClC(Cl)Cl.ClCCl.O>[CH:12]([C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16][O:15][CH2:14]1)=[O:11]
Reactant: CCCC1(CO)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCC1(C=O)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
A solution of dimethyl sulphoxide (12 ml) in dry trichloromethane (4.0 ml) was added to a solution of oxalyl chloride (7.4 ml) in dichloromethane (25 ml) stirred at -70° under nitrogen. After the addition was complete the resulting mixture was stirred for a further 5 minutes at -70° before a solution of 3-hydroxymethyl-3-n-propyl oxetane (10.0 g) in dichloromethane (25 ml) was added, dropwise, over 10 minutes. The resulting mixture was allowed to stir for a further 30 minutes when neat triethylamine (54 ml) was added over approximately 30 minutes. The reaction mixture was allowed to warm to room temperature over 3 hours when it was poured into water. The organic phase was separated and the aqueous layer was further extracted with dichloromethane. The combined organic extracts were washed with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The resulting organic phase was dried over anhydrous magnesium sulphate and evaporated in vacuo to give 3-formyl-3-n-propyloxetane (10.5 g) (European Patent Application No. 216624) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Br:11]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(Br)ccc1N
Temperature: 0 °C
Yield: 53.2 %

Procedure:
To a cooled solution of (2-aminophenyl)acetonitrile (13 g, 98 mmol) in dimethylformamide (150 mL) at 0° C., was added N-bromosuccinimide (19.3 g, 108 mmol) in portions for 30 minutes and maintained at 0° C. for 1 hour. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×100 mL) and saturated sodium chloride (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford (2-amino-5-bromophenyl)acetonitrile (11 g, 53%) as solid. 1HNMR (CDCl3) δ 7.35 (s, 1H), 7.25 (d, 1H), 6.65 (d, 1H), 3.7 (br, 2H), 3.52 (s, 2H).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[C:8]([F:29])[C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[C:8]([F:29])[C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4.5 g of ethylamine are added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 7.1 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 100 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 1 hour and a half. After cooling to a temperature close to 20° C., the product is drained and washed with twice 30 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-tri fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a cream solid melting at 284° C., which is used for the subsequent steps without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24].O.C([O-])(O)=O.[Na+]>CC(C)=O.Cl.CCOC(C)=O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=3)[N:7]=2)[CH:10]=1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc(OC)c1OC

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (100 mg, 0.39 mmol) and 3,4,5-trimethoxyaniline was suspended in acetone (7 mL) and water (2 mL) with 2 drops of conc. HCl. The mixture was heated in a sealed tube to reflux overnight. The mixture was poured into EtOAc (100 mL) and sat. aq. NaHCO3. The organics were separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified via preparative HPLC. MS m/z=404. Calc'd for C22H21N5O3: 403.16.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)=[CH:6][C:5]=1[F:27]>C1COCC1>[NH2:26][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1ccc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)cc1F
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 3.0 g (8.0 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluorobenzoic acid methyl ester using 12 mL (12 mmol) 1 N NaOH in 30 mL THF. The product precipitates and is isolated by filtration. The product is washed with water. Yield: 2.2 g (76%).
Reaction SMILES: FCC[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][CH2:14][CH2:15][F:16])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[CH:7][C:8]=1[O:13][CH2:14][CH2:15][F:16]
Reactant: O=C(OCCF)c1ccc(Cl)c(OCCF)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c(OCCF)c1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 4-chloro-3-(2-fluoro-ethoxy)-benzoic acid 2-fluoro-ethyl ester (1.57 g, 5.93 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added slowly over a time period of 15 min under cooling to −10° C. a solution of diisobutylaluminium hydride (17.8 mL, 17.80 mmol, 3.0 equiv; 1 M solution in toluene). After 1 h, the reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (2:3) to give 1.19 g (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[CH:4][C:3]=1[OH:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29](F)[CH:30]=1)[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:21][C:3]2[CH:4]=[C:5]([CH2:8][N:9]3[C:10](=[O:11])[C:12]4[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:14]3=[O:15])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH:30]=1)[C:26]#[N:27]
Reactant: O=C(O)c1ccccc1C(=O)NCc1ccc(Cl)c(O)c1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Yield: 22.7 %

Procedure:
3-Chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile was prepared in a in a similar manner as described herein from 2-({[(4-chloro-3-hydroxyphenyl)methyl]amino}carbonyl)benzoic acid (3.0 g, 10.4 mmol), 3-chloro-5-fluorobenzonitrile (2.5 g, 15.6 mmol), K2CO3 (4.3 g, 31.0 mmol) and NMP (25.0 mL). Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (1.0 g, 24%) as a solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[N:9][CH:8]=1)C.C1COCC1.Cl>CCOC(C)=O.O.CO>[Cl:13][C:12]1[C:7]([C:6]([OH:15])=[O:5])=[CH:8][N:9]=[C:10]([Cl:14])[CH:11]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cnc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Sodium hydroxide (40 mL, 6.25 M solution) was added to a stirred solution of 4,6-dichloronicotinic acid ethyl ester (22) (25.95 g, 118 mmol) in 4:1:1 THF:MeOH:water (600 mL). After 30 minutes, the reaction mixture was acidified to pH 2 with concentrated HCl, diluted with 1:1 EtOAc:Et2O and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. The resulting off-white solid was twice concentrated from toluene to give the desired product (23) as a white solid (21.73 g, 96%).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[O:8]=[C:9]1[NH:16][CH2:15][CH:14]2[CH:10]1[CH2:11][CH2:12][CH2:13]2.[OH-].[Na+]>C1C=CC=CC=1>[CH3:5][O:8][C:9]1[CH:10]2[CH:14]([CH2:15][N:16]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: COS(=O)(=O)OC
Reactant: O=C1NCC2CCCC12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COC1=NCC2CCCC12
Reaction time: 1 h

Procedure:
Over a period of 1 hour, 94.7 ml of dimethyl sulfate are added dropwise to a solution, maintained at reflux, of 125.2 g of 2-oxo-3-azabicyclo(3,3,0)octane in 350 ml of anhydrous benzene. Reflux is then maintained for 4 hours. After cooling, the reaction mixture is poured onto 100 ml of concentrated sodium hydroxide solution. The organic layer is decanted, and the aqueous layer is extracted twice with 200 ml of benzene each time. The benzene extracts are combined, dried over magnesium sulfate and concentrated in vacuo and the residue is distilled. In this manner 79.5 g of 2-methoxy-3-azabicyclo(3,3,0)oct-2-ene are obtained, b.p.: 64°-68° C., nD23 =1.4718.
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C)C=CC=1O)([O-])=O.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[N:33][C:34]1[CH:39]=[C:38]([C:40]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=1[OH:48])([O-])=O>>[OH:48][C:35]1[CH:36]=[CH:37][C:38]([C:40]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:41])=[CH:39][C:34]=1[N:33]1[N:32]=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=[N:23]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 85.1 %

Procedure:
The same procedure as in Example 7 was repeated, except that 2-nitro-2'-hydroxy-5'-t-butylazobenzene 15.0 g was replaced by 2-nitro-2'-hydroxy-5'-t-octylazobenzene 17.7 g, thus producing 13.7 g of 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole having a melting point of 103° to 105° C. at the yield of 85.0%.