Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].S(Cl)([Cl:17])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:17])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccsc1NC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)sc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 19.9 parts of methyl 2-acetamidothiophene-3-carboxylate in 200 parts by volume of chloroform, 8.2 parts by volume of sulfuryl chloride is added dropwise at below 30°C. The mixture is stirred at room temperature for 30 minutes and then cooled with ice. To the mixture, about 300 parts by volume of saturated aqueous sodium bicarbonate solution is cautiously added with stirring. The chloroform layer is separated, washed with water and dried over sodium sulfate. Evaporation of the solvent gives methyl 2-acetamido-5-chlorothiophene-3-carboxylate as crystals. Recrystallization from methanol gives needles melting at 110°-110.5°C. This compound is identical with that obtained in Reference Example 17.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:11])[NH:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:14](OC)(=O)[CH3:15].O>O1CCCC1>[CH3:14][C:15]1[O:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[N:11]=1
Reactant: COC(C)=O
Reactant: N=C(NO)c1cccc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cccc(N)c2)no1
Temperature: 65 °C

Procedure:
To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21]CC)=[O:20])=[N:13][C:9]=3[C:8]=2[F:27])=[CH:3][CH:2]=1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([OH:21])=[O:20])=[N:13][C:9]=3[C:8]=2[F:27])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Agent: C[Si](C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-({[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}methyl)cyclopropanecarboxylate (0.046 g, 0.102 mmol) was dissolved in 1 mL of THF and treated with KOTMS (0.037 g, 0.288 mmol). The reaction mixture was stirred at ambient temperature overnight, and then diluted with EtOAc and washed with 2 N HCl. The acidic aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C24H18F2N2O3 420.41, observed m/e 420.9 (M+H)+ (Rt 2.21/4 min). 1H NMR (500 MHz, CD3OD): δ7.73-7.64 (m, 4H), 7.51 (d, 2H), 7.48-7.41 (m, 2H), 7.35 (m, 1H), 7.03 (d, 1H), 4.55 (dd, 1H), 4.29 (dd, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.28 (m, 1H), 1.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:48][C:45]4[CH:46]=[CH:47][N:42]=[CH:43][N:44]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A flask was charged with perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate (Intermediate ZZZZZ; 0.060 g, 0.098 mmol), pyrimidin-4-amine (9.81 mg, 0.103 mmol), and THF (0.982 ml) and cooled to 0° C. LHMDS (1.0M in THF) (0.206 ml, 0.206 mmol) was added drop wise and the reaction was stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-10% MeOH:DCM) to afford 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide (0.044 g, 0.084 mmol, 86% yield) as an -off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.49 (s, 1H), 8.57 (s, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.22 (d, J=6.9 Hz, 1H), 8.08 (dd, J=1.8, 8.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.59 (dt, J=6.3, 8.1 Hz, 1H), 7.48-7.41 (m, 2H), 7.37-7.29 (m, 2H), 7.00 (d, J=5.0 Hz, 1H), 3.74 (s, 3H). m/z (ESI) 522.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:29])[NH:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:26]=[C:25]1[C:24]2[C:23](=[CH:22][C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:31][CH:30]=2)[C:28](=[O:29])[NH:27]1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)C(=O)NC4=O)c2cc1OCC
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 305 mg (1.88 mM) of 4-Aminophthalimide in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 348 mg of 4-(1,3-Dioxo-2,3-dihydro-1H-isoindol-5-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 402.9, mp=248-251° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[N:22][N:23]=[C:17]2[CH:16]1[C:32]1[O:36][N:35]=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[N:33]=1)=O)(C)(C)C>ClCCl>[Cl:43][C:39]1[CH:38]=[C:37]([C:34]2[N:33]=[C:32]([CH:16]3[NH:15][CH2:20][CH2:19][N:18]4[C:21]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:22][N:23]=[C:17]34)[O:36][N:35]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2nnc3n2CCNC3c2nc(-c3cccc(Cl)c3)no2)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 8-[3-(3-chloro-phenyl) -[1,2,4]oxadiazol-5-yl]-3-(4-methoxy-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylic acid tert-butyl ester (72.5 mg, 0.14 mmol) in dichloromethane (1 mL) at 0° C. The reaction mixture was then diluted with dichloromethane, After 15 minutes, the reaction was warmed to room temperature and stirred for an additional hour. washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash column chromatography on silica gel using 85-90% ethyl acetate in hexanes to 2% ammonia in methanol in dichloromethane followed by trituration with diethyl ether to afford the titled compound (40.6 mg, 69%). 1H NMR (CDCl3) δ (ppm): 8.10 (m, 1H), 8.00 (m, 1H), 7.67 (m, 2H), 7.48 (m, 2H), 7.05 (m, 2H), 7.86 (m, 1H), 4.09 (m, 3H), 3.89 (s, 3H), 3.47 (m, 2H), 3.24 (m, 1H), 2.83 (bs, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[C:22]#[N:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.N.CO.C(O)C.[Ni]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][NH2:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: NCc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Reaction time: 6 h

Procedure:
To 100 mg of (0.288 mmol) 2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 63) in 2 ml THF and 6 ml 10% ammonia in methanol are added ca. 50 mg Raney-Ni in ethanol. The solution is hydrogenated at rt for 6 h. The catalyst is filtered off and the raw material is purified by chromatography on silica gel (CH2Cl2-methanol 9:1) and crystallization (ethyl-acetate-hexane). mp: 163-1650° C.; MS: 351 (M++1); HPLC: tret=6.42 min (Grad 1).
Reaction SMILES: [OH:1][C:2]1([C:9]([F:18])([F:17])[C:10](O)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:9]([F:17])([F:18])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(O)(C(F)(F)C(O)(O)C(F)(F)F)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCC(O)(C(F)(F)C(=O)C(F)(F)F)CC1

Procedure:
In 80 ml of toluene was dissolved 10.0 g of 4-hydroxy-4-(2,2-dihydroxy-1,1,3,3,3-pentafluoropropyl)cyclohexanone obtained in <7-1>. The solution was heated under reflux. The water formed was removed, leaving a toluene solution of 4-hydroxy-4-(2-oxo-1,1,3,3,3-pentafluoropropyl)cyclohexanone. Under nitrogen and with stirring at room temperature, this solution was added dropwise to a solution of 3.3 g lithium aluminum hydride in 100 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for 24 hours and then cooled to 5° C. The reaction mixture was combined with 100 ml of ethyl acetate and then with 100 ml of 20% hydrochloric acid. The mixture was stirred at room temperature for 3 hours and then extracted with toluene. Through conventional work-up including washing, drying and concentration, 8.0 g (yield 84%) of the target compound was obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8](=[O:15])[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].Cl.O1CCOCC1>C(=O)(O)[O-].[Na+]>[F:12][C:11]([F:13])([F:14])[CH2:10][CH2:9][C:8](=[O:15])[CH2:7][CH2:6][CH:2]=[O:1]
Reactant: O=C(CCC1OCCO1)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CCCC(=O)CCC(F)(F)F
Yield: 69 %

Procedure:
Crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g, prepared above) in 1:1 2N HCl-dioxane (80 ml) was heated to reflux for 20 minutes, then neutralized with aqueous sodium bicarbonate (100 ml), then extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×50 ml), then concentrated under reduced pressure to provide crude 7,7,7-trifluoro-4-oxo-heptanal (10 g), which may be used without further purification. 1H NMR (CDCl3) δ9.80 (1H, s), 2.85-2.70 (6H, m), 2.47-2.35 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: ClCc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g) , thionyl chloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours. After cooling the mixture was concentrated in vacuo, the residue was taken up in ether, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give 3,5-dichlorobenzyl chloride as a light yellow solid, which was used without further purification, 28 g, mp. 32°-36° C.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12]([I:29])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[I:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([I:29])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1
Reactant: COc1ccc(Oc2c(I)cc(OC(=O)c3ccccc3)cc2I)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Oc2c(I)cc(O)cc2I)cc1C(C)C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
A mixture of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenyl benzoate (0.10 g, 0.16 mmol) and 1 N NaOH (0.81 mL, 0.81 mmol) in methanol (1.63 mL) was at room temperature for 24 h. The reaction mixture was neutralized with 2 N HCl, diluted with H2O and extracted with CH2Cl2 (10 mL×2). The organic layers were concentrated under reduced pressure and the crude product was purified preparatory TLC with acetone-hexanes (1:4) as mobile phase to afford 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenol as an off-white solid (0.079 g, 95%): 1H NMR (300 MHz, DMSO-d6): δ 9.99 (s, 1H), 7.28 (s, 2H), 6.81 (d, J=12.0 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 6.30 (m, 1H), 3.72 (s, 3H), 3.18 (m, 1H), 1.11 (d, J=6.9 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (7:3); Rf=0.42.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16]C)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[OH-].[Li+].Cl>CO>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Li+]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.0 g (5.7 mmol) methyl (3RS,4RS)-1-benzyl-4-methyl-pyrrolidine-3-carboxylate (as the trifluoroacetate salt) are dissolved in 4 ml of methanol and combined with 5 ml lithium hydroxide solution (8% in water). The mixture is stirred for five hours at RT, then mixed with 3.2 ml 4N hydrochloric acid and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([C:27]([OH:29])=[O:28])[NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][CH2:24][C@@H:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:27]([OH:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@H](COCc1ccccc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](COCc1ccccc1)C(=O)O
Yield: 34 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with O-benzyl-D-serine to provide the title compound in 34% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][CH2:9][CH:10]([CH3:36])[CH2:11][O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)(C)(C)C>Cl.O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH2:11][CH:10]([CH3:36])[CH2:9][O:8][CH2:7][C:6]([OH:37])=[O:5])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)COCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)COCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 70 mg (0.14 mmol) rac.-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2-methylpropoxy)acetic acid tert.-butyl ester in 2.0 ml 4 N hydrogen chloride in dioxan and stir for 16 h at RT. Purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 48 mg (76% of theor.) of the desired product is obtained as racemate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COC(=O)c1cc2cccnc2nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2ncccc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-methoxy-1,8-naphthyridine-3-carboxylate (87.0 mg, 0.40 mmol) was dissolved in MeOH. NaOH (1.2 ml, 1M aqueous solution) was added to the solution and the mixture stirred at room temperature for 18 h. The organic solvent was removed under reduced pressure. The remaining aqueous residue was treated with HCl (1M aqueous solution) until slightly acidic and the product extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated yielding 2-methoxy-1,8-naphthyridine-3-carboxylic acid which was coupled without further purification to 3-(trifluoromethyl)benzylamine using the general amide coupling procedure. The crude product was purified by flash chromatography, CH2Cl2/MeOH 96:4, yielding 124 mg (86%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:27])[N:15]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C>[CH2:2]([S:9]([NH:12][C:13]1[C:14](=[O:27])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Reaction time: 2 h

Procedure:
HCl gas was bubbled through a stirred suspension of 3-benzylsulfonylamino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.7 g, 4.5 mmol), as prepared in the preceding step, in ethyl acetate (15 mL) at 0° C. until a solution was formed. After 2 h at room temperature, a thick suspension was formed. The mixture was degassed with nitrogen and filtered to give the title compound a white solid (1.4 g, 97%). 1H-NMR (300 MHz, CDCl3) δ8.76 (s, 1H), 7.45 (dd, J=7.0, 1.8 Hz, 1H), 7.32 (m, 5H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 6.16 (t, J=7.1 Hz, 1H), 4.69 (s, 2H), 4.56 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.[Pd]>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[C:7]([CH2:8][CH2:9][CH3:10])=[CH:2][N:3]=[C:4]([CH3:24])[N:5]=3)[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(Cl)nc(C)nc1Cn1ccnc1-c1ncccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCc1cnc(C)nc1Cn1ccnc1-c1ncccc1F
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-5-propyl-pyrimidine (55.3 mg, 0.16 mmol), K2CO3 (30 mg) and Pd—C (10%, 6 mg) in ethanol is stirred at room temperature under H2 (H2 balloon) over night. After filtration, the solvent is removed and the residue is purified by preparative TLC to give the title compound. 1H NMR (CDCl3) 8.34 (s, 1H), 8.31-8.33 (m, 1H), 7.50-7.55 (m, 1H), 7.23-7.28 (m, 2H), 7.10 (s, 1H), 5.73 (s, 2H), 2.54 (s, 3H), 2.48 (t, 2H), 1.44-1.53 (m, 2H), 0.89 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)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].O>[CH3:17][C:12]([N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[C:8]1=[O:11])([CH3:18])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)C(C)(C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Temperature: 82.5 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
The compound of example 338 (2.4 g, 0.0076 mol), (4-nitrophenyl)boronic acid (1.649 g, 0.0098 mol) and Pd(dppf)Cl2: CH2Cl2 (0.186 g, 0.00022 mol) were taken in DMF (60 mL) under an argon atmosphere. To this reaction mixture, 2M solution of Na2CO3 (2.33 g, 0.022 mol, 10.99 mL) was added and the reaction mixture was stirred at 80 to 85° C. for 1 to 1.5 h. After completion of the reaction, water was added to the reaction mixture and the product obtained was extracted with diethyl ether. The combined ether layers were washed with water and brine, dried over anhydrous Na2SO4. The solvent was evaporated and the product was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to afford the title compound.