Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:32])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:32][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (40 mg, 0.09 mmol) in ethanol (2 mL) and THF (3 mL) was added a solution of sodium hydroxide (262 uL, 1.0 N) at room temperature. The resulting mixture was stirred for 5 hours. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL) and acidified with 1.0 N hydrochloric acid. The mixture was allowed to stand for 3 h, then the solid was filtered off and air-dried to afford {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid (37 mg, 95%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.50 (s, 1 H), 8.86 (s, 1 H), 8.77 (s, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.84 (s, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.41-7.58 (m, 3 H), 7.30 (t, J=7.8 Hz, 2 H), 7.19 (d, J=1.2 Hz, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 6.99 (t, J=7.2 Hz, 1 H), 3.85 (s, 2 H), 2.12 (s, 3 H). HRMS calcd. for C26H22ClN2O3 [(M+H)+] 445.1314, obsd. 445.1311.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][NH:23][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12]
Reactant: NNc1c(F)cccc1F
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1nccc(I)c1C(=O)NNc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 4-iodo-2-methoxynicotinic acid (1.00 g) obtained in Step C of Example 6 in DMA (10 mL) were added (2,6-difluorophenyl)hydrazine hydrochloride (647 mg), EDCI hydrochloride (824 mg) and HOBt (581 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (1.32 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>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.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)cc1
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)cc1
Yield: 100.1 %

Procedure:
5-Bromo-3-(4-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (117, 100.0 mg, 0.23 mmol), thiophene-2-boronic acid (59 mg. 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.017 mmol), potassium carbonate (80 mg, 0.58 mmol), tetrahydrofuran (15.0 mL) and water (5.0 mL) were combined under an atmosphere of nitrogen. The reaction mixture was refluxed overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give compound 118 (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:26]([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of compound 4 (10.9 mmol) in DMF (35 mL) were added TBDPSCl (24.0 mmol) and imidazole (32.7 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then diluted with DCM (140 mL) and washed sequentially with 1N HCl (140 mL) and H2O (140 mL). Organics were dried, concentrated, and purified by silica gel chromatography (PE/EtOAc) to yield compound 5 as a colourless oil in 65% yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH:13]1([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: Cl[Mg]C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)[PH](=O)C1CCCCC1

Procedure:
Following a procedure analogous to that of Example 1, but using 9.81 g of ethyl diethoxymethylphosphinate and 50 ml of a 2 molar solution of cyclohexylmagnesium chloride in diethyl ether and adding 20.7 g of potassium carbonate in 25 ml of water to precipitate inorganic salts, cyclohexyl(diethoxymethyl)phosphine oxide is obtained as colourless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1>N1C=CC=CC=1>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Yield: 76.2 %

Procedure:
A mixture of 4-phenylbenzaldehyde (5.17 g, 28.4 mmol), malonic acid (4.0 g), pyridine (20 ml), and piperidine (0.5 ml) was heated until gas evolution began. Heating was continued until gas evolution ceased (about 30 minutes at 90°-100° C.). The mixture was cooled, and the solid product triturated with boiling methanol (150 ml) and enough concentrated HCl to make the mixture acidic. The mixture was cooled, and the product collected by filtration, washed with water and methanol, and dried in vacuo to provide 4-phenylcinnamic acid (4.85 g, 76% yield), mp 220°-225° C. This material was dissolved in ethanol (150 ml) containing concentrated sulfuric acid (0.5 ml) and triethyl orthoacetate (3.5 ml), and refluxed for 24 hours. Removal of the solvent and recrystallization of the residue from methanol-water provided the ethyl ester (5.0 g, 92% yield), mp 88°-89° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1>CN(C=O)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 59.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 59% yield: LCMS (ESI) m/z 423 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: Fc1cccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)c1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4cccc(F)c4)noc3C(F)(F)F)c2)nc1
Yield: 68 %

Procedure:
As described for Example 4, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (500 mg, 1.68 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (495 mg, 68%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[O:11])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ncnc2ccsc12
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(CNC(=O)c2ncnc3ccsc23)cc1

Procedure:
Compound 7.3 (1.0 mmol) and Pd/C (10 w/w %, 60 mg) in MeOH—H2O (12 mL) is stirred under a hydrogen atmosphere at room temperature until the reaction is complete. The catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure to provide thieno[3,2-d]pyrimidine-4-carboxylic acid 4-amino-benzylamide (compound 7.4).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43]C=1F)[N:41]([C@@H:46]1[CH2:48][C@@H:47]1[F:49])[CH:40]=[C:39]([C:50]([OH:52])=[O:51])[C:38]2=[O:53].[OH-].[Na+]>CO.[C].[Pd]>[NH2:19][C:16]1([C@@H:13]2[CH2:14][CH2:15][N:11]([C:9]3[CH:43]=[C:42]4[C:37]([C:38](=[O:53])[C:39]([C:50]([OH:52])=[O:51])=[CH:40][N:41]4[C@@H:46]4[CH2:48][C@@H:47]4[F:49])=[CH:36][C:35]=3[F:34])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1([C@@H]2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)C2)CC1
Reaction time: 2 h
Yield: 77 %

Procedure:
A 322 mg (0.89 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine was dissolved in 10 ml of methanol to which was subsequently added 100 mg of 5% palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 5 ml of acetonitrile to which were subsequently added 0.5 ml of triethylamine and 113 mg (0.4 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of heating under reflux. After completion of the reaction, the reaction solution was spontaneously cooled to collect the thus formed crystals by filtration. With cooling in an ice bath, to the thus obtained crystals was added dropwise 5 ml of concentrated hydrochloric acid, followed by 30 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried on sodium sulfate, and then the solvent was evaporated. Thereafter, the resulting residue was recrystallized from liquid ammonia-ethanol to yield 120 mg (77%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O-:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.F[C:48]1[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=1[F:58]>C(OCC)(=O)C>[Cl:21][C:20]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17](=[O:22])[N:18]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=2[F:58])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([O-])ncc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3F)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A two liter round bottom flask was charged with tetrabutylammonium 4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g, 158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene (30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for 12 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (500 mL) and distilled water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the residue was added 500 mL of 20% ethyl acetate in diethyl ether and the mixture was stirred for 12 hours at room temperature. The slurry was then cooled to 4° C. and stirring was continued for additional 1 hour. The solid was collected by filtration and dried under vacuum for 4 hours at 45° C. to yield t-butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (58 g, 70% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.85-7.89 (m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m, 1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m, 4H), 1.48 (s, 9H); MS m/e 501.2 (M+H+).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH3:18])[CH:12]=1.N1C=CC=CC=1>O>[CH3:7][NH:8][C:9](=[O:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:13]([CH3:18])[CH:12]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C
Reaction time: 1 h

Procedure:
Ethanesulfonyl chloride (2.2g., 0.0171 mole) was added dropwise to a stirred solution of 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.0166 mole) in 20 ml. of pyridine. The temperature rose to a maximum of 38° C. and then subsided. Stirring was continued at ambient temperature for one hour, and the reaction mixture poured into excess water to give an insoluble precipitate. Recrystallization from ethanol-water gave the product as a beige powder, m.p. 146.5°-48.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]([CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Cl)ncc2ncn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml). Cs2CO3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently. The reaction is stirred at room temperature overnight, poured into water. After extraction with CH2Cl2, the organic layer is washed with H2O and brine, dried (Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[CH:11]=1>O1CCOCC1>[CH3:6][N:4]([CH:3]=[C:11]1[C:10](=[O:9])[CH:15]=[C:14]([CH3:16])[O:13][C:12]1=[O:17])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(O)cc(=O)o1
Solvent: C1COCCO1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N-dimethylformamide dimethyl acetal (150 ml) is added dropwise to a mixture of 4-hydroxy-6-methyl-2-pyrone (100 g) in dioxane (400 ml) at 0° C. over 20 minutes. The mixture is warmed to room temperature and stirred an additional 4 hours. The precipitated solid is filtered, washed with isopropanol and dried to give 85.0 g of the title compound. The filtrate is concentrated and isopropanol (300 ml) is added to the residue. This mixture is kept at 0° C. overnight to give an additional 18.8 g of the title compound. Physical characteristics are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]([CH3:14])[CH3:15])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
This crude methyl [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethyl-amino)pyrimidin-5-yl]acetate was dissolved in THF (3 mL) and treated with 1N NaOH (2 mL) and stirred at room temperature for 24 hour. Et2O was added and the organic phase was siphoned off. The remaining aqueous layer was acidified with 6N HCl to pH˜5 and the separated solids were collected by suction and rinsed with water and diisopropyl ether. Drying under high vacuum at room temperature for 4 hours then gave [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]-benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetic acid (0.029 g, 27% yield) as a pale yellow powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[N:15][CH:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.NC1C(NCC2C=C[C:41]([O:44]C)=CC=2)=NC(C2C=CC=C3C=2C=CC=N3)=CN=1>FC(F)(F)C(O)=O.ClCCl.C1(S)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:12]=[C:13]4[NH:18][C:41](=[O:44])[NH:17][C:14]4=[N:15][CH:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N
Reactant: COc1ccc(CNc2nc(-c3cccc4ncccc34)cnc2N)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2[nH]1
Temperature: 70 °C
Yield: 57 %

Procedure:
5-(5-Quinolyl)pyrazine-2,3-diamine. (3-Amino-6-(5-quinolyl)pyrazin-2-yl)[(4-methoxy phenyl)methyl]amine (see Example 1.B) (0.210 g, 0.588 mmol) was dissolved in trifluoroacetic acid/dichloromethane (2 mL:2 mL) with PS-thiophenol as a scavenger. The solution was heated to 70° C. in a sealed tube for two hours and then concentrated under reduced pressure and diluted with methanol. The methanol/product solution was filtered through a Phenomenex Strata-X-C solid phase extraction column to remove TFA. Additional water was added to the eluted compound to induce precipitation. The precipitate was filtered and dried under vacuum to afford the title compound (0.080 g, 57% yield). MS (ESI) m/z 238.1 [M+1]+.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4]
Reactant: CC(O)CN
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NCC(C)O)s1
Yield: 49 %

Procedure:
As described for example 53, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) was converted, using rac-1-amino-2-propanol instead of 2-amino-1,3-propandiol, to the title compound (65 mg, 49%) which was obtained as an off white oil. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:23][N:22]([CH3:33])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCC(N)c1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCC(NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)c1ccccc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N1,N1-dimethyl-3-phenylpropane-1,3-diamine (17.8 mg, 0.1 mmol). The title compound was obtained as a solid (15.8 mg, 31% yield). MS m/z: 510.89, 513.89 [M+H]+.