Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:4](O)=[O:5].[CH3:20][O-:21].[Na+].[CH3:23]OS(OC)(=O)=O.Cl>CS(C)=O.C1(C)C=CC=CC=1.O>[CH3:20][O:21][C:4](=[O:5])/[C:3](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:2]/[O:1][CH3:23]
Reactant: O=C(O)/C(=N/O)c1ccccc1Oc1ccccc1
Reactant: C[O-]
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1
Yield: 73.1 %

Procedure:
To a solution of E-α-hydroxyimino-2-phenoxyphenylacetic acid (10.00 g, 0.0389 mole) in dimethyl sulfoxide (50 ml) and toluene (50 ml) was added sodium methoxide (4.83 g, 0.0894 mole) with stirring under ice cooling, and the mixture was stirred at room temperature for 20 minutes and then cooled. Dimethylsulfate (11.28 g, 0.0894 mole) was added at 6°-18° C. over 6 minutes, followed by stirring at room temperature for 4.5 hours. After completion of the reaction, conc. hydrochloric acid (1.2 ml) and water (100 ml) were added to the reaction mixture with stirring under ice cooling, followed by extraction with toluene. The extract was washed with water and concentrated under reduced pressure, and then the resulting residue was recrystallized (methanol) to obtain E-α-methoxyimino-2-phenoxyphenylacetic acid methyl ester (8.11 g, yield: 73.1%) as colorless crystals (melting point: 107°-109° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.CN1CCCC1=O.[Br-].[CH2:38]([Zn+])[CH:39]([CH3:41])[CH3:40]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[CH2:38][CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)C[Zn+]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(CC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 86 mg (0.20 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 15, Step A), 5.1 mg (0.01 mmol) of bis(tri-tert-butylphosphine)palladium(0), and 200 μL of 1-methyl-2-pyrrolidinone in 5.0 mL of THF was added 475 μL (0.24 mmol) of isobutylzinc bromide (0.5 M in THF). The reaction mixture was refluxed for 4 h, cooled to rt, and filtered through a cake of Celite. The filtrate was concentrated. Chromatography on Biotage 40S cartridge using 7:93 v/v Et2O/hexanes as the eluant afforded 55 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 0.99 (d, J=6.7, 6H), 1.44 (s, 9H), 2.28 (m, 1H), 2.58 (t, J=7.7, 2H), 2.66 (s, 3H), 2.93-2.97 (m, 4H), 7.18-7.20 (m, 2H), 8.01 (d, J=8.5, 1H), 8.42 (d, J=1.8, 1H), 9.22 (d, J=1.9, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1coc(-c2ccc(F)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
A solution of 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.5 g, 2.3 mmol) in THF—H2O (15 mL, 8:2 v/v) was cooled to 0° C. and triphenylphosphine (892 mg, 3.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature and then stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 1.5N HCl. The aqueous layer was washed with CH2Cl2 and then the pH of the aqueous layer was adjusted to ˜8-9 using 10% NaOH solution. The organic product was extracted with CH2Cl2 and organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford (2-(4-fluorophenyl)oxazol-4-yl)methanamine (330 mg, yield 75%) as a pale yellow liquid, which was carried through without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.01-7.98 (m, 2H), 7.94 (s, 1H), 7.38-7.34 (m, 2H), 3.65 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C10H9FN2O: 192.07. found: 193.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>CCOCC>[CH3:15][O:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[O:12]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc2[nH]ccc12
Solvent: CCOCC
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a 0° C. solution of indole-4-carboxylic acid (1.00 g, 6.21 mmol) in ether (60 mL) was added diazomethane (0.3M solution in ether, 24.8 mL, 7.45 mmol) and the reaction mixture was stirred for 0.5 hours at 0° C. An additional 20 mL of diazomethane solution was then added and stirring was continued for 1 hour at 0° C. The reaction mixture was quenched with formic acid (1.0 mL) and concentrated in vacuo to give 4-methoxycarbonylindole (1.1 g) as an off white powder.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][C:16](OC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1c2ccccc2-c2c(O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2-c2c(O)cccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a stirred solution of 277.5 mg (1.09 mmol) of the ester prepared in Step A of Example 30 in 5 mL of anhydrous THF at 0° C. was added dropwise 1.1 mL (1.1 mmol) of a 1M solution of lithium aluminum hydride in ether. The resulting mixture was stirred at 0° C. under nitrogen for 1.5 hours and then carefully quenched with Glaubers salt. The mixture was partitioned between EtOAc, ice, 2N HCl, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by PLC with CH2Cl2-EtOAc (10:1) to give 236.8 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:18][C:17]2[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1>>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: Cc1ccc(Br)cn1
Product: Cc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 63 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 63% yield starting from [(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]boronic acid and 5-bromo-2-methylpyridine (1.6 equiv): 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, 1 H), 7.48 (dd, 1 H), 7.30-7.36 (m, 4 H), 7.23-7.29 (m, 5 H), 7.07-7.23 (m, 4 H), 7.00 (d, 1 H), 3.63 (s, 4 H), 2.90-3.04 (m, 2 H), 2.74-2.86 (m, 1 H), 2.68-2.73 (m, 2 H), 2.67 (s, 3 H), 2.11-2.19 (m, 1 H), 1.67-1.82 (m, 1 H); MS (ESI) m/z 420[M+H+].
Reaction SMILES: [Br:1][C:2]1[N:6](C(OC(C)(C)C)=O)[C:5]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:4]=2[C:3]=1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[NH:6][C:5]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:4]=2[C:3]=1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution (0.1 M) of methyl 5-bromo-4-(tert-butoxycarbonyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in WO2005/023819) in CH2Cl2 was treated with trifluoroacetic acid (1:1). The reaction mixture was stirred at RT for 1 h. All volatiles were evaporated giving a residue that was purified by flash chromatography (PE:EtOAc, 7:3) giving the title compound (79%) as solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.60 (s, 1H), 3.80 (s, 3H), 2.66-2.55 (m, 1H), 1.85-1.20 (m, 10H). MS (ES+) m/z: 342, 344 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.O.C(#N)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2ccccc2)ncn1
Yield: 46 %

Procedure:
First, in a recovery flask equipped with a reflux pipe were put 4.90 g of 4-chloro-6-methylpyrimidine, 4.80 g of phenylboronic acid, 4.03 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, in the flask were further put 2.28 g of phenylboronic acid, 2.02 g of sodium carbonate, 0.082 g of Pd(PPh3)2Cl2, 5 mL of water, and 10 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and extraction with dichloromethane was carried out. The obtained solution of the extract was washed with a saturated sodium carbonate aqueous solution, water, and then with saturated saline, and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1, so that a pyrimidine derivative Hmppm, which was the objective substance, was obtained (orange oily substance, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (b-1) of Step 1 is shown below.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:38]=[CH:37][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:26][CH:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][CH:23]2[CH2:35][OH:36])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN(CC)CC>C(Cl)Cl>[O:27]([C@H:25]1[CH2:26][N:22]([C:20]([O:19][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:38][CH:37]=2)=[O:21])[C@H:23]([CH:35]=[O:36])[CH2:24]1)[Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a stirred mixture of molecular sieves dried DMSO (15.0 ml, 212 mmol) and dichloromethane (1.24l ) at -78° C. was added oxalyl chloride (10.0 ml, 114 mmol) dropwise over 5 minutes and stirring was continued for additional 10 minutes. To this solution was added a mixture of 1-(4-nitrobenzyloxycarbonyl) -2-hydroxymethyl-4-(tertbutyldimethylsiloxy) pyrrolidine (31.0 g, 75.6 mmol) and CH2Cl2 (155 ml) dropwise over 15 minutes and the stirring was continued for 30 minutes at the same temperature. After addition of Et3N (52.5 ml, 377 mmol), removing of cold bath to warm to room temperature, washed with aqueous saturated NaHCO3 (300 ml), dried (MgSO4) of organic portion and concentrated in vacuo to afford the oily product which became solid after storage at room temperature. This crystalline product was washed with diethyl ether-hexane (1:10), collected by filtration and dried to give (2S, 4R)-4-tert-butyl-dimethylsiloxy-2-formyl-N-(4-nitrobenzyloxycarbonyl)pyrrolidine (29.7 g, 96% yield).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[F:13])#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)=[N:4][C:3]([C:1]([NH:27][NH2:28])=[NH:2])=[CH:12]2
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(F)c23)C1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(F)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (600 mg, 1.61 mmol) in MeOH (15 mL) was added NH2NH2—H2O (10 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was removed in vacuo to afford the title compound as a white solid, which was used without further purification (500 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:27])[C:5]=2[NH:4][N:3]=1.O.O.[OH-].[Li+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:27])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
(S)-Methyl 2-(1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (220 mg, 0.429 mmol) was dissolved in a mixture of methanol (5.0 mL) and tetrahydrofuran (5.0 mL). Water (5.0 mL) was added to the mixture followed by lithium hydroxide hydrate (66.0 mg, 1.573 mmol). Reaction was warmed to 60° C. and held with stirring for 1.25 hours. Mixture was cooled to room temperature and then neutralized with 1.6 mL 1N hydrochloric acid. Mixture was concentrated by roto-vap. Residue was partitioned between ethyl acetate and water. Layers were separated and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 96% yield. MS (M−H)−=498.1, 496.1, 500.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(N=Cc2ccccc2)ccc1O
Yield: 47 %

Procedure:
2-Hydroxy-5-aminobenzoic acid (10.0 g, 65 mmole) was mixed with benzaldehyde (30 ml) and heated to boiling until a clear solution was obtained. To the solution ice-cooled toluene (100 ml) was added, the precipitated crystals filtered off and washed with cold absolute ethanol (2×25 ml) followed by petroleum ether (3×25 ml) and dried, in vacuo, to give the title compound (6.8 g, 47%), m.p. 213°-215° C. Found (Calc. for C14H11NO3) C 69.28 (69.70), H 4.73 (4.56), N 5.73 (5.81).
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:5]([NH2:7])=[S:6])[CH2:2][CH3:3].Br[CH:19]([CH3:31])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[O:29][CH3:30])=O>C(O)C>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:7]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[N:13]4)[S:6][C:19]=2[CH3:31])=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: COc1cc(Cl)ccc1C(=O)C(C)Br
Reactant: CCCN(C(N)=S)c1cccc2ncccc12
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2OC)c(C)s1)c1cccc2ncccc12
Product: Cl
Yield: 110.9 %

Procedure:
A solution containing 0.4 g of N-propyl-N-quinol-5-ylthiourea (Compound 31) and 0.5 g of 2-bromo-1-(4-chloro-2-methoxyphenyl)propan-1-one in 15 ml of ethanol is heated at reflux for 6 hours. The reaction mixture is evaporated to dryness and then, successively, the residue is taken up in water, basified with 33% sodium hydroxide and extracted with ethyl acetate. The residue is purified on a column of silica gel eluted with a 1/1 (v/v) ethyl acetate/hexane mixture, to provide 0.46 g of a yellow oil. 1H NMR (CDCl3): 0.91 (t, J=7.3, 3H, --CH3), 1.61-1.78 (m, 2H, --CH2 --CH3), 2.02 (s, 3H, heterocycle --CH3), 3.83 (s, 3H, --OCH3), 3.97 (t, J=7.5, 2H, --CH2 --N<), 6.88 (dd, J=2.5, J=8.4, 1H, H5), 7.0 (d, J=2.5, 1H, H3), 7.36 (d, J=8.5, 1H, H6), 7.46 (dd, J=4.2, J=8.6, 1H, H3,), 7.63 (d, J=7.2, 1H, H4,), 7.80 (t, J=7.9, 1H, H7,), 8.17 (d, J=8.4, 1H, H6,), 8.33 (d, J=8.4, 1H, H8,), 8.96-8.99 (m, 1H, H2,).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl>N1C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][CH:14]=[C:5]([S:2](=[O:4])(=[O:3])[NH:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:6]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 3-(chlorosulfonyl)benzoate (5.0 g, 21.31 mmol) in pyridine (50 ml), was added dropwise a solution of tert-butyl 3-aminopropanoate hydrochloride (5.11 g, 23.44 mmol) in pyridine (10 ml) at 0° C. The resulting solution was allowed to warm to RT and stirred for 4 h. 1N HCl (50 ml) was added to the reaction mixture and the aqueous phase was separated and extracted with DCM (3×20 ml). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford a viscous amber oil. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.63 (1H, t) 5.38 (1H, t), 3.97 (3H, s), 3.20 (2H, m), 2.48 (2H, t), 1.43 (9H, s).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1ccncc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 g, 48.1 mmol) in toluene (250 ml) at 0° C., trimethylaluminum (2M solution in toluene, 36.1 ml, 72.2 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-cyanopyridine (10 g, 96.2 mmol) in toluene (250 ml) was added over 10 minutes and the mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate and filtered. The pale yellow solid (4.8 g, 36%) was used in the next reaction without further purification. Anal. Calc'd. for C13H14N3SClO2H2O: C, 47.34, H, 4.89, N, 12.74, S, 9.72. Found: C, 47.69, H, 4.35, N, 12.77, S, 9.74.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-alaninamide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=6.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.55 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 477.1141 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6](=[O:35])[N:7]([CH3:34])[C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[N:9]=2)=[O:4].CC([O-])=O.[Na+]>CN(C=O)C.O.CCOC(C)=O>[C:16]([N:15]1[C:14]2[C:13]3[CH:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[C:10]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])=[N:9][C:8]=3[N:7]([CH3:34])[C:6](=[O:35])[C:5]=2[C:3]([OH:4])=[CH:2]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1c(C(=O)CBr)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(O)c2c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc3c21
Reaction time: 8 h

Procedure:
To the product of Step A (25 mg) was added NaOAc (60 mg) in DMF (2.5 mL) and water (0.3 mL) at room temperature. The reaction stirred overnight and was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. The concentrated residue was purified by flash chromatography on silica gel with a gradient elution of 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 512.0 (M+1), 514.0 (M+3); Rt=4.18 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]([NH:29][CH2:30][CH2:31][OH:32])([CH3:28])[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH2:30][CH2:31][OH:32])[CH:26]([CH3:28])[CH3:27])=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)NCCO
Product: Cc1ccc(N(CC(=O)N(CCO)C(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-isopropylamino-ethanol