Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:38])[CH:17]=[C:18]([C:23]([NH:25][CH2:26][CH:27]([NH:31][C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:28]([OH:30])=[O:29])=[O:24])[CH:19]=2)[CH:14]=1)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:38])[CH:17]=[C:18]([C:23]([NH:25][CH2:26][CH:27]([NH:31][C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)[C:28]([OH:30])=[O:29])=[O:24])[CH:19]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(C(=O)NCC(Nc3ncccn3)C(=O)O)cc(=O)n2c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCOc1ccc2cc(C(=O)NCC(Nc3ncccn3)C(=O)O)cc(=O)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 3-{[7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionic acid (35 mg)in 4N HCl in dioxane (6 ml) was stirred for 0.5 hr at room temperature. The reaction mixture was evaporated down to dryness. NMR showed presence of small amount of starting material. The above procedure was repeated with 4N HCl in dioxane (room temperature, 45 minutes). The mixture was evaporated to dryness, triturated with ether, dissolved in water (6 ml) and lyophilized yielding pure product (XXI) (30 mg, 77%). Which was characterized by 1H NMR (400 MHz, CD3CD) δ: 8.42-8.92 (3H, broad signal with one doublet (J=2.2 Hz) in the middle), 7.90 (1H, d, J=9.6 Hz), 7.53 (!H, dd, J=2.3, 9.5 Hz), 7.34 (1H, d, J=1.3 Hz), 7.08 (1H, t, J=5.3 Hz), 6.89 (1H, d, J=1.7 Hz), 5.06 (1H, dd, J=4.2, 6.5 Hz), 4.30 (2H, t, J=5.8 Hz), 4.14 (1H, dd, J=4.2, 14.1 Hz), 3.93 (1H, dd, J=6.6, 14.1 Hz), 3.21(2H, t, J=7.2 Hz), 2.22-2.29 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([CH:31]1[C:32](=[O:33])[O:34][C:27]([CH3:35])([CH3:26])[O:28][C:29]1=[O:30])=[O:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(=O)Cc2cc(F)c(F)cc2F)C(=O)O1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
114 g (0.60 mol) of 2,4,5-trifluorophenylacetic acid was dissolved in 600 mL of THF. To this mixture, 107 g (0.66 mol) of carbonyldiimidazole was added with stirring (when a part of carbonyldiimidazole was added, a lot of solid was formed; subsequently, the solid thereby dissolved in the solution with further addition). Upon completion of the addition, the reaction mixture was warmed to 50° C. 95.1 g (0.66 mol) of Meldrum's acid was added, and the mixture was aged for 3 hours at 50° C. The mixture was concentrated to remove THF and the residue was dissolved in water (600 mL) and dichloromethane (800 mL), and then the pH value was adjusted to 2. The aqueous phase was separated and the organic phase was washed with 0.1N HCl and water (600 mL) respectively. The organic phase was dried and concentrated to obtain 182 g of a condensate, 5-[2-(2,4,5-trifluorophenyl)-acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione, as a solid (the re-crystallization can be carried out in ethyl acetate to obtain a white solid). Melting point: 101.5-103.5° C., Yield: 96%.
Reaction SMILES: [C:1]([N+:4]1([O-])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19](C)[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O1CC[CH2:30][CH:29]1[C:33]([N:35]1CCC(=C2C3=NC=CC=C3CCC3C=C(Cl)C=CC2=3)C[CH2:36]1)=O>>[N:35]1[CH:33]=[CH:29][CH:30]=[C:2]([C:1]([N:4]2[CH2:5][CH2:6][C:7](=[C:10]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[CH2:14][CH2:13][C:12]4[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]3=4)[CH2:8][CH2:9]2)=[O:3])[CH:36]=1
Reactant: CC(=O)[N+]1([O-])CCC(=C2c3ccc(Cl)cc3CCc3cc(C)cnc32)CC1
Reactant: O=C(C1CCCO1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Product: O=C(c1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
1-acetyl-4-(8-chloro-5,6-dihydro-3-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide, i.e., ##STR7## 1-acetyl-4-(3,8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide, i.e., ##STR8## 1-(2-tetrahydrofuroyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidine;
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][CH:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:36][NH2:37]>O1CCOCC1>[NH:36]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][CH:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:37]
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 21-2 (0.4 g, 0.8 mMol) in anhydrous 1,4-dioxane (3 mL) was added hydrazine (0.45 mL, 14.5 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times to yield 21-3.
Reaction SMILES: [C:1]1([CH:7]([NH2:11])[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>ClCCl>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]#[CH:10])=[O:17]
Reactant: C#CCC(N)c1ccccc1
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 187 mg of 1-phenylbut-3-yn-1-amine (Formula 17) in 5 mL of dichloromethane was added 0.16 mL of 2-chloroethyl isocyanate and 0.26 mL of triethylamine. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane was removed. Column chromatography (3% methanol/dichloromethane) followed by recrystallization from chloroform to give 25 mg of 1-(2-chloroethyl)-3-(1-phenylbut-3-ynyl)urea (Formula 18) as a white solid and 200 mg of impure material which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.02-2.04 (m, 1H), 2.64-2.82 (m, 2H), 3.49-3.61 (m, 4H), 4.80 (br, 1H), 4.92-5.05 (m, 2H), 7.26-7.37 (m, 5H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[C:14]([S:15][CH3:16])[C:9]=1[C:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[NH:1][CH:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)=[O:23]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: O=C1CCOCC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC1CCOCC1

Procedure:
The title compound, white solid, MS: m/e=433.2 [(M+H)+], was prepared in accordance with the general method of example 11 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and tetrahydro-4H-pyran-4-one.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>O.CO>[O:15]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([NH2:13])=[O:14]
Reactant: O=C1C=CC(=O)N1
Reactant: Nc1ccccc1N
Solvent: O
Solvent: CO
Product: NC(=O)CC1Nc2ccccc2NC1=O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-phenylenediamine (21.5 g, 0.2 mol) in water (450 mL) was added dropwise a solution of maleimide, (20.0 g, 0.2 mol) in methanol (180 mL) over 60 min. The mixture was then stirred at 95° C. for 2 hours followed at rt overnight. The precipitate was collected via filtration and was washed with small amount of water for a few times to yield the title compound as a pale gray solid (pure product): 1H NMR (DMSO-d6) δ=10.2 (bs, 1H), 7.37 (bs, 1H) 6.88 (bs, 1H), 6.74–6.68 (m, 3H), 6.31–6.57 (m, 1H), 5.78 (bs, 1H), 4.08–4.04 (m, 1H), 2.63 (dd, 1H, J=3.6, 15.5 Hz), 2.32 (dd, 1H, J=3.3, 15.5 Hz); HPLC (CH3CN—H2O-0.1% TFA): Rf=9.49 min.
Reaction SMILES: C[O-].[Na+].[P:4]([O-:11])([O:8][CH2:9]C)[O:5][CH2:6]C.[CH:12]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O>CO>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]([P:4](=[O:11])([O:8][CH3:9])[O:5][CH3:6])[O:18]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCOP([O-])OCC
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of sodium methoxide (5.4 M, 4.8 mL) in MeOH (20 mL) was added diethyl phosphite (3.31 g, 24 mmol) at 0° C. followed by addition of 2-formylbenzoic acid (3.0 g, 20 mmol) portion-wise over a period of 20 min. The resulting mixture was warmed up to rt and continued to stir for 2 h. Methanesulphonic acid (2.69 g, 28 mmol, 1.4 equiv.) was added to the above mixture over a period of 30 min. The reaction mixture was stirred for 30 min and concentrated to remove most of the MeOH. The residue was partitioned between DCM (100 mL) and water (50 mL). The aqueous layer was extracted DCM twice. The combined organic layer was dried over Na2SO4 and concentrated to give dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.6 g, 90%). LRMS (M+H+) m/z 257.1.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[N:5]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:4]=1)#[N:2].[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].O.C(OCC)C>C(N(CC)CC)C.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:3]1[C:7]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[N:5]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:4]=1)#[N:2]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-n2cccc2)c1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1-n1cccc1
Temperature: 70 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodo-5-(N-pyrrolyl)pyrazole (0.55 g) in triethylamine (1 ml) and dimethylformamide (10 ml) was added trimethylsilylacetylene (1 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium (II) chloride (30 mg). The reaction mixture was heated at 70° C. for 24 hours, and then poured into water (100 ml) and diethyl ether (100 ml). The organic layer was dried over MgSO4 and the solvent was evaporated. The crude product was purified by chromatography on silica gel (50 g), eluting with dichloromethane: hexane (1:1), giving the title compound as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([O:23]C)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(4-chlorophenyl)thiophene-2-carboxylate a (0.135 g, 0.29 mmol) in 1:1 THF/MeOH (2 mL) at rt was added a 3 N aq NaOH (1 mL) and the resulting mixture was warmed to 65° C. for 30 min then cooled to rt and concentrated to remove the volatile solvents. The remaining aqueous portion was cooled in an ice bath and 1 N aq HCl was added until pH ˜2 was reached. The slurry was stirred for 1 h then collected the resulting solid by vacuum filtration, rinsed with water and dried under vacuum to afford 86 mg (66%) of an off-white solid as compound b. HPLC Ret time=4.32 min.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:13][S:14][CH3:15].ClN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH2:13][S:14][CH3:15])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CSC
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c([N+](=O)[O-])cc(F)c1F
Yield: 34.9 %

Procedure:
To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) is added gradually N-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixture is stirred for 30 minutes, and thereto is added triethylamine (2.89 g), and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=30:1) and then recrystallized from n-hexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, m.p. 110°-111.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27].FC(F)(F)C(C1ON=C(NC(=O)[O-])C=1)(C)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:23])=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Agent: CC(C)(c1cc(NC(=O)[O-])no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline from the previous step (150 mg, 0.476 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (224 mg, 0.714 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. An additional amount of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg, 0.159 mmol) was added, and stirred for an additional 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (137 mg, 54%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.01 (brs, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 8.07 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 6.91 (s, 1H), 4.00 (s, 6H), 1.56 (s, 6H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:11][CH3:12])[C:7](=[O:8])[CH:6]([CH3:9])[NH:5][C:4]1=[O:10])[CH3:2].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:16]1[CH:15]=[C:14]([N:5]2[CH:6]([CH3:9])[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH2:11][CH3:12])[C:4]2=[O:10])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CCC1(CC)C(=O)NC(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCC1(CC)C(=O)C(C)N(c2ccc(C#N)c(Cl)c2)C1=O

Procedure:
Using 3,3-diethyl-5-methylpyrrolidine-2,4-dione (150 mg), 4-bromo-2-chlorobenzonitrile (230 mg), cesium carbonate (433 mg), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76.9 mg), and in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals (yield: 101 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl chloride (0.27 g), 3,5-bis-(trifluoromethyl)phenylboronic acid (0.45 g), tetrakis(triphenylphosfine)palladium (0.1 g) and sodium carbonate (0.48 g) in water (2 ml) and 1,2-dimethoxyethane (10 ml) was stirred under an argon atmosphere at 85° C. for 2 hours. After cooling, the reaction solution was diluted with ethyl acetate and further stirred for 10 minutes by adding water thereto. After washing the organic layer with a saturated salt solution, it was dried over anhydrous magnesium sulfate. The solution was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain 4-(3,5-bis-trifluoromethyl-benzyl)-2-methyl-nitrobenzene (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2([F:18])[F:17])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:23][C:24]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>C(#N)C.O.N1C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2([F:18])[F:17])[C:9]([NH:19][C:20]2[CH:21]=[C:22]([CH:34]=[CH:35][C:36]=2[F:37])[CH2:23][C:24]2([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Reactant: O=C(O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(c3ccc(Cl)cc3)C3CCCC3(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
490 mg (1.78 mmol) of (4-chlorophenyl)(2,2-difluorocyclopentyl)acetic acid (as diastereomer mixture) were added to a mixture of 4.0 ml of DMF and 1.0 ml of pyridine. At RT, 568.0 mg (2.14 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate and 881.7 mg (2.34 mmol) of HATU were added to the resulting solution and the mixture was stirred at RT overnight. The reaction mixture was then added to saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). Further purification of the product obtained in this manner was carried out by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 774.0 mg (83.1% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: NCCCCF
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1NCCCCF

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.836 mmol) was treated with 4-fluorobutylamine following general procedure B to afford 6-Chloro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (185 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (105 mg) following general procedure E. The above ethylamide (100 mg, 0.28 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 9-chloro-3-ethyl-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (54 mg). LCMS: m/z 380 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([O:15]C)=O)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([NH:20][C:21]3[S:22][C:23]([CH3:26])=[CH:24][N:25]=3)=[O:15])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)C1=C(O)c2ccc(F)cc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3ccc(F)cc3S(=O)(=O)N2C)s1
Yield: 56.9 %

Procedure:
0.29 gm (1 millimol) of methyl 7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 0.125 gm (1.1 millimols) of 2-amino-5-methyl-thiazole were refluxed in 50 ml of xylene for 24 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was recrystallized from xylene/cyclohexane. 0.21 gm (57% of theory) of 7-fluoro-4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:34](Br)[CH3:35].O>CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[N:17]([CH2:34][CH3:35])[C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCBr
Reactant: O=C1NC(=O)C(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)S1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)SC(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
5-[3-(3,5-Difluoro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione (Compound No. 58, 0.10 g, 0.21 mmol) was dissolved in 1.0 mL of anhydrous dimethylformamide. Sodium carbonate (26.5 mg, 0.25 mmol) was added under nitrogen atmosphere and ethyl bromide (23.90 μL, 0.32 mmol) was added 10 minutes later. The mixture was stirred for 4 hours at room temperature. Water was added after the reaction was completed. The resultant solid was washed with water (10 mL×3 times). The solid was dried to obtain 85.3 mg (80%) of the target product.