Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>N1CCCCC1.C(Cl)(Cl)Cl>[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([CH:4]2[C:9]([OH:10])=[C:8]([C:11](=[O:13])[CH3:12])[C:7](=[O:14])[O:6][C:5]2=[O:15])=[O:3])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a mixture of 2.11 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 1.63 g. (0.01 m.) of p-acetamidobenzaldehyde in 200 ml. of chloroform is added with stirring 25 drops of piperidine. The resulting solution is refluxed and azeotroped for 12 hours, filtered hot and the solid is washed with dilute hydrochloric acid, water and ether to give 3-(p-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 230°-231° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH:38]([CH3:40])[CH3:39].[BH4-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:31]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:39])[CH2:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl
Reactant: CC(C)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CC=C(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Dissolve 4-(3-chloro-4-fluorophenyl)-6-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-(pyridin-4-yl)pyrimidine (40 mg) and 2-bromopropane (0.1 mL) in DMF (1.5 mL) under nitrogen atmosphere. Heat the mixture in a sealed tube at 120° C. for 48 hours. Cool the mixture to room temperature and then add NaBH4 (50 mg). Stir the mixture at room temperature for 20 hours, dilute with water (5 mL), extract with EtOAc (3×3 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 20% EtOAc/hexane to afford the title product as white solid. Mass spec m/z=561.27.
Reaction SMILES: ClC1C=C(CCCNC(=O)/C=C2\OC(C)(C)OC\2=O)C=CC=1Cl.[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][CH2:53][C:54](O)=[O:55]>>[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][CH2:53][C:54]([NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:55]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Agent: CC1(C)OC(=O)/C(=C/C(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCN1C(=O)c2ccccc2C1=O
Yield: 97.3 %

Procedure:
By appropriate application of the method used to synthesize Intermediate 5, tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (400 mg, 1.6 mmol) and 3-(1,3-dioxoisoindolin-2-yl)propanoic acid (388 mg, 1.8 mmol) were combined to provide Intermediate 7A (700 mg, 87% yield). HPLC/MS (Method C) RT=2.80 min, [M+H]+ 450.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CS(C)=O.[CH2:12](Cl)[C:13]#[CH:14]>O.C(=O)([O-])[O-].[Ag+2]>[C:12]([O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)#[C:13][CH3:14]
Reactant: Oc1ccncc1
Reactant: C#CCCl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC#COc1ccncc1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of 20.0 g (0.21 mole) 4-hydroxypyridine and 200 ml dimethyl sulfoxide was added 102 g (0.1 mole) silver carbonate. Propargyl chloride (22.5 g, 0.3 mole) was added to this suspension and the mixture heated at 50° for 6 hrs. After cooling to room temperature, the reaction mixture was diluted with water and extracted two times with ether. The combined ether extract was dried, filtered and concentrated as before to give 1.0 g of 4-(propynyloxy)pyridine. The product was 95% pure by vpc. The nmr and ir were compatible with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: O=CC(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 790 mg (1.77 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.18 mL (3.54 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford the title compound. 1NMR(CDCl3) δ 0.94 (d, J=6.7 Hz, 3H), 3.44 (d, J=6.5 Hz, 1H), 3.77 (m, 1H), 3.97 (s, 2H), 4.02 (s, 2H), 4.34 (m, 1H), 4.53 (s, 1H), 6.69 (m, 1H), 6.78 (m, 2H), 7.28 (d, J=8.5 Hz, 4H), 7.38 (d, J=8.5 Hz, 4H); Mass Spectrum: m/e=462 (M+1 35Cl, 35Cl) and 464 (M+1 35Cl, 37Cl).
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[NH2:19]N>O>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:19])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: CNc1nc2c(C)cccc2s1
Agent: Br
Solvent: OCCO
Solvent: O
Product: Cc1cccc2sc(NN)nc12
Yield: 90 %

Procedure:
4-Methyl-2-methylaminobenzothiazole hydrobromide (443 g.; 1.71 mole) was added with stirring to 1.7 liter of ethylene glycol. 85% Hydrazine hydrate (400 grams; 6.75 mole) was added in several portions. The reaction mixture was heated to 130°-135°C. under N2 atmosphere and maintained for about four hours, then cooled slowly with stirring. The product was isolated by addition of water and separated by filtration. It was then dried overnight in a vacuum oven, yielding 275.5 g. (90% yield) of 4-methyl-2-hydrazinobenzothiazole. The nmr spectrum agreed with a reference spectrum and showed no evidence of starting material or other impurity. Non-aqueous titration showed the product to be 97.5% pure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N)c(N)c1

Procedure:
Five-percent palladium on carbon (0.50 g) was added to a solution of 4.00 g of ethyl 3-amino-4-nitro-benzoate in 100 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 50° C. for 16 hours. The solid material was separated through filtration, and the filtrate was concentrated to obtain ethyl 3,4-diaminobenzoate. Twenty milliliters of trifluoroacetic acid were added thereto, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated, and chloroform was added thereto. The crystals precipitated were separated through filtration, and were dried to give 4.46 g of 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole (157).
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:45]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[N+:55]([C:52]1[C:51]2[N:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:45]([C:2]#[N:3])=[CH:54][CH:53]=1)([O-:57])=[O:56]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)c2cccnc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
Zn(CN)2 (739 mg, 6.3 mmol), DIPEA (0.41 ml, 2.37 mmol), X-phos (225 mg, 0.47 mmol) and Pd2 (dba)2 (90 mg, 0.16 mmol) were added to a degassed (with argon) solution of 5-bromo-8-nitroquinoline 470 (400 mg, 1.58 mmol) in DMF (4 ml) and the mixture was heated at 100° C. in microwave for 20 min. After cooling, the mixture was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (96:4) as the eluent to give the title compound (230 mg, 63%).
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[I:19]I.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH:1]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([I:19])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccc(SC2CCCC2)c1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1cccc(SC2CCCC2)c1
Yield: 42.3 %

Procedure:
To a solution of 1-(cyclopentylthio)-3-bromobenzene (3.6 g) in dry THF (40 ml) at −60° under nitrogen was added n-butyl lithium (10 ml, 1.6M in hexanes). After stirring for 15 min a solution of iodine (4.3 g) in dry THF (30 ml) was added dropwise and the solution was allowed to warm to 0°. Wet THF was added to the brown solution, followed by aqueous sodium sulphite. The resulting colourless solution was extracted with diethyl ether and the combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by column chromatography on silica using cydohexane as eluant. This gave the title compound (1.8 g). LCMS RT=4. 1 min
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:37]=1)(=[O:31])=[O:32]
Reactant: Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)N(CCO)CCO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedure II. Light yellow solid. MS (ISP) 640.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:19][C:20]1[C:21](=[O:39])[N:22]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=2)[CH:25]=1.O>CN(C)C=O>[CH:36]1([CH2:35][N:22]2[C:21](=[O:39])[C:20]([CH2:19][CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=3)=[N:23]2)[CH2:38][CH2:37]1
Reactant: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)n(CC3CC3)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
After 55% sodium hydride (322 mg, 7.38 mmol) was added to a solution of di-tert-butyl malonate (970 mg, 4.48 mmol) in N,N-dimethylformamide (10 mL), 4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.8 g, 4.90 mmol) was added under ice-cold stirring. The reaction mixture was stirred at room temperature for 1 hour, poured into water, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to yield the title compound as a yellow powder (yield: 1.39 mg, 61.8%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.O.[Na].Cl[C:15]1[N:20]=[C:19]([OH:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>C(O)C.[Ni].O>[OH:21][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=[C:15]([NH:9][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:20]=1
Reactant: CSc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1O
Agent: [Ni]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSc1ccc(Nc2ncc([N+](=O)[O-])c(O)n2)cn1

Procedure:
4.5 gm (0.0264 mol) of 2-methylthio-5-nitro-pyridine were hydrogenated at 50° C. and 5 bars pressure in ethanol in the presence of Raney nickel as the catalyst. After the catalyst had been filtered off and after evaporation of the filtrate in vacuo an oil was obtained. A solution of 6.84 gm (0.032 mol) of the sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitro pyrimidine in 150 ml of water was added to the solution of this oil in water. The aqueous solution was heated for 30 minutes on a steam bath, and the resulting precipitate suction-filtered off, washed with water and dried. 4-Hydroxy-2-(6'-methylmercapto-3-pyridyl)amino-5-nitro-pyrimidine was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:42][CH3:43])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:29]=2)[N:24]=[CH:23][N:22]=1.Cl.C(=O)([O-])O.[Na+]>C(O)CCC>[CH3:43][O:42][C:27]1[CH:26]=[C:25]2[C:30]([C:21]([NH:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[S:8][C:4]=4[CH:3]=3)=[N:22][CH:23]=[N:24]2)=[CH:29][C:28]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5ccccc5)sc4c3)c2cc1OCCCN1CCN(C)CC1
Reaction time: 8 h

Procedure:
N-(6-{7-Methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4yl-amino}benzothiazol-2-yl)benzamide was prepared by heating a mixture of N-(6-amino-benzothiazol-2-yl)benzamide (Intermediate 2, 40 mg. 0.148 μmol), 4-chloro-7-methoxy-6-[3-(4methylpiperazin-1-yl)propoxy]quinazoline (IM 8, 52 mg, 0.148 mmol), and HCl (112 μL, 4 M solution in dioxane, 0.444 mmol) in n-butanol (6 mL) to 110° C. for 5 h. Saturated sodium hydrogencarbonate solution was added and the product was extracted with ethyl acetate. After washing with water and drying over Na2SO4, the solvent was removed. The residue was taken up in little methanol, then water was slowly added. After stirring the mixture overnight, a grey solid was obtained (39 mg, 66 μmol, 45%). LC(ESI-MS: m/z=584 [M+H]+; m/z=582 [M−H]−; Rt=2.26 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12](#[N:16])[CH2:13][CH2:14][CH3:15].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:11][C:12](=[NH:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCC#N
Reactant: CCOC(=O)c1cccn1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCC(=N)Nn1cccc1C(=O)OCC
Temperature: 75 °C
Yield: 74.1 %

Procedure:
To a solution of 1-amino-1H-pyrrole-2-carboxylic acid ethyl ester (10.8 g, 70.1 mmol) in 250 mL of dioxane in a sealed tube at room temperature was added butyronitrile (61 mL, 700 mmol) followed by 4 N HCl in dioxane (70 mL, 280 mmol). The tube was flushed with Ar, sealed, and heated at 75° C. for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and then diluted with 240 mL of dioxane. Triethylamine (78 mL, 560 mmol) was added and the reaction was heated at 75° C. for 6 h. After cooling to room temperature, the reaction was concentrated in vacuo to give the crude product. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:1) gave the title compound as a light brown solid (11.6 g, 74%): 1H NMR (CDCl3) δ 6.80 (q, 1H, J=1.96 Hz), 6.59 (t, 1H, J=2.16 Hz), 6.03 (q, 1H, J=2.6 Hz), 4.54 (brs, 2H), 4.11 (q, 2H, J=7.12 Hz), 2.27 (t, 2H, J=7.96 Hz), 1.66 (hex, 2H, J=7.72 Hz), 1.19 (t, 3H, J=7.12 Hz), 0.95 (t, 3H, J=7.32 Hz); 13C NMR (CDCl3) δ 166.7, 160.2, 124.8, 119.8, 116.0, 107.2, 60.0, 35.6, 20.6, 14.9, 14.1; MS (ESI+) 224.10 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc(F)cc1

Procedure:
Fluorobenzene (0.5 mL), acryloyl chloride (0.23 g), and aluminium chloride (0.33 g) were treated in the same manner as described in Example 1 to obtain the title compound (90 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:3]=1.[CH2:12]([O:19][CH2:20][C:21](Cl)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[NH2:11][S:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:9])=[O:10]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cccc(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A suspension of 1-aminobenzene-3-sulfonamide (1 g; 5.8 mmol; 1 eq) in a mixture of acetone (10 mL) and water (10 mL) is stirred at room temperature until complete dissolution. Benzyloxyacetyl chloride (1.4 mL; 8.7 mmol; 1.5 eq) is added at 0° C. followed by the addition of NaHCO3 (1.4 g) over 15 min. After 30 min, the reaction mixture is allowed to stir at room temperature for 2 h. The reaction mixture is then filtered off and the solid residue is washed with MeOH and ACN. The filtrate is concentrated to dryness, affording 1.8 g (97%) of the title compound as a brown foam. 1H NMR (DMSO-d6) δ 8.25 (br s, 1H), 7.81-7.75 (m, 1H), 7.55-7.48 (m, 2H), 7.42-7.28 (m, 8H), 4.62 (s, 2H), 4.13 (s, 2H). HPLC (max plot) 91%; Rt 2.53 min. UPLC/MS: (ES+) 321.2; (ES−) 319.2.
Reaction SMILES: [BrH:1].[CH:2]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]2[CH:16]=1)([CH3:4])[CH3:3].[H][H]>[Pd].CO>[BrH:1].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([CH:16]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:6]=2)[CH:9]=1
Reactant: CC(C)c1cn2cc([N+](=O)[O-])ccc2n1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CO
Product: CC(C)c1cn2cc(N)ccc2n1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a methanol solution (20 ml) containing 2-isopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide (280 mg), 10% palladium-on-carbon (30 mg) was added, and inside the reaction system was substituted with hydrogen, followed by an hour's stirring at room temperature. The reaction liquid was filtered through Celite™. Concentrating the filtrate under reduced pressure, crude 6-amino-2-isopropylimidazo[1,2-a]pyridine hydrobromide (250 mg) was obtained.
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])(=[O:28])[CH3:27].C(N(CC)CC)C>C(O)C>[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][N:33]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:32]1)[CH3:30])(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Reactant: CC(=O)N(C)C1CCNC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCC(N(C)C(C)=O)C3)c(F)cc2c1=O
Yield: 82.3 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (26.7 g) obtained according to the Reference Example 2, 3-(N-acetyl-N-methylamino)pyrrolidine (15.5 g), triethylamine (10.0 ml), and ethanol (300 ml) was heated under reflux for one hour. The reaction mixture was concentrated to a half volume under reduced pressure. To the mixture was added water (200 ml), and the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 24.8 g of ethyl 7-[3-(N-acetyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 227°-229° C. A solution of the above ester (20.0 g) in 20% hydrochloric acid (120 ml) was heated under reflux for 3 hours. After the reaction was completed, water (60 ml) and ethanol (120 ml) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (800 ml) and the solution was treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of 27% aqueous ammonia. The crystals were collected by filtration, washed with water, and dried to give 11.0 g of the compound 4, m.p. 243°-245° C.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:20]([CH3:22])=O)[C:18]=2[OH:19])[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:23]([C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[S:26])[NH2:24].Cl>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:20](=[N:24][NH:23][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]3)=[S:26])[CH3:22])[C:18]=2[OH:19])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)C1CCN(C(=S)NN)CC1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCN(C(=S)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a dimethylformamide solution (600 μL) of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (30 mg, 0.10 mmol) and methyl 1-hydrazinothiocarbonyl-piperidine-4-carboxylate (46 mg, 0.20 mmol) prepared in Reference Synthetic Example 2, concentrated hydrochloric acid (9 μL, 0.1 mmol) was added at room temperature, and the resulting solution was stirred at room temperature for 8 hours, then mixed with water and extracted with ethyl acetate. The extract was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from chloroform to give the desired product (yield 55%).