Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil are added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide. The mixture is then stirred for 5 hours at 40° to 50° C. and at 25°-30° C. 56.4 g=39.2 ml (0.33 mol) of benzyl bromide are added dropwize. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol. Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:14]([C:18]1[CH:30]=[CH:29][C:21]([O:22][C:23]2[C:27](Cl)=[N:26][S:25][N:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27]2[C:23]([O:22][C:21]3[CH:29]=[CH:30][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)=[N:24][S:25][N:26]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(Oc2nsnc2Cl)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2nsnc2Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a suspension formed by suspending 0.16 g of sodium hydride (60%) in N,N-dimethylformamide was added 0.6 g of 4-t-butylphenol and after stirring the mixture for one hour at 60° C., 0.81 g of 3-(4-t-butylphenoxy)-4-chloro-1,2,5-thiadiazole was added to the mixture followed by stirring for 12 hours at 100° C. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer collected was washed twice each time with a diluted aqueous sodium hydroxide solution, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to provide 0.84 g of 3,4-bis(4-t-butylphenoxy)-1,2,5-thiadiazole.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (3.7 ml) and triethylamine (14 ml) were added to a solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (4.9 ml) in dichloromethane (175 ml). After stirring for 1 h at room temperature, the reaction mixture was washed with water, an aqueous HCl solution (1 N), water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH2:20][C:21]#[N:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:16][C:17]=1[O:18][CH3:19])[C:13](=[O:14])[NH:22][C:21]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:20]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)c(CC#N)cc1OCc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Product: COc1cc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1

Procedure:
Similar procedure as described in example 2c was used, starting from 4-Benzyloxy-2-cyanomethyl-5-methoxy-benzoic acid and 3-amino-5-methyl-1H-pyrazole to give 6-Benzyloxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one. LC-MS: m/e 377 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[N+:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[C-:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:18]=[N:17][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of ethyl isocyanoacetate and subsequently with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at room temperature for 48 hours. After distillation of the solvent, the residue is extracted with ethyl acetate/water. The crude product obtained after evaporation is chromatographed on a 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate/hexane there is obtained ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazole-carboxylate in the form of yellow crystals of m.p. 109°-110°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:30])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:30])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1cccc(CF)n1)c1ccc(F)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol, Example 190(E)) and (4-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 300 mg (0.75 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1.Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:20][NH:19][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][C:9]=2[CH:15]=1)=[NH:17]
Reactant: NO
Reactant: N#Cc1ccc2[nH]c(-c3ccccn3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]c(-c3ccccn3)nc2c1
Yield: 46 %

Procedure:
A mixture comprising 2-pyridin-2-yl-1H-benzimidazole-5-carbonitrile (110 g, 0.5 mmol), hydroxylamine hydrochloride (38.2 mg, 0.55 mmol), potassium carbonate (104 mg, 0.75 mmol) and methanol (10 mL) was heated at reflux for 2.5 hours and then concentrated to dryness. The residue was taken up and purified by preparative reverse phase HPLC. The combined pure fractions were lyophilized to provide N-hydroxy-2-pyridin-2-yl-1H-benzimidazole-5-carboxamidine (40 mg, 0.23 mmol); 1H-NMR (300 Mhz, DMSO-d6): 7.53-7.57 (m, 2H), 7.80 (d, 1H), 8.01-8.04 (m, 2H), 8.32 (d, 1H), 8.75 (d, 1H), 9.20 (b, 2H); MS (ESI), Calculated for C13H11N5O: 253.1, Found (MH+): 253.7.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]3[N:8]([N:9]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:16]=4)[C:11]=3[C:12]([NH2:14])=[O:13])[C:4]=2[CH:3]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[C:30]([NH:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]3[N:8]([N:9]=[C:10]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)[C:11]=3[C:12]([NH2:14])=[O:13])[C:4]=2[CH:3]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1ccc(N)cc12
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2c1
Yield: 8.3 %

Procedure:
To a solution of 7-amino-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide (45 mg, 0.11 mmol) in 10 mL of DCM at 0° C. was added TEA (36 mg, 0.35 mmol). Acryloyl chloride (11 mg, 0.12 mmol) in 2 mL of DCM was added dropwise over a period of 20 min. The mixture was stirred until TLC and LCMS analysis showed that most of starting material was consumed. The mixture was then partitioned between water (50 mL) and DCM (20 mL), extracted with additional 20 mL of DCM. The combined organic layer was washed with brine, dried over Na2SO4, concentrated and purified by Pre-TLC (DCM/MeOH=20/1) to get 4 mg (7.8%) of 7-acrylamido-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide as a grey solid. 1H NMR (400 MHz, CD3OD-d4) δ 8.25 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.42-6.25 (m, 2H), 5.69 (dd, J=9.6, 1.9 Hz, 1H). MS (ESI) m/e [M+1]+ 438.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CCNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.8 mmol) of the compound from Example 12A, 57 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine were initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 13 mg (12% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=O)[NH:22][C:23]=1[CH3:24]>N1CCCC1.C(O)C>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:25]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])[NH:22][C:23]=1[CH3:24]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCO)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (177 mg, 1.0 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) and 3 drops of pyrrolidine in 2.0 mL of ethanol was refluxed at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 360.6 mg (98%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH2:1][C:2](=[O:27])[C@@H:3]([NH:19]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:19][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[C:2]([NH2:1])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(C[C@H](N)C(N)=O)cc2)cc1

Procedure:
(S)-tert-Butyl 1-amino-3-(4′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamate (Example 3, step (ii), 3.13 g) was dissolved in dichloromethane (30 mL) and TFA (1.32 mL) was added. The dichloromethane was distilled off on a rotary evaporator at atmospheric pressure to leave ˜5 mL of solvent. The reaction was monitored by HPLC/MS and when complete was partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaporated. The resulting solid was purified by chromatography on silica eluting with ethyl acetate then ethyl acetate containing 10% methanol to afford the sub-titled compound (1.95 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2.[Cl:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:20].[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: Oc1ccc2c(c1)CCC(CN1CCCCC1)C2
Reactant: ClCc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2sc(COc3ccc4c(c3)CCC(CN3CCCCC3)C4)nc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
To a solution of 6-hydroxy-2-piperidinomethyltetralin hydrochloride (205 mg, Reference Example 19) and 2-chloromethylbenzothiazole (183 mg) in DMF (10 ml) was added potassium carbonate (327 mg) and the reaction mixture was stirred at room temperature for 4 days and further at 60° C. for 7 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol=10:1), alumina column chromatography (eluent: ethyl acetate: hexane=1:4) and converted into its hydrochloride, which was recrystallized from methanol-ethyl acetate to obtain the titled compound (158 mg).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[F:6][C:7]([F:26])([F:25])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]3[CH2:20][C:21](=[O:23])[CH2:22][CH:17]3[C:16]2=[O:24])=[CH:11][CH:10]=1.O>C1COCC1>[OH:23][C:21]1([CH2:1][CH2:2][CH3:3])[CH2:22][CH:17]2[C:16](=[O:24])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]([F:6])([F:25])[F:26])=[CH:10][CH:11]=3)[CH2:19][CH:18]2[CH2:20]1
Reactant: CCC[Mg]Br
Reactant: O=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(O)CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 35 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
Propylmagnesium bromide (0.2 mL, 0.6 mmol, 3M) was added to a solution of 2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrole-1,5-dione (0.1 g, 0.33 mmol) in THF (10 mL), and the mixture was stirred for 3 h at room temperature and overnight at 35° C. The solution was cooled, then poured into water (25 mL) and extracted with ether (3×20 mL), dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum/ethyl acetate=1:1) to yield the title compound (25 mg, 21%). 1H NMR (300 MHz, CDCl3): δ 7.62-7.60 (m, 2H), 7.32-7.23 (m, 2H), 4.11 (t, 1H, J=9.5 Hz), 3.71-3.67 (m, 1H), 3.18 (t, 1H, J=9.5 Hz), 2.95 (d, 1H, J=9.6 Hz), 2.25-2.21 (m, 1H), 1.98-1.88 (m, 2H), 1.81-1.76 (m, 1H), 1.61-1.34 (m, 4H), 0.95 (t, 3H, J=7.2 Hz); LC-MS: 344.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15](=O)[NH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>N1C=CC=CC=1>[Cl:28][C:15]1[O:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCc1[nH]c(=O)oc1-c1ccc(F)c2ccccc12
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1nc(Cl)oc1-c1ccc(F)c2ccccc12
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[5-(4-fluoro-1-naphthyl)-2-oxo-4-oxazolin-4-yl]butanoate (3.09 g), phosphorus oxychloride (6.00 g) and pyridine (0.80 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate (100 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-5-(4-fluoro-1-naphthyl)-4-oxazolebutanoate was obtained as a yellow oil (903 mg, 28%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:27][CH2:28][CH2:29][N:30]([CH2:34][C:35]([NH2:37])=[S:36])[C:31](=[O:33])[CH3:32])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:37]=[C:35]([CH2:34][N:30]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[C:31](=[O:33])[CH3:32])[S:36][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OCCN(CC(N)=S)C(C)=O
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CCOC(C)=O)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, by reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-[N-(2-acetoxyethyl)-N-acetylamino]thioacetamide in ethanol gave 1-ethyl-6-fluoro-1,4-dihydro-7-[2-[[N-(2-acetoxyethyl)-N-acetylamino]methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 148°-152° C., resolidified and melted 164°-165° C., which was hydrolyzed with refluxing 6 N hydrochloric acid to afford the titled compound, mp 290° C. (dec).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1.Cl[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[CH3:17][O:16][C:14]([C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1)=[O:15]
Reactant: Brc1cscc1Br
Reactant: COC(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cscc1Br
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of isopropylmagnesium chloride (1.0 g, 9.7 mmol, 1.2 eq.) in THF (5 mL) was added to a solution of 3,4-dibromo-thiophene (2 g, 8.3 mmol, 1.0 eq.) in THF (15 mL), and stirred for 3 hours while the temperature was maintained at 0-5° C. in an ice/salt bath. Methyl chloroformate (1.6 g, 16.9 mmol, 2 eq.) was added dropwise with stirring. The resulting solution was stirred for an additional 16 hours at room temperature. The reaction was then quenched with water (1 mL). The resulting mixture was concentrated under vacuum, then diluted with EtOAc (50 mL). The resulting mixture was washed 1N HCl (1×100 mL) and saturated aqueous NaCl (2×100). The organic layer was concentrated to provide a crude residue, which was applied onto a silica gel column and eluted with EtOAc/PE (1:50) to yield 4-bromothiophene-3-carboxylic acid methyl ester (1.0 g) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br>O>[Br:12][C:8]1[NH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=1
Reactant: BrBr
Reactant: CC(C)(C)c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1n[nH]c(Br)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
The mixture of 2.51 g of 3-t-butyl-1H-1,2,4-triazole, 35 ml of water and 2.5 ml of 50% aqueous solution of sodium hydroxide was cooled to 0° C., then 3.5 g of bromine was added to it. It was stirred at room temperature for 3 hours. The reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 3.80 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)oxy)benz oate (65 mg, 0.14 mmol) and lithium hydroxide monohydrate (30 mg, 0.72 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give the title compound. MS (ESI+) m/z 437.21 [M+H]+.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:10][C:11](N)=[O:12].S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.Cl>C(OCC)(=O)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:10][C:11]([NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])=[O:12]
Reactant: NC(N)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: C[Si](C)(C)NC(=O)N[Si](C)(C)C

Procedure:
10 ml of hexamethyldisilazane (48 mmoles) were added to 2.4 g (40 mmoles) of urea and 73 mg (0.4 mmole) of saccharin in 15 ml of refluxing ethyl acetate and evolution of ammonia started immediately and was completed after refluxing for 20 minutes established by titration with 1 N HCl. The volatile material was evaporated under vacuum and the residue was vacuum dried to obtain 8.06 (99%) of N,N'-bis-(trimethylsilyl)-urea melting at 219°-222° C. Without the addition of saccharin as a catalyst, evolution of ammonia was slow and the reaction had to be carried out for at least 24 hours for completion.