Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([O:15]C)=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([OH:15])=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of compound 11e (390 mg, 1.33 mmol) and LiOH (159 mg, 6.65 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. The reaction was concentrated under reduced pressure and then water was added to the residue. The aqueous mixture was acidified with 1N HCl to pH ˜4. A white precipitate was filtered and washed with water and Et2O. The crude product was dried under vacuum to give compound 11f which was used without purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CCOC(C)=O.O>[C:1]1([CH:7]2[CH2:10][C:9](=[N:21][OH:22])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: ON=C1CC(c2ccccc2)C1
Yield: 78.9 %

Procedure:
A yellow slurry of 3-phenylcyclobutanone (1.09 g, 7.44 mmol), MeOH (33.8 mL), water (3.38 mL), potassium carbonate (2.26 g, 16.4 mmol), and hydroxylamine hydrochloride (1.14 g, 16.4 mmol) was heated at 50° C. for 14 hours. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (0-50% EtOAc/hexanes, gradient elution) to provide the title compound (947 mg, 5.87 mmol, 79% yield). MS (DCI) M/Z 162 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CCN(CC)CC.O>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Yield: 76.2 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (11.1 g, 50 mmol) in CHCl3 (100 mL) was added 2,6-difluoroaniline (8.07 mL, 75 mmol, 1.5 eq) followed by Et3N (10.43 mL, 75 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated and the crude product was recrystallized from 200 mL of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2ccccc2nc1Cl
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2-chloroquinoline-3-carbaldehyde (1.0 g, 5.21 mmol) in anhydrous ethanol (20 mL) at 0° C., was added sodium borohydride (0.197 g, 5.21 mmol). The reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, as monitored by TLC and HPLC, the reaction mixture was quenched with water. The solvent was evaporated, and the crude residue was extracted with dichloromethane. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate to provide the (2-chloroquinolin-3-yl)methanol as a white solid (0.96 g, 95% yield); M+ 193.64.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1)([OH:20])=[O:19]>>[F:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(C(F)(F)F)nc2c1
Yield: 19 %

Procedure:
Followed the coupling procedure described in Step 1 of Compound VIII-2 (Example 65), where the starting materials were 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and 4-carboxy-2-fluorobezeneboronic acid. After H2O quench, the aqueous layer was acidified with 0.1M HCl to pH=1, followed by EtOAc/aqueous workup and column purification to give 3-fluoro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (50 mg, yield 19%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: Cc1ccccc1Br
Reactant: O=C1CN2C(=O)CCC2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Ma2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with IPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.
Reaction SMILES: [Br:1]Br.Cl.[CH:4]([C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:8]=1[NH2:9])([CH3:6])[CH3:5].Cl>C1CCCCC1>[BrH:1].[Br:1][C:12]1[CH:13]=[C:7]([CH:4]([CH3:6])[CH3:5])[C:8]([NH2:9])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cl
Solvent: C1CCCCC1
Product: Br
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 10 °C
Yield: 169.3 %

Procedure:
19.1 g of bromine are added dropwise at 70° C. over 2 hours to a suspension of 24.1 g of 2,6-diisopropylaniline hydrochloride in 150 ml of cyclohexane. The hydrogen chloride evolved in the course of this addition escapes continuously. The reaction mixture is cooled to 10° C. and then filtered. The filter residue is washed with cyclohexane and dried at 40° C. under vacuum, affording 34.1 g of 4-bromo-2,6-diisopropylaniline hydrobromide (99.9% of theory) in the form of yellow crystals of 98.7% purity and having a melting point of 234°-235° C. (compound 1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:11][C:12]1([CH3:30])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[O:13]1.IC>ClCCl>[CH3:1][N:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[B:14]1[O:13][C:12]([CH3:30])([CH3:11])[C:16]([CH3:17])([CH3:18])[O:15]1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+. 130b) N-[2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (625.0 mg, 2.934 mmol) and N-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1000.0 mg, 3.2133 mmol) in a manner analogous to Example 2c. Product was isolated as white solid (0.479 g, 51%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.52 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35 (d, J=7.2 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 5.94 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H). MP=209-211° C. MS=318 (MH)+. 130c) N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[O:11][CH2:10]1)(=[O:3])[CH3:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])([OH:11])[CH2:10][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, 0.07 mol) in DMF (250 ml), 1,2,4-triazole (16.6 g, 0.24 mol) and potassium carbonate (33.2 g, 0.24 mol) were added, followed by stirring at room temperature for 12 hours and then at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ethyl ether and an insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether-ethyl acetate, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (12.2 g, yield: 37.8%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-methyl-3-nitrobenzoic acid (5.52 g, 30.5 mmol) in MeOH (100 mL) was added 98% sulfuric acid (2 mL) and the resultant mixture was refluxed overnight, then cooled to room temperature. The mixture was concentrated and the residue was dissolved in CH2Cl2 (50 mL) and water (20 mL). Solid Na2CO3 was added until the aqueous phase was basic to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 5.79 g (97%) of 4-methyl-3-nitrobenzoic acid methyl ester as a white solid. To a solution of 4-methyl-3-nitrobenzoic acid methyl ester (5.01 g, 25.7 mmol) in CCl4 (65 mL) was added N-bromosuccinimide (5.04 g, 28.3 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.21 g, 4.96 mmol). The resultant mixture was refluxed for 24 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (9:1:hexanes-EtOAc) provided 4.30 g (61%) of 4-bromomethyl-3-nitrobenzoic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.98 (s, 3H), 4.85 (s, 2H), 7.67 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8, 1.5 Hz), 8.66 (d, 1H, J=1.5 Hz).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][C:6]1[C:11]2[O:12][C@:13]3([CH3:53])[O:16][CH:17]=[CH:18][C@H:19]([O:51][CH3:52])[C@@H:20]([CH3:50])[C@@H:21]([O:46][C:47]([CH3:49])=[O:48])[C@H:22]([CH3:45])[C@H:23]([OH:44])[C@H:24]([CH3:43])[C@@H:25]([OH:42])[C@@H:26]([CH3:41])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:40])[C:31]([NH:33][C:34]4[C:38](=[O:39])[C:8](=[C:9]([C:36](=[O:37])[CH:35]=4)[C:10]=2[C:14]3=[O:15])[C:7]=1[OH:54])=[O:32]>CNC=O.C(Cl)Cl>[CH3:41][C@@H:26]1[C@H:25]([OH:42])[C@@H:24]([CH3:43])[C@@H:23]([OH:44])[C@@H:22]([CH3:45])[C@H:21]([O:46][C:47]([CH3:49])=[O:48])[C@H:20]([CH3:50])[C@@H:19]([O:51][CH3:52])[CH:18]=[CH:17][O:16][C@:13]2([CH3:53])[C:14](=[O:15])[C:10]3[C:11]([O:12]2)=[C:6]([CH3:5])[C:7]([OH:54])=[C:8]2[C:38](=[O:39])[C:34](=[C:35]([NH2:1])[C:36]([C:9]=32)=[O:37])[NH:33][C:31](=[O:32])[C:30]([CH3:40])=[CH:29][CH:28]=[CH:27]1
Reactant: [N-]=[N+]=[N-]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: [Na+]
Solvent: CNC=O
Solvent: ClCCl
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O

Procedure:
3-amino-4-deoxo-4-imino-rifamycin S, (a) above, is described in U.S. Pat. No. 4,017,481, where it is made by reacting 3-amino-rifamycin S with gaseous ammonia. The reaction is carried out in a solution of tetrahydrofuran at room temperature for 15 hours with further addition of ammonia. The starting material, 3-amino-rifamycin S may obtained as described in U.S. Pat. No. 4,007,169, where it is obtained by reacting sodium azide with rifamycin S. The reaction is carried out in methylformamide at 35° C. for 60 minutes. The reaction mixture is diluted with methylene chloride and washed with water. The aqueous phase contains rifamycin SV which may be oxidized by, for example, nitrous acid to the starting material rifamycin S. The organic phase is washed with water, dried with sodium sulphate and evaporated to yield 3-amino rifamycin S which is recrystallized from 2-methoxy ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1COCC1.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of (6-methylpyridin-3-yl)methanol (1.08 g) in THF (15.0 mL) was added thionyl chloride (1.57 g) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.81 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.[CH3:20]COCC>ClC(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:9]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)[CH3:20])=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: CCOCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(c1ccc(Br)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the compound p-bromoacetophenone (36.85 g, 185 mmol) in trichloromethane (300 ml) was added 1,3-propanedithiol (25 g, 230 mmol) and boron trifluoride etherate (3 ml). The resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane (500 ml), washed twice with 10% sodium hydroxide (200 ml), water, and brine, and then dried (Na2SO4). The product was concentrated to an oil. A portion was stirred with ether (100 ml) and a crystalline product was formed. The crystalline product was recovered by filtration and purified by recrystallization to yield 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (23.4 g, 110 mmol) described in Manufacturing Example 2-1-2, nitromethane (33.6 g, 550 mmol), ammonium acetate (17.0 g, 220 mmol) and acetic acid (200 mL) was stirred for 1 hour and 45 minutes at 100° C. The reaction solution was stirred on an ice bath while adding a small amount of water, and the precipitated solids were filtered to obtain the title compound (21.0 g, 74.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CO>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(C)(OC)C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(C)(OC)C(=O)C=CN(C)C
Yield: 90.1 %

Procedure:
100 g (0.76 mol) of 3,3-dimethoxy-2-butanone (16) were stirred together with 90.2 g of N,N-dimethylformamide dimethyl acetal (17) (0.76 mol) at 120° C. for 48 h. The methanol which was formed in the reaction was removed continuously from the reaction solution by means of distillation. Crystallization occurred spontaneously when the solution was cooled, with the crystallization being brought to completion by adding a little heptane. This resulted in 128.24 g of crude product 18 (yield 90%), which was reacted without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
4-Hydroxy-7-methoxy-3-quinolinecarboxylic acid (21.4 g, 0.1 mol) was added with diphenyl ether (150 ml) and decarboxylated at 250° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and added with ethyl acetate (300 ml). The resulting precipitates were collected by filtration to obtain crude 4-hydroxy-7-methoxyquinoline (15.0 g). This was recrystallized from water (about 300 ml) to obtain 14.8 g (86%) of 4-hydroxy-7-methoxyquinoline.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].C(CC(C)(C)C)(C)C>ClCCl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.3 %

Procedure:
To a stirred solution of 42.5 g (0.25 mol) of phenyl ether in 200 mL of dichloromethane at −20° C. under argon was slowly added 23.3 g (0.20 mol) of chlorosulfonic acid. After the addition was complete, the reaction was allowed to slowly warm to room temperature. After 16 hours, 150 mL of isooctane was added and the solution was concentrated to an oily residue. Redissolution in 200 mL of 1:3 dichloromethane/isooctane and reconcentration with cooling to about 100 mL gave a solid. The supernatant was decanted, and the solid triturated with additional isooctane and then dried in vacuo to give 55.2 g of crude 4-phenoxybenzene sulfonic acid. The crude acid was dissolved in 200 mL of dichloromethane, and 22 mL (32 g, 0.25 mol) of oxalyl chloride was added, followed by 2.5 mL of N,N-dimethylformamide. After 2 days, the reaction solution was poured into 200 mL of ice water, and extracted with 400 mL of hexane. The organic layer was washed with 100 mL of water and 100 mL of brine, dried over magnesium sulfate, and concentrated. Recrystallization of the residue from dichloromethane/isooctane gave 38.5 g of 4-phenoxybenzenesulfonyl chloride as a white solid: mp 41.5° C.; 1H-NMR (CDCl3) δ 7.10 (apparent t, 4H, J=7 Hz), 7.28 (t, 1H, J=7 Hz), 7.46 (t, 2H, J=8 Hz), 7.98 (d, 2H, J=8.8 Hz).
Reaction SMILES: C(OC(=O)C)(=O)C.[Br:8][C:9]1[S:13][C:12]2=[C:14](C(O)=O)[N:15]=[CH:16][N:11]2[CH:10]=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:8][C:9]1[S:13][C:12]2=[CH:14][N:15]=[CH:16][N:11]2[CH:10]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 130 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
Acetic anhydride (0.1 ml, 1.06 mmol) was added to a solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (36 mg, 0.14 mmol) in 1,2,4-trichlorobenzene (1 ml), and the mixture was stirred at 130° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 1 M hydrochloric acid (2 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (4 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate =1:1→1:2) to give 2-bromoimidazo[5,1-b]thiazole (22.2 mg, 76%) as a white solid.