Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].CS(C)=[O:22]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(F)cc1

Procedure:
Bis-(4-fluorophenyl) sulphone (100 g; 0.394 mole), potassium hydroxide solution (91.98 g; 0.787 mole KOH) and dimethyl sulphoxide (400 cm3) were stirred together in a stainless steel vessel under nitrogen at 57° C. for 24 hours. Two liquid phases remained throughout the reaction. The reaction mixture was diluted with water and twice extracted with diethyl ether to recover non-phenolic material (9 g). The aqueous phase was then acidified and the phenolic component (86 g; m.p. 150°-154° C.) was extracted with more ether. By subliming this product under a diffusion pump at 180° C., followed by recrystallisation from toluene (400 cm3), 4-(4-fluorophenylsulphonyl)phenol (72.5 g) was obtained, m.p. 158°-159° C. The potassium salt was obtained from this phenol as a very pale yellow solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][CH:7]([F:22])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1.CC(OC)(C)C.[OH-].[Na+]>S(=O)(=O)(O)O>[F:22][CH:7]([F:6])[C:8]1([C:15]2[CH:20]=[C:19]([N+:1]([O-:4])=[O:2])[CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: NC1=NC(c2ccccc2F)(C(F)F)COC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Potassium nitrate (60.3 g, 596 mmol) was added portionwise to 600 ml sulfuric acid (Temperature<20° C.). This solution was added dropwise to a solution of 5-difluoromethyl-5-(2-fluoro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (112 g, 459 mmol) in 600 ml sulfuric acid, while keeping the reaction temperature<22° C. with an ice bath. After stirring for 1 h, the mixture was poured onto 10 Kg ice. TBME (6 L) was added and the pH was adjusted to 12-14 by the addition of about 5 L 30% aqueous NaOH. The phases were separated and the aqueous phase was extracted twice with TBME. The combined organic layers were dried with sodium sulfate and evaporated to give 130 g of a yellow solid that was used further without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[CH2:25]([O:26][N:11]([CH3:12])[C:10]([N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14])=[O:14])[C:24]1[CH:23]=[CH:27][CH:3]=[CH:1][CH:2]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CN(OCc1ccccc1)C(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: -70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (3.01 g, 10 mmole) was dissolved into THF (60 ml), which was cooled to -70° C. To this mixture, a solution of 1.0M lithium bis(trimethylsilyl)amide dissolved into THF (24 ml) was added. Furthermore, N-benzyloxy-N-methylphenylcarbamate (2.9 g, 12 mmole) was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate, which was washed with an aqueous solution of 0.1N hydrochloric acid, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=10:1), whereby 1.5 g of the objective compound (Ia-11) was obtained as white amorphous in 32% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:19].[OH-].[Na+].[Cl-].[Zn+2:23].[Cl-]>O>[Zn+2:23].[CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[C:4]([C:5]([O-:7])=[O:6])[C:3]=1[OH:19].[CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[C:4]([C:5]([O-:7])=[O:6])[C:3]=1[OH:19]
Reactant: CCCCCCCCc1cc(C)c(O)c(C(=O)O)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1cc(C)c(O)c(C(=O)[O-])c1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
3-Methyl-5-n-octyl salicylic acid (prepared as described above, 48 g) was added with stirring to a solution of 14.5 g of a 50% aqueous solution of sodium hydroxide and 200 mL water in a 4 L beaker. To this was added 1 L of water and the solution was heated to 65° C. To the hot solution was then added with stirring 24.5 g of zinc chloride in 40 ml of water. A gummy solid precipitated. The solution decanted and the remaining solid was dissolved in 300 mL hot 95% ethanol. The hot solution was diluted with 500 ml of water and refrigerated. The product was filtered and washed (3×500 mL water) to give 53 g of off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].[H-].[Na+].I[CH2:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1.Cl.[OH-].[K+]>CN(C)C=O.C(O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH2:16][CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1cc(C#CCCCc2ccccc2)cs1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1cc(C#CCCCc2ccccc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Methylmalonic acid diethylester (1.57 g, 9.02 mmol) was dissolved in dimethylformamide (30 ml), and sodium hydride (0.38 g, 9.47 mmol) was added thereto in an ice bath, and then the mixture was stirred for 1 hour at room temperature in a nitrogen atmosphere. The dimethylformamide solution (30 ml) of 2-(2-iodoethyl)-4-(5-phenylpent-1-ynyl)thiophene obtained in Example 25 (e) was added dropwise to the reaction solution in an ice bath, and the mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere. After the reaction solution was cooled down, acidified with 1N hydrochloric acid, and the resulting solution was extracted with ethyl acetate, and then the ethyl acetate layer was washed with a 1N aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was partially purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=50:1-20:1). The obtained mixture was dissolved in a mixture of ethanol (9 ml) and water (1 ml), and potassium hydroxide (0.80 g, 14.3 mmol) was added thereto in an ice bath, and then the reaction mixture was stirred for 3 days at room temperature. After the reaction solution was acidified with 1N hydrochloride acid, the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; dichloromethane:methanol=50:1) to afford the title compound (1.02 g, 28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[C:6]2[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]cc(N3CCN(C)CC3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(N3CCN(C)CC3)c2c1
Yield: 27.8 %

Procedure:
A solution of 6-methoxy-4-(4-methylpiperazin-1-yl)isoquinolin-1(2H)-one (0.16 g, 0.585 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% MeOH in CHCl3) to get desired compound (0.05 g, 27.8%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.15(d, J=12 Hz, 1H), 7.92 (s, 1H), 7.45-7.42 (d, J=12 Hz, 1H), 7.36 (s, 1H), 3.97 (s, 3H), 3.09 (m, 4H), 2.52 (m, 4H), 2.31 (s, 3H); MS: MS m/z 292.15 (M++1).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C@H:4]2[CH2:5][C@H:3]2[CH2:2][I:43])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CI)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 4 (2.0 g, 7.8 mmol), PPh3 (2.68 g, 10.2 mmol), imidazole (1.07 g, 15.7 mmol), and iodine (2.98 g, 11.7 mmol) were dissolved in THF (15 mL), and the resulting solution was stirred at RT for 2 h. The solution was quenched with sat. Na2S2O3, and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10/1 hexanes/EtOAc) which provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C:15](=[O:18])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C@:15]([OH:18])([CH3:20])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1C(=O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C2(CC2)[C@]1(C)O
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-[(6S)-6-methyl-4,7-dioxo-5-azaspiro[2.4]hept-5-yl]benzonitrile (35 mg) in tetrahydrofuran (6.0 mL) was added dropwise 1 mol/L-methylmagnesium bromide/tetrahydrofuran solution (1.3 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>C(O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][S:7][CH2:6][C:5]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSCC(OCC)OCC
Yield: 58.5 %

Procedure:
Sodium ethoxide (2.83 g) is added to a solution of ethyl thioglycolate (5.00 g) and bromoacetaldehyde diethylacetal (8.20 g) in ethanol (150 ml), and the mixture is refluxed for three hours. The reaction mixture is allowed to stand at room temperature, water is added to the mixture, and the whole is extracted with diethyl ether. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (5.75 g).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][SH:14])=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]([C:19]1[C:20](S(C)(=O)=O)=[N:21][S:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[C:20]([S:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)=[N:21][S:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]
Reactant: COC(=O)c1c(S(C)(=O)=O)nsc1NC(=O)OC(C)(C)C
Reactant: SCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of n-BuLi (2.5M, 11.5 mL, 28.8 mmol) in THF (20 mL) at 0° C. is added (4-Chloro-phenyl)-methanethiol (4 mL, 30 mmol) dropwise over 15 min. After 1 hr., a solution of 18 (2 g, 6 mmol) in THF (15 mL) is added. The reaction is then stirred at 0° C. for 1 hour and 2 hrs. at room temperature. The reaction was then quenched with water and extracted with EtOAc (3×50 mL). The combined organics are then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (3% EtOAc/hexane) provides 19 (1.98 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.00 (1H, br. s), 7.29 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 4.36 (2H, s), 3.89 (3H, s), 1.53 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.C[N:16]1C(=O)CCC1.N>O>[Cl:1][C:2]1[C:3]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([F:9])[C:5]([NH2:16])=[N:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: Fc1ncc(Cl)c(-n2cccn2)c1F
Agent: N
Solvent: O
Product: Nc1ncc(Cl)c(-n2cccn2)c1F

Procedure:
A mixture of 5-chloro-2,3-difluoro-4-(1H-pyrazol-1-yl)pyridine (37 g, 0.17 mol, 1.0 equiv) and NMP (200 mL) in a pressure vessel was stirred at 50° C. under 20 psi of ammonia gas overnight. The mixture was diluted with water (400 mL) and extracted with EtOAc (2×300 mL). The organic fractions were combined, dried over Na2SO4, and concentrated under vacuum. To the residue was added water (300 mL) with stirring. The resulting solid was collected by filtration, and the cake was washed with isopropanol (100 mL) and dried under vacuum to give the desired product (24 g) as a yellow solid. The solid was recrystallized from isopropanol (40 mL) and EtOAc (20 mL) to give 19 g of pure product as an off white solid. The mother liquors were concentrated under vacuum and recrystallized from isopropanol (30 mL) to give another 5.1 g for a combined total of 24 g (67%) of desired product as an off white solid.
Reaction SMILES: [Na].[OH:2][CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].CN1CCN(C)C1=O.[CH:17]1([N:20]2[C:25]3[CH:26]=[C:27]([F:31])[C:28]([F:30])=[CH:29][C:24]=3C(=O)O[C:21]2=O)[CH2:19][CH2:18]1>CN(C=O)C.O>[CH:17]1([N:20]2[C:25]3[C:24](=[CH:29][C:28]([F:30])=[C:27]([F:31])[CH:26]=3)[C:3](=[O:2])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:21]2)[CH2:18][CH2:19]1
Reactant: COC(=O)C=CO
Reactant: O=c1oc(=O)n(C2CC2)c2cc(F)c(F)cc12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 15 ml single neck round-bottom flask equipped with magnetic stirrer and under nitrogen atmosphere was added 60 mg (0.484 mmol) of the sodium salt of methyl 3-hydroxyacrylate in 1.5 ml of DMF. The resulting solution was stirred in the presence of 4A molecular sieves overnight and then filtered into another reaction vessel fitted with condenser, nitrogen line and a magnetic stirrer. To the mixture was charged 52 μl (0.467 mmol) N,N'-dimethylimidazolidinone and the solution was heated to 55° C. To this reactor was added a solution of 93 mg (0.388 mmol) of N-cyclopropyl-6,7-difluoro-2H-3, 1-benzoxazine-2,4(1H) dione in 1.5 ml of DMF. The reaction mixture was stirred at 55° C. for 1 hour. The system was allowed to cool to room temperature and was then added to 30 ml of water at pH 4.0. The pH of the resulting suspension was adjusted to 5.5 and the mixture was cooled to 0° C. and filtered. After drying there was obtained 50 mg (46%) of methyl 1-cyclopropyl-6,7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate, m.p.: 223° -224° C. The filtrate was extracted with methylene chloride and after drying and evaporation there was obtained an additional 47 mg (43.5%, total yield: 89.5%) of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH3:11])[C:4]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=O.[Br-].[CH2:31]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33].C(N(CC)CC)C.[BH4-].[Na+]>C(OCC)(=O)C.CO.O1CCCC1>[OH:33][CH:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:31]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH3:11])[C:4]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[O:22][C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cccc(C=CC(O)c2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1 h
Yield: 65.4 %

Procedure:
10 ml of a tetrahydrofuran suspension containing 152 mg (0.392 mmol) of N-(2-formyl-6-methoxymethylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 53), 199 mg (0.432 mmol) of phenacyltriphenylphosphoniumbromide and 48 mg (0.471 mmol) of triethylamine was heated for 6 hours under reflux. At the end of this time, the mixture was allowed to return to room temperature. 4 ml of methanol were added, and then 155 mg (4.10 mmol) of sodium borohydride were gradually added to the mixture, which was then stirred for 1 hour. The reaction solution was then diluted with ethyl acetate, and washed several times with water. The solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through 20 g of silica gel. Elution with a 4:1 by volume mixture of methylene chloride and ethyl acetate afforded 126 mg (yield 66%) of the title compound as crystals, melting at 204.5-206.5° C. (after recrystallization from methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C(O)(=[O:12])C.OO.C(=O)([O-])[O-].[Na+].[Na+].[K+].[Br-]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1C
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Br-]
Solvent: O
Product: COc1ccc[n+]([O-])c1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 8.7 %

Procedure:
To a solution obtained by dissolving 3-methoxy-2-methylpyridine (14.8 g, 0.12 mol) in acetic acid (44 g, 0.12×2.5 mol) was added 31% hydrogen peroxide (33 g, 0.12×2.5 mol), followed by stirring in an oil bath at 100° C. for 16 hours. The reaction solution was then cooled and poured into iced-water. To the mixture was then added sodium carbonate (solid) so as to be weak alkalinity. The resultant solution was extracted with ethyl acetate to obtain 1.45 g (percent yield: 16.7%) of 3-methoxy-2-methylpyridine-N-oxide IR KBr cm−1: 1668, 1647, 1584, 1503, 1302, 1266, 1188, 1128, 792. 1H-NMR (60 MHz, CDCl3, δ): 2.4 (3R, s, CH3), 3.8 (3H, s, OCH3), 6.5-7.2 (2H, m, pyridine ring H×2), 7.7-8.0 (1H, m, pyridine ring H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([NH:14][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: BrCc1ccccn1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Nc1nc2c(OC)ccc(NCc3ccccn3)c2s1
Temperature: 70 °C
Yield: 36.3 %

Procedure:
To a stirred solution of 40 mg (0.16 mmol) (7-amino-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 2 ml DM F at room temperature were added 66 mg (0.47 mmol) potassium carbonate and 40 mg (0.16 mmol) 2-(bromomethyl)pyridine hydrobromide and the mixture heated at 70° C. for 16 h. The mixture was then concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/hexane) afforded 20 mg (37%) {4-methoxy-7-[(pyridin-2-ylmethyl)-amino]-benzothiazol-2-yl}-carbamic acid methyl ester as a yellow solid. ES-MS m/e (%): 367 (M+Na+, 54), 345 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(Cl)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cccc(Cl)c2[nH]1
Yield: 95.9 %

Procedure:
A mixture of 3.40 g (15.2 mmol) of ethyl 7-chloro-2-indolecarboxylate, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter ice water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid and extracted three times with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 2.85 g (95.8%) of 7-chloro-2-indolecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[N:7]([C@H:9]([CH2:18][O:19][C:20](=[O:32])[NH:21][C:22]1[N:23]=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][NH:5][C:6](=[O:33])[N:7]([C@H:9]([CH2:18][O:19][C:20](=[O:32])[NH:21][C:22]1[N:23]=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH3:8]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 180.9 %

Procedure:
To a mixture of (S)-tert-butyl 3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoate (0.8 g, 1.47 mmol) and DCM (10 mL) was added TFA (10 mL). The resulting solution was stirred at RT for 1 h. The mixture was concentrated, and the remaining residue was dried in vacuo to give (S)-3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoic acid (1.3 g), which was used without further purification. LRMS (M+H+) m/z 489.1.