Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Cl)(=[O:3])[CH3:2].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([O:17][CH3:18])=[O:16])[CH3:6]
Reactant: COC(=O)c1ccccc1O
Reactant: CC(=O)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1C(=O)OC
Temperature: 70 °C
Yield: 91 %

Procedure:
Chloroethyl acetate was slowly added to a mixture of methyl salicylate (100 g, 0.657 mol) and K2CO3 (100 g, 0.723 mol) in DMF (400 mL) at ambient temperature (20-30° C.). The reaction mixture was heated at 65-75° C. for 12-18 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of reaction, the inorganics were filtered off and washed with DMF. DMF was recovered from the filtrate to obtain the product meeting the desired specifications. Yield—91-95%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15]3)[CH:4]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2ccc(C)c(B3OC(C)(C)C(C)(C)O3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2 g) was dissolved in DMF (20 ml). To this was added 3-methoxyaniline (0.985 g), DIPEA (4 ml) and HATU (3.05 g). The mixture was stirred for 18 h at room temp. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic layer was dried (magnesium sulphate) concentrated under vacuum and purified using a silica Biotage cartridge (90 g) eluting with 1:4 ethyl acetate/cyclohexane to give the title compound as a white solid (2.06 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:35]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:42]([O:44][CH3:45])=[O:43])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 95.7 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 7.7 g at a yield of 95.7% in the same manner as in Example 1 except that 5.0 g (23 mmol) of 5-(N-t-butoxycarbonylamino)pentanoic acid instead of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 25 ml of THF and 4.1 g (25.3 mmol) of CDI was added; 9.05 ml (69 mmol) of diisopropylamine and 25 ml of THF were added and 42 ml (69 mmol) of 1.63N BA solution was added dropwise; 10.4 g (69 mmol) of methyl phenylacetate was dissolved in 25 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 50 g of 4N hydrochloric acid was added, and 100 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)ccn2c1=O
Yield: 39.6 %

Procedure:
Methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (195 mg, 0.66 mmol) and (3-aminophenyl)-boronic acid (119 mg, 0.87 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (91 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:20]
Reactant: Cc1ccc(N)cc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:25]/[C:24]#[N:23]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (387 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (525 mg, 2.82 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (Z)—N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (400 mg, 96%) which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[Li+].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-chloro-4-(cyclobutylamino)nicotinate (2) (3 g, 12.3 mmol) in ethanol (20 mL) and water (10 mL) was stirred at rt. LiOH (61.7 mmol, 5 equiv.) was added and the reaction mixture was stirred at room temperature for 4 h. The solvent was concentrated under reduced pressure. Diluted with EtOAc and added water. The aqueous layer was collected and acidified to pH 3-4 using solid citric acid. Solid material precipitated out. Filtered the solid material and dried under vacuum to furnish the title compound (3). 1H NMR: 400 MHz, DMSO-d6: δ 1.20 (d, J=6.40 Hz, 6H), 3.80-3.88 (m, 1H), 6.80 (s, 1H), 8.20 (d, J=7.60 Hz, 1H), 8.51 (s, 1H), 13.33 (bs, 1H).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16])=[CH:9][CH:8]=1.Cl[C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:24]([O:23][C:21]([C:20]1[C:14]([C:13](=[O:18])[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)=[C:15]([CH3:16])[O:17][N:26]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To 7.04 mL of 21% sodium ethoxide in ethanol (18.8 mmol) in 60 mL ethanol at 0° C. was added 4.70 g of 1-(4-methoxyphenyl)butane-1,3-dione (17.1 mmol) in 60 mL ethanol dropwise over 24 minutes. After 30 min a solution of 2.59 g of ethyl chloro-(hydroximino)acetate (17.1 mmol) in 30 mL ethanol was added dropwise over 6 minutes. The reaction was warmed to room temperature slowly. When TLC indicated the reaction was complete, the reaction was concentrated in vacuo. Water and saturated NaHCO3 was added and the product extracted with ethyl acetate. The ethyl acetate extracts were dried with Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography eluting with 8:1 hexane:ethyl acetate to give 4-(4-methoxybenzoyl)-5-methylisoxazole-3-carboxylic acid ethyl ester which was dried overnight under high vacuum to give 3.74 g (71.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:19][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 34.5 %

Procedure:
To a solution of 2-amino-4-chloropyridine (2.50 g, 19.4 mmol) in N-methylpyrrolidone (20 ml) were added 3-methyl-4-nitrophenol (5.94 g, 38,8 mmol) and diisopropylethylamine (13.5 ml, 77.5 mmol), followed by stirring at 150° C. under a nitrogen atmosphere. The reaction mixture was cooled down to room temperature, and diisopropylethylamine in the mixture was evaporated under a reduced pressure. The resultant residue was partitioned between ethyl acetate (150 ml) and a 1 N aqueous solution of sodium hydroxide (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/2, ethyl acetate, then ethyl acetate/methanol=20/1) to provide the titled compound (1.64 g, 34.4%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate (5.8 g, 15.54 mmol), 4-(trifluoromethoxy)phenylboronic acid (8.2 g, 38.85 mmol), potassium carbonate (5.4 g, 38.85 mmol), [1′1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with methylene (1:1) (4.41 g, 5.44 mmol) in dioxane-water (10:1, 154 mL) was stirred at 70° C. for two days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and then concentrated to an oil. This residue was crystallized from ethyl ether to afford the title compound as an off-white solid, m.p. 77-78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42-7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20]>C(#N)C.C(OCC)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)N1CCN(CCCO)CC1
Yield: 79.4 %

Procedure:
1-Acetylpiperazine (15.0 g, 117 mmol) was dissolved in acetonitrile (200 ml) and potassium carbonate (40.4 g, 293 mmol) was added followed by 3-bromo-1-propanol (10.6 ml, 117 mmol). The mixture was heated at reflux for 2.5 hours, cooled, filtered and concentrated under reduced pressure. The resulting viscous oil was cooled in ice for 3 hours and the crystalline product that formed was suspended in diethyl ether and filtered off. The hydroscopic solid was dried under vacuum (P2O5) overnight to give 3-(4-acetylpiperazin-1-yl)propan-1-ol (17.3 g, 90%) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1.CCOCC>[ClH:28].[C:22]1([S:19]([C:16]2[S:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:18][CH:17]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a solution of 0.73 mmol 4-(5-benzenesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dioxane was added dropwise 7.32 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 80° C. for 2.5 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a light brown crystalline solid (yield 81%). MS (m/e): 309.9 (M+H+, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 77.5 °C
Yield: 76.7 %

Procedure:
To a solution of 48 (256.0 mg; 0.69 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL) was added aqueous lithium hydroxide (3.5 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude beige residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 10% v/v over 350 mL gradient elution) to give the title product as a white solid (187 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:22])=[N:13][C:14]([S:17][CH2:18][C:19](=[O:21])[NH2:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:22])=[N:13][C:14]([S:17]([CH2:18][C:19](=[O:21])[NH2:20])=[O:31])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(SCC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(S(=O)CC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Yield: 65.7 %

Procedure:
A solution of 2-carbamoylmethylsulfanyl-4-methylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (77 mg, 0.24 mmol) and m-CPBA (64 mg, 0.37 mmol) in 2 mL of dichloromethane was stirred at ambient temperature for 16 h. The reaction was concentrated in vacuo and chromatographed through SiO2 (5–10% methanol/dichloromethane), to afford 53 mg (66% yield) of the titled product. ApcI-MS m/z 337 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]#[C:20][CH3:21]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:19]#[C:20][CH3:21]
Reactant: CC#CCBr
Reactant: Oc1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Following the same procedure as in Example 2), a mixture of 4.0 g (0.029 moles) of 5-hydroxy-2,3-dihydrobenzofuran, 4.0 g (0.029 moles) of anhydrous potassium carbonate in ml 25 of acetone was added with 3.9 g (0.029 moles) of 1-bromo-2-butyne. The mixture was heated to reflux for 6 hrs. After cooling to room temperature, the mixture was filtered and the filtrate evaporated u.v (20° C./ 21 mbar). The residue so obtained was purified by chromatography on silica column (eluant n-hexane/ethyl acetate 5/1 (v/v))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][CH:26]1[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@@H:26]([CH3:25])[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Reactant: CC1NC(=O)OC1c1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4S,5R)-(+4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO.[Br:15]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Br:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)ccc(N)c1C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixture of methyl 3-amino-2-methylbenzoate (5.00 mL, 34.7 mmol) in acetic acid (100 mL)-methanol (200 mL) was added bromine (5.55 g, 34.7 mmol) under ice-cooling, and the mixture was stirred for 5 min. The reaction solution was diluted with saturated aqueous sodium thiosulfate solution, and the organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→20/80) to give the title compound (4.66 g, yield 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:21]=[CH:22][C:23]([NH2:28])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 60.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-phenylenediamine (540 mg, 5 mmol) to give 115 mg of the title compound (61%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.11 (s, 1H), 10.32 (s, 1H), 9.93 (br, 2H), 7.67 (d, 1H, J=8.9 Hz), 7.29 (d, 2H, J=8.6 Hz), 7.50 (dd, 2H, J=8.6 Hz), 7.23 (bs, 1H), 7.20 (bs, 1H), 5.18~5.27 (m, 1H), 3.08 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.70 (m, 2H), 2.08 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(Cc2cc(Br)ccc2O)c1

Procedure:
Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3′-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:19]>O1CCOCC1>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=1)=[O:29])[C:6]1[S:7][C:8]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: CNS(=O)(=O)c1sc(NCCN(C)C)nc1C
Solvent: C1COCCO1
Product: CCOc1ccc(NC(=O)N(CCN(C)C)c2nc(C)c(S(=O)(=O)NC)s2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 g (3.59 mmol) of 2-{[2-dimethylaminoethyl]amino}-N,4-dimethyl-1,3-thiazole-5-sulphonamide and 586 mg (3.59 mmol) of 4-ethoxyphenyl isocyanate are dissolved in 30 ml of dioxane and stirred at room temperature for 12 h. The mixture is then concentrated in vacuo, and the residue is recrystallized from 2-propanol.