Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH2:11][C@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C=[N+]=[N-])(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13]([C:15]([O:17][CH3:27])=[O:16])=[CH:12][CH2:11][C@@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C(=O)O)=CC[C@H]1c1cc(F)c(F)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 39 %

Procedure:
Alternative resolution procedure: A solution of Example 39A (510 mg) was dissolved in methanol (1 mL) and CH2Cl2 (1 mL), and then (trimethylsilyl)diazomethane solution (0.4 mL, 2M in ether) was added. After ten minutes, acetic acid (0.2 mL) was added. The resultant solution was concentrated in vacuo and partitioned between ethyl acetate and bicarb. The organic extract was washed with brine and dried over sodium sulfate. The crude material was deprotected using the procedure of Step B in Example 20D; and the product was partitioned between sodium bicarbonate and ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The crude product (410 mg) was dissolved in 30 ml of ethanol. 420 mg (0.8 eq) of dibenzoyl (D)-tartaric acid was added, and the mixture was stirred until homogeneous. The resultant solution was allowed to stand overnight and the crystalline product was collected by filtration (yield 39%, ee>98%). The crystalline solid was dissolved in tetrahydrofuran (10 mL). Then, di-tert-butyl dicarbonate (1.1 eq.) and saturated sodium bicarbonate solution (5 mL) were added. After thirty minutes, the reaction mixture was concentrated and subjected to column chromatography (eluting with 20% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([CH:24]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.[Cl:27][C:28]1[C:29]2[C:39]([F:40])=[CH:38][CH:37]=[C:36]([F:41])[C:30]=2[S:31][C:32]=1[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:33]([C:32]1[S:31][C:30]2[C:36]([F:41])=[CH:37][CH:38]=[C:39]([F:40])[C:29]=2[C:28]=1[Cl:27])=[O:34])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:13][CH2:14]1
Reactant: COc1ccc(Br)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(Br)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 219 (0.50 g, 1.17 mmol) is treated with acid chloride 8 (344 mg, 1.29 mmol) using Method D to give the title compound.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)nc(Cl)n1

Procedure:
A solution of 2-hydroxy-4,6-dimethylpyrimidine (5.0 g) in phosphorous oxychloride (19 ml) was refluxed under heating for 9 hr. The reaction mixture was added dropwise to an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (3.0 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=30:1) to give the title compound (2.4 g) as a pale-yellow oil.
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]2[CH:11]3[CH2:15][CH:14]([C:2]1=2)[CH2:13][CH2:12]3.C(O)C.[OH-].[Li+].Cl>O.C1COCC1>[S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH:11]3[CH2:15][CH:14]([C:2]1=2)[CH2:13][CH2:12]3
Reactant: CCOC(=O)c1cc2c(s1)C1CCC2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)C1CCC2C1
Temperature: 50 °C
Yield: 94.4 %

Procedure:
A 100-mL single-neck round bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 1d (930 mg, 4.19 mmol), ethanol (7 mL), THF (7 mL), water (7 mL) and lithium hydroxide (301 mg, 12.6 mmol) and the mixture heated at 50° C. for 4 h. After this time, the reaction was cooled to room temperature and acidified to pH 1.5 with 2N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2×10 mL) and dried overnight under vacuum to afford a 94% yield (768 mg) of 1e as a white solid: mp 183-184° C.; 1H NMR (500 MHz, DMSO-d6) δ 12.66 (br s, 1H), 7.48 (s, 1H), 3.59 (m, 1H), 3.41 (m, 1H), 1.97-1.83 (m, 3H), 1.61 (dt, 1H, J=9.0, 2.5 Hz), 0.96 (dd, 2H, J=12.5, 3.5 Hz); MS (APCI−) m/z 193.2 (M−H).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[C:16]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:17]=1.CN(C)C=O>C(OCC)(=O)C>[C:22]([NH:21][S:18]([C:16]1[CH:17]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=[CH:14][C:15]=1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 0.34 ml of formic acid and 0.70 ml of acetic anhydride is heated at 50° C. for 2 hours, and a solution of 0.85 g of 5-amino-N-tert.-butyl-2-dimethylaminocarbonyl-benzenesulfonamide (Example e) and 3.5 ml of dimethylformamide (DMF) is added. After 4 hours, the mixture is taken up in ethyl acetate and washed successively with dilute hydrochloric acid and saturated NaHCO3 solution. After the mixture has been dried over MgSO4 and the organic phase has been concentrated, 0.88 g of a highly viscous substance, which is used in subsequent reactions without further purification (Example j), is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]CCCC.B(F)(F)F.CCOCC.[CH2:27]([O:34][C@H:35]1[CH2:40][CH2:39][C@@H:38]2[O:41][C@@H:37]2[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:27]([O:34][C@@H:35]1[CH2:36][C@@H:37]([OH:41])[C@H:38]([CH2:1][S:2]([C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:39][CH2:40]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(CO[C@H]2CC[C@@H]3O[C@@H]3C2)cc1
Reactant: CSc1ccc(S(C)(=O)=O)cc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1ccc(S(=O)(=O)C[C@@H]2CC[C@H](OCc3ccccc3)C[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
1-Methanesulfonyl-4-methylsulfanyl-benzene (3.25 g) was dissolved in THF (50 mL) and cooled to −78° C. prior to the addition of 1.6 M nBuLi (10 mL). After 0.5 h, BF3-Et2O (2.04 mL) was added followed by (±)(1S*,2R*,4S*)-4-(benzyloxy)-1,2-epoxycyclohexane (2.19 g) (Chini et al. J. Org. Chem. 1990, 55, 4265) in THF (20 mL). After an addition 1 h at −78° C., the solution was warmed to 0° C. After 2 h, the solution was cooled to −78° C. and saturated NH4Cl solution (aq) was added. The solution was warmed to rt and EtOAc was added. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (±)(1R*,2R*,5S*)-5-benzyloxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexanol (3.5 g) as the major product: 1H NMR (CDCl3, δ ppm, 300 mHz) 1.41 (m, 2H), 1.59 (m, 1H), 1.95 (m, 1H), 2.05-2.35 (m, 2H), 2.54 (s, 3H), 2.96 (dd, 1H), 3.64 (m, 2H), 3.81 (s, 1H), 4.48 (m, 2H), 7.3 (m, 7H), 7.82 (d, 2H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.[CH:18]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: BrC1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 100 °C
Yield: 11.7 %

Procedure:
Potassium carbonate (2.26 g, 16.4 mmol) was added to a solution of methyl-4-hydroxybenzoate (1.0 g, 6.6 mmol) and cyclohexyl bromide (1.62 ml, 13.1 mmol) in dimethylformamide (20 ml). The mixture was heated at 100° C. for 24 hours, cooled, filtered and concentrated in vacuo. Work up followed by flash chromatography over silica gel (hexane:ethyl acetate, 5:1) afforded methyl-4-cyclohexylbenzoate (169 mg). This was dissolved (162 mg, 0.69 mmol) in a mixture of 1,4-dioxane (10 ml) and water (5 ml) and lithium hydroxide monohydrate (32 mg, 0.76 mmol) added. The mixture was stirred at room temperature for 18 hours. A further quantity of lithium hydroxide was added (32 mg) and stirring continued for 4 hours. The mixture was added to ethyl acetate, washed with brine and concentrated to yield the title compound as a yellow solid (27 mg ).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-methylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=90%, [M+H]+=386. Remaining 10% identified as N(CH3)2 adduct.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C:21]#[N:22])[CH2:10][C@@H:9]2[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH2:21][NH2:22])[CH2:10][C@@H:9]2[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NC[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of (1R,2R)-1-(3-chlorophenyl)-2-{2-[(phenylmethyl)oxy]ethyl}cyclopropanecarbonitrile (1.26 g, 4.0 mmol) in diethyl ether at 0° C. was treated with 2 equivalents of LAH (1M in diethyl ether). After 1.5 hours at 0° C., water was added dropwise until no further evolution of gas was observed. The aluminum salts were filtered off and washed with diethyl ether. Evaporation of the diethyl ether afforded the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.5 (dd, J=5.9, 4.8 Hz, 1H) 1.0 (dd, J=8.9, 4.7 Hz, 1H) 1.2 (m, 1H) 1.4 (s, 2H) 1.8 (m, 2H) 2.9 (m, 2H) 3.6 (m, 2H) 4.6 (s, 2H) 7.2 (m, 3H) 7.3 (m, 2H) 7.4 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:16]([O:23][C:24](=[O:42])[CH:25]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:26][S:27](Cl)(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:42])[C@@H:25]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:26][S:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:29])=[O:28])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC(CS(=O)(=O)Cl)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: O=C(N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a solution of morpholine (Aldrich, 1.27 mL, 14.6 mmol) and N,N-diisopropyl-N-ethylamine (DIPEA, Aldrich, 2.5 mL, 14.6 mmol) in acetonitrile (25 mL) at rt is added solid 2-benzyloxycarbonylamino-3-chlorosulfonylpropionic acid benzyl ester (3.0 g, 7.3 mmol), (prepared as described in Ross, D. L.; Skinner, C. G.; Shive, W. J. Org. Chem. 1959, 24, 1372-1374; and b) Byrnes, S.; Burckart, G. J.; Mokotoff, M. J. Med. Chem. 1978, 21, 45-49], in small portions over 10 min. A clear colorless solution resulted from which white solid began to precipitate within minutes. After 10 min, a thick white suspension was formed. The reaction was diluted in CH2Cl2 to redissolve all solids and the solution washed with 1M HCl. The aqueous layer was separated and extracted with additional CH2Cl2. The organic layer was washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, 3.35 g (99%) of 2(R)-benzyloxycarbonylamino-3-(morpholin-4-sulfonyl)propionic acid benzyl ester was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[CH3:38])[C:31]([O:33]C)=[O:32].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.[OH-].[Na+]>CN(C)C=O.ClCCl.CO.O1CCCC1>[CH3:38][C:37]1[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[NH:27][C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:26][CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 60 °C
Yield: 86.7 %

Procedure:
To a stirred solution of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.02 g, 2.99 mmol), prepared as described in Example 10, methyl 3-amino-4-methylbenzoate (496 mg, 3.01 mmol), and Hunig's base (1.57 mL, 9.01 mmol) in dimethylformamide (15 mL) was added HATU (1.14 g, 3.00 mmol). The stirred mixture was heated to 60° C. overnight, then cooled to rt. The reaction was diluted with dichloromethane and washed with 2 N aqueous sodium hydroxide. The organic layer was then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was sonicated with acetonitrile and filtered to give a light yellow solid that was suspended in a mixture of methanol (22 mL) and tetrahydrofuran (11 mL). AlN aqueous solution of sodium hydroxide (11 mL) was added and the stirred mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to rt, concentrated on a rotary evaporator and redissolved in water, which was then made acidic with 1 N aqueous hydrochloric acid until the pH of the solution reached 5. The precipitate that formed was collected and dried in vacuo to afford 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzoic acid (1.23 g, 86%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.82 (s, 1H), 8.18 (d, 2H), 8.00 (d, 2H), 7.95 (s, 1H), 7.90-7.78 (m, 5H), 7.72 (dd, 1H), 7.66-7.64 (m, 3H), 7.42 (ddd, 1H), 7.36 (d, 1H), 2.31 (s, 3H). MS (EI) for C29H22N4O3: 475.3 (MH+).
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+].Cl.O>O1CCCC1.C(O)C>[CH2:1]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
Compound 1 (2.0 g) was dissolved in tetrahydrofuran (9.0 mL) and ethanol (9.0 mL). Thereto, 5 N aqueous sodium hydroxide solution (2.2 mL) was added, followed by stirring at 70° C. for 14 hours. To the reaction solution, 5 N hydrochloric acid (2.2 mL) and water (18 mL) were added and cooled to 40° C. The obtained solid was filtered and dried under reduced pressure to obtain the title compound (1.9 g) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Oc1cccnc1F
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Reaction time: 8 h

Procedure:
A mixture of crude 5-bromo-2-(2-fluoropyridin-3-yloxy)benzoic acid (8.00 g, 25.6 mmol), diethylamine (6.63 mL, 64.1 mmol) and TBTU (8.23 g, 25.6 mmol) in 8 mL of DMF was stirred overnight. The reaction was quenched with sat. NaHCO3, extracted with EA/H=2:1, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA 100:5 to 100:10 to 100:20 to 3:1) gave 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]#[CH:23])[CH2:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]#[C:23][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C(#Cc1ccccn1)CCN1CC=C(c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A solution of 2-bromopyridine (0.99 mL, 0.01 mol) and the alkyne prepared in Example 9, Step (a) (2.0 g, 0.0095 mol) in 20 mL of piperidine is degassed by bubbling in dry nitrogen for 15 minutes, and 0.03 g (1.4×10-4 mol) of palladium (II) acetate and 0.07 g, (2.8×10-4) of triphenylphosphine are added. The flask is flushed with nitrogen and the mixture is heated at 80° C. for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extraced with 25 mL of dichloromethane and the combined organic layers are washed with 25 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound; mp 87.5°-88.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[C:9]([CH:18](OCC)[O:19]CC)[N:8]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:6]=2[N:7]=1.O>CC(O)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[C:9]([CH:18]=[O:19])[N:8]([CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:6]=2[N:7]=1
Reactant: CCOC(OCC)c1c(-c2ccccc2C)c2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1c(C=O)n(CCNC(=O)OC(C)(C)C)c2nc(Cl)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate (0.85 g, 1.74 mmole) in AcOH (10 mL) was added water (1.5 mL), stir at room temperature for 16 hrs. The crude reaction was then concentrated under vacuum. After addition of ethyl acetate (50 mL) the organic layer was washed with satd. NaHCO3. The organic layer was dried with magnesium sulfate and then concentrated under vacuum to afford the crude intermediate, tert-butyl N-[2-[2-chloro-6-formyl-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. To this crude intermediate in DMF (5 mL) was added oxone (1.3 g). After stirring for 2.5 hrs, water (20 mL) and ethyl acetate (100 mL) was added. The organic layer was separated, dried and then concentrated under vacuum to afford the crude product which was columned over silica gel using hexane/ethyl acetate (0-50%) to afford 7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.112 g). LCMS (ESI) 431 (M+H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([CH3:25])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:25][N:23]1[CH:24]=[C:20]([CH2:19][OH:18])[N:21]=[C:22]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(CO)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
A solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-2-phenyl-1H-imidazole (1.25 g, 2.93 mmol) in dry THF (25 mL) was cooled to 0° C. and tetrabutylammonium fluoride (5.9 mL, 5.86 mmol, 1M in THF) was added dropwise. The reaction mixture was allowed to warm up to room temperature and further stirred for 3 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 2-4% MeOH in CH2Cl2) to get (1-methyl-2-phenyl-1H-imidazol-4-yl)methanol (0.26 mg, yield 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.68-7.66 (m, 2H), 7.50-7.41 (m, 3H), 7.11 (s, 1H), 4.92 (br s, 1H), 4.37 (s, 2H), 3.71 (s, 3H). MS (ESI) m/z: Calculated for C11H12N2O: 188.09. found: 188.9 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:16](=[O:25])[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]=2[CH3:26])[N:9]=1>CN(C)C=O>[C:1]([S:3][CH2:7][C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:16](=[O:25])[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]=2[CH3:26])[N:9]=1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc2nc(CBr)n(-c3ccccc3Cl)c(=O)c2c1C
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc2nc(CSC(C)=O)n(-c3ccccc3Cl)c(=O)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Sodium thioacetate (235 mg) was added to an ice-cooled, stirred solution of 1 g of 2-bromomethyl-3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-4(3H)-quinazolinone in 4 ml of dimethylformamide. After stirring for an additional 30 minutes, the mixture was poured into ice-water. The resulting precipitate was filtered off, washed with water, and dried in vacuo. The crude product was chromatographed on a column of silica gel using 5% ethyl acetate in benzene as an eluent to give 619 mg (yield, 62.5%) of 2-(acetylmercaptomethyl)-3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-4(3H)-quinazolinone melting at 103°-105° C. (recrystallized from methanol).