Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:8]([O:23][CH3:24])[CH:7]=1>O.O1CCCC1>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:25])=[O:4])=[CH:7][C:8]=1[O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(F)ccc2Cl)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH (14.1 g, 0.59 mol, 1.1 equiv.) dissolved in H2O (200 mL) was added drop-wise over 45 minutes to a solution of 34 (180 g, 0.53 mol, 1 equiv.) in tetrahydrofuran (1800 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue re-dissolved in water (ca. 3 L). The insoluble solid was filtered off. Under vigorous stirring, the aqueous filtrate solution was acidified with concentrated HCl aqueous solution (37%) until pH<2. The resulting white solid precipitate was filtered and washed with water. The wet filter cake was then transferred to a flask and dried on rotary evaporator under vacuum at 50° C. overnight to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid 35 as a dry, fine white powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.90 (s, 1H), 10.01 (s, 1H), 8.22 (d, 1H), 7.65-7.45 (m, 4H), 7.45-7.30 (m, 1H), 3.88 (s, 1H). MS (ES) m/z 322.0 (MH)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH2:11]1)[CH3:16]
Reactant: CCN1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(NC)CC1
Yield: 93 %

Procedure:
To a solution of (1-ethylpiperidin-4-yl)-methylcarbamic acid tert-butyl ester (1.65 g, 6.8 mmol) in dichloromethane (15 mL) was added TFA (5 mL). After 1 hour at ambient temperature the reaction mixture was concentrated in-vacuo and the residue loaded onto a 70 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as an orange oil (900 mg, 94%). 1H NMR (300 MHz, CD3OD): 2.95 (d, J=11.6 Hz, 2H), 2.48-2.36 (m, 3H), 2.35 (s, 3H), 1.96-1.95 (m, 4H), 1.40-1.38 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=4)=[CH:30][N:25]3[N:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].O>ClCCl>[CH2:11]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:32]=[CH:33][C:34]([C:35]([O:1][N:2]5[C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=6[N:4]=[N:3]5)=[O:36])=[CH:38][CH:39]=4)=[CH:30][N:25]3[N:24]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: On1nnc2ccccc21
Reactant: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)On5nnc6ccccc65)cc4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.4 %

Procedure:
To a solution of 1-hydroxybenzotriazole (1.67 g) and 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoic acid (4.2 g) in dichloromethane (170 ml) was added 1-ethyl-3-(31-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (2.95 g) and stirred for 6 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoyloxy]benzotriazole (2.456 g).
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:13][CH:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a hydrogen bottle containing 0.5 g of 10% palladium on carbon and acetic acid (250 ml) was added the above 1-benzyloxy-4-(3-phthalimidopropoxy)benzene (16 g). The mixture was shaken at 50° in the Parr hydrogenation apparatus for about 4 hours and cooled to room temperature. The mixture was filtered and the solvent distilled in vacuo. The residue was crystallized from toluene to yield 10.8 g (88%), mp 135°-7° of 4-(3-phthalimidopropoxy)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[C:10]([F:23])=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1
Reactant: F[B-](F)(F)F
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1F
Reaction time: 20 h

Procedure:
The product of Example 3 (0.1 g) was dissolved in methanol (10 ml), Selectfluor™ (0.12 g) added and stirred for 20 h. The mixture was evaporated and purified by silica gel chromatography (5% methanol/DCM) to yield the title product as a white solid. Yield 19 mg.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[CH2:24]([NH:36][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCN
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In 120 ml of methylene chloride was dissolved 5.60 g (33.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.53 ml (39.7 mmol) of triethylamine. 3.07 ml (39.7 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. 5.34 g (28.8 mmol) of dodecylamine was added to 7.12.g of the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.86 g of the desired compound (yield: 29.5%, yellow oil).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH:9]([OH:13])[C:10]([OH:12])=[O:11]>>[C:1]([O:13][CH:9]([C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([Br:5])[CH:7]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(O)c1cccc(Br)c1
Product: CC(=O)OC(C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl Chloride (1.5 mL) was added to 3-bromomandelic acid 1 (1.00 g, 4.33 mmol) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide compound 2 which was used in the next reaction without further purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:16]=1>C(Cl)Cl>[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[C:17]([N:29]2[CH2:34][CH2:33][N:32]([C:11]([CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1]3)=[O:12])[CH2:31][CH2:30]2)[N:16]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C1CCc2ccccc2O1
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)C4CCc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 20 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
A solution consisting of chroman-2-carbonyl chloride (1.13 g.) in dry methylene chloride (20 ml.) was added dropwise to a stirred suspension of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline (1.38 g.) in dry methylene chloride (30 ml.) with ice bath cooling. The resulting reaction mixture was then stirred at room temperature (20° C.) overnight (approximately 16 hours), and the solid product so obtained was subsequently partitioned between aqueous sodium carbonate solution (30 ml., 1.0 N) and chloroform (220 ml.). The chloroform layer which separated was subsequently evaporated in vacuo and the resulting residue (2.5 g.) was thereafter chromatographed on silica gel (100 g.), eluting first with chloroform (200 ml.) and then with chloroform-methanol (800 ml., 97.5:2.5 parts by volume). The appropriate fractions were then collected and subsequently combined and evaporated in vacuo, and the resulting final product thereafter recrystallized from ethyl acetate to give pure 4-amino-2-[4-(chroman-2-carbonyl)piperazino]-6,7-dimethoxyquinazoline (yield, 625 mg.), m.p. 165°-167° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[O:28][C:24]([C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=3)=[C:25]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[N:26]=2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(-c2nc(-c3ccccn3)c(Br)o2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.75 g, 8.90 mmol), 2-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridine (1.9 g, 5.94 mmol), Pd(PPh3)4 (0.343 g, 0.297 mmol) and sodium carbonate (11.8 ml, 2 M, 23.74 mmol) in DMF (100 ml) was heated at 120° C. overnight. Then the DMF was removed under reduced pressure, and the resulting residue was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 422.23 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.CS(C)=O>O>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4cc(Cl)cc(Cl)c4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 3,5-dichloro phenyl boronic acid according to the procedure of Example 2, m.p. 138-140 DMSO: δ 12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.38 (s, 2H). CHN 53.84, 3.20, 2.62 (0.5 M H2O) Found 53.97, 3.02, 2.40.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)CCCC(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)CCCC(C)=O
Temperature: 65 °C
Yield: 92 %

Procedure:
43 g of a racemate of 2-methyl-6-oxoheptanoic acid (purity 99.65%, 0.27mmol) was dissolved in214.25 g of methanol, then, 2.14 g of concentrated sulfuric acid was added and mixed. Next, the mixture was heated up to 65° C., then, reacted for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled down to room temperature. Next, the reaction mixture was concentrated under reduced pressure until reaching about one-forth of the original weight, then, 30 g of water was added. Further, 128.55 g of methyl t-butyl ether (MTBE) was added, then, 55.06 g of a 5% sodium hydrogen carbonate aqueous solution was dropped at room temperature while stirring. The resultant mixture was stirred sufficiently at room temperature, then, liquid-partitioned, and the aqueous layer was further partitioned with 64.27 g of MTBE. The resultant organic layer was combined, and concentrated under reduced pressure, to obtain 45.4 g (content 94.3%, yield 92%) of a coarse product of a racemate of 2-methyl-6-oxoheptanoic acid methyl ester as colorless oil. The resultant coarse product was used as it is in the subsequent reaction (the resultant coarse product may be, if necessary, distilled (boiling point 107° C./1333 Pa), then, used in the next reaction).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22](C)(C)C[C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:22][O:23][C:24]1[CH:20]=[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:12])[CH2:11][CH2:10]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:18]=[CH:17][C:16]=1[O:15][CH3:14]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: CN(C)CCCN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-(3-dimethylaminopropyl)piperazine as described for compound 8. M.p. 223–226° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:15])([OH:13])[CH2:14][O:23][C:20]2[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(I)cc1
Yield: 81 %

Procedure:
Reaction of epoxide 140 (see Example 2B) with 4-iodophenol as in Example 2AA at 83° C. for 8 h, followed by chromatography of the product on silica gel, eluting with 0-2% EtOAc/CH2Cl2 (foreruns) and then with 5% EtOAc/CH2Cl2, gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-(4-iodophenoxy)-2-methyl-2-butanol (143) (81%) as a cream solid: mp (CH2Cl2/pentane) 91-93° C.; 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.59 (dt, J=8.9, 2.6 Hz, 1H), 6.69 (dt, J=8.9, 2.6 Hz, 1H), 4.28 (ddd, J=14.1, 9.6, 6.3 Hz, 1H), 4.23 (ddd, J=14.1, 9.4, 6.5 Hz, 1H), 3.82 (d, J=9.0 Hz, 1H), 3.79 (d, J=9.0 Hz, 1H), 2.22 (ddd, J=13.8, 9.2, 6.5 Hz, 1 H), 2.20 (s, 1H), 2.02 (ddd, J=13.8, 9.6, 6.6 Hz, 1H), 1.39 (s, 3H); HRESIMS calcd for C14H16ClIN3O4 m/z [M+H]+ 453.9840, 451.9869. found 453.9832, 451.9857.
Reaction SMILES: [OH-].[Ba+2:2].[OH-].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([O-:6])=[O:5]>O>[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O-:13])([O-:6])=[O:5].[Ba+2:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O-:13])([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccccc1[O-]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Heat 3.1 of distilled water in a 4-L. flask to 75° C. on a steam bath. Add 16.67 g of barium hydroxide, [Ba(OH)2.8H2O] and 21.67 g. of o-nitrophenol. Stir vigorously for 1 hour at 75° C. and let stand overnight at room temperature. Decant to another flask, heat to 75° C., add 4.17 g. of o-nitrophenol, stir and let stand overnight at room temperature. Decant and filter on a Buchner funnel through Whatman No. 4 paper and adjust the filtrate to 3 l. with distilled water.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[S:10][C:9]([NH:11][C:12]3[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]=2[C:29]([F:32])([F:31])[F:30])=[N:4][N:3]=[N:2]1.[CH3:33]N(CCCN=C(N)C1C=CC(C2NC(C3C=CC(C(N)=NCCCN(C)C)=CC=3)=CC=2)=CC=1)C>>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:13]1[C:12]([NH:11][C:9]2[S:10][C:6]([C:5]3[N:1]=[N:2][N:3]([CH3:33])[N:4]=3)=[C:7]([C:29]([F:31])([F:32])[F:30])[N:8]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C)CCCN=C(N)c1ccc(-c2ccc(-c3ccc(C(N)=NCCCN(C)C)cc3)[nH]2)cc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(-c2nnn[nH]2)s1
Product: Cn1nnc(-c2sc(Nc3cccnc3Oc3ccccc3C(C)(C)C)nc2C(F)(F)F)n1

Procedure:
Example A133 was prepared from N-(5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 404) following the procedure described for Example A132.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([CH3:25])[C:10](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:11])=[CH:5][CH:4]=1.[OH-:26].[Li+].OO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([CH3:25])[C:10]([OH:11])=[O:26])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1ccc([C@@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of (S)-3-((R)-2-(4-methoxyphenyl)propanoyl)-4-benzyloxazolidin-2-one (1.50 g, 4.42 mmol) in THF (20 ml) was added to a mixture of lithium hydroxide (750 mg, 17.6 mmol) and hydrogen peroxide (0.9 ml, 26.5 mmol, 30% in water). The reaction mixture was stirred at room temperature for 3 h. Then the solvent was evaporated, the residue was acidified with diluted HCl (10 ml) and extracted with DCM (3×50 ml). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (20%) in petroleum ether as eluent to afford 600 mg (76%) of (R)-2-(4-methoxyphenyl)propanoic acid as colorless liquid.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[CH:43][C:38]([C:35](=[O:37])[CH3:36])=[CH:39][CH:40]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C(C)=O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-acetylphenylboronic acid (97 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (26 mg, yield 52%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[Br:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][C:17](=[S:37])[NH:18][C:19]1[S:29][C:22]2[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]=2[C:20]=1[C:30]([O:32]C(C)(C)C)=[O:31])=[O:15]>>[Br:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][C:17](=[S:37])[NH:18][C:19]1[S:29][C:22]2[CH2:23][O:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21]=2[C:20]=1[C:30]([OH:32])=[O:31])=[O:15]
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2Br)sc2c1CC(C)(C)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccccc3Br)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of 40% v/v TFA/DCM (13.4 mL) was added to tert-butyl 2-(3-(2-bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.25 g, 0.48 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(2-Bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.16 g, 0.33 mmol, 69% yield) was isolated as a pale, yellow solid. 1H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 13.48 (s, 1H), 12.21 (s, 1H), 7.72 (apparent dd, J=7.8, 1.2 Hz, 1H), 7.62 (apparent dd, J=7.4, 1.8 Hz, 1H), 7.53-7.42 (m, 2H), 4.66 (s, 2H), 2.75 (s, 2H), 1.23 (s, 6H). 13C NMR (101 MHz, DMSO) δ 174.29, 167.42, 165.95, 147.16, 137.00, 133.01, 132.56, 129.70, 129.60, 128.04, 124.63, 119.33, 116.98, 70.62, 59.29, 37.74, 26.65. LCMS retention time: 3.193 min; LCMS purity at 214 nm=98%. HRMS m/z calculated for C18H18BrN2O4S2 [M++1]: 468.9886. found 468.9860. Melting point 188.4° C., decomposition.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[F:17])[N:13]=[CH:12][N:11]=[C:10]2O.C(N(CC)CC)C>>[Cl:3][C:10]1[C:9]2[C:14](=[CH:15][C:16]([F:17])=[C:7]([F:6])[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2cc(F)c(F)cc12
Solvent: CCN(CC)CC
Product: Fc1cc2ncnc(Cl)c2cc1F
Temperature: 100 °C
Yield: 87 %

Procedure:
To POCl3 (15 mL) was added 6,7-difluoro-4-hydroxyquinazoline (910 mg, 5 mmol) followed by triethylamine (700 uL, 5 mmol). The solution was then heated at 100° C. for 4 hours and concentrated in vacuo. The resulting sludge was triturated with EtOAc (2×100 mL), and the combined decanted org layers were flushed through a plug of silica gel to give 4-chloro-6,7-difluoroquinazoline (870 mg, 4.35 mmol, 87%). LC-MS (ESI) m/z 201 (M+H)+.