Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][C:31]=2[CH3:37])=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCCC>[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[N:11][C:12]=3[CH:16]([CH3:18])[CH3:17])=[CH:32][C:31]=2[CH3:37])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(NCc2ccc(O)cc2C)cc1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)c1ccc(NCc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 0° C. solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (309 mg, 1.08 mmol), 4-(4-hydroxy-2-methyl-benzylamino)-benzoic acid methyl ester (292 mg, 1.08 mmol), and tri-n-butylphosphine (344 mg, 1.70 mmol) in toluene (50 mL) is added 1,1′-(Azodicarbonyl)-dipiperidine (450 mg, 1.78 mmol). The reaction mixture is stirred for 1.5 h. The reaction mixture is diluted with heptane, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (40 g silica, gradient EtOAc/Hexane) to give 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid methyl ester (309 mg, 1.08 mmol). MS: 539.0 (M+1).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:14])[C@H:6]([CH3:13])[NH:7][C:8](=[O:12])[C@H:9]([CH3:11])[NH2:10])[CH3:3].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:14])[C@H:6]([CH3:13])[NH:7][C:8](=[O:12])[C@H:9]([CH3:11])[NH:10][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)N
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
2.35 g (0.0087 mol) of L-alanyl-L-alanine ethylamide hydrobromide were suspended in 40 ml of pyridine and 2.04 ml (0.02 mol) of benzoyl chloride were added. The mixture was then stirred for 2 hours at room temperature. The solvent was evaporated and the residue recrystallised from isopropanol to yield 1.3 g (51%) of N-benzoyl-L-alanyl-L-alanine ethylamide of melting point 237°-239° C; [α]D20 =-17.8° (c=1.01% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][CH:14]([F:19])[O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100-L round bottom flask equipped with overhead stirrer, thermocouple, nitrogen inlet, condenser and steam bath was charged with 2-fluoro-5-(trifluoromethyl)phenol (5.50 kg), sodium chlorodifluoroacetate (9.31 kg), and DMF (4 L). There was an exotherm to 46.7° C. when the 4 L of DMF was charged to the flask. The temperature of the reaction was immediately reduced to 19° C. by rapid cooling with an ice/water bath. An additional 37.3 L of DMF (total DMF, 41.3 L) was then slowly charged, maintaining the internal temperature below 30° C. After cooling to ambient temperature, water (5.5 L) was charged, resulting in a 10° C. exotherm. Potassium carbonate (5.28 kg) was then added. The ice water bath was removed and the batch was heated to 97° C. using a steam bath. The reaction was complete after aging for 2 h at 97° C., as evidenced by HPLC assay, with <1% starting material remaining. The reaction was cooled to ambient temperature, and water (42 L) was slowly added. The batch was transferred to a 170-L extractor and extracted with MTBE (2×18 L). The organic layers were combined and washed with water (1×11 L) and brine (1×11 L). The MTBE solution was pumped into a 22-L flask equipped with a thermocouple, distillation apparatus, and a heating mantle. The MTBE was distilled off at 55-118° C. and atmospheric pressure. The desired product was purified by distillation at 120-157° C. and atmospheric pressure, and was isolated as a clear oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:5]1
Reactant: COC(=O)C1CNCC(C)C1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(C)CN(Cc2ccccc2F)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (8 mL) and acetic acid (8 drops) was added to methyl 5-methylpiperidine-3-carboxylate (300 mg, 1.9 mmol) and 2-fluorobenzaldehyde (3.8 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (1.6 g, 7.6 mmol) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:42])=[CH:17][C:18]3[C:35](=[O:36])[C:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:20]4[CH:21]([CH2:25][O:26]C5CCCCO5)[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:42])=[CH:17][C:18]3[C:35](=[O:36])[C:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:20]4[CH:21]([CH2:25][OH:26])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
In 2 ml of ethanol was dissolved 90 mg of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-(2-tetrahydropyranyloxymethyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. To the resulting solution was added 10 mg of p-toluenesulfonic acid monohydrate. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Ethanol was added to the residue obtained, and the resulting crystals were collected by filtration to obtain 47 mg (yield: 61.0%) of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][C:14]([CH2:18][OH:19])([CH3:17])[CH2:13]1.[H-].[Na+].I[CH3:23].O>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][C:14]([CH2:18][O:19][CH3:23])([CH3:17])[CH2:13]1
Reactant: CC1(CO)CCN(CC2COc3ccccc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(C)CCN(CC2COc3ccccc3O2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 56 mg (0.21 mmol) of [1-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanol in 1.5 ml of tetrahydrofuran was added to a flask containing 58 mg (2.40 mmol) of sodium hydride, previously washed with heptane under argon. The reaction mixture was stirred at 60° C. for 2 h, cooled to 0° C. followed by dropwise addition of a solution containing 16 μl (0.25 mmol) of iodomethane in tetrahydrofuran (0.5 ml). The reaction mixture was allowed to warm to room temperature and the stirring was continued for 1½ h. Water was slowly added and tetrahydrofuran was evaporated off and the water phase was extracted with dichloromethane (3×25 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by column chromatography (silica gel, ethyl acetate/heptane, 7:13) yielded the desired pure methyl ether.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccnc4ccsc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
Thieno[3,2-b]pyridin-7-ol (203 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (4 mg, yield 1%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using [5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>C(Cl)(Cl)Cl>[CH:33]([C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:34]
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Oc2c(C=O)sc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.088 mmol) in CHCl3 (1.5 mL) at 0° C. was added POCl3 (0.5 mL, 5.36 mmol) followed by DMF (0.5 mL, 6.46 mmol). The resulting mixture was stirred at 0° C. for 5 min and then allowed to warm to room temperature for 2 h after which time the reaction was again cooled to 0° C. and quenched by dropwise addition of water. The mixture was then partitioned between 1N aqueous NaOH and CH2Cl2. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (31 mg, 0.084 mmol, 95% yield) which was used without further purification. LC/MS (m/z, MH+): 369.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]C)=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cccc2nccn12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cl)cc1-c1cccc2nccn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred solution of 5-(5-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine (1.82 g, 7.03 mmol) in dichloromethane (30 mL) at −78° C. was added boron tribromide (1.0 mL, 10.6 mmol). The mixture was allowed to warm to ambient temperature and stirred for 4 h and cooled to 0° C. The reaction mixture was cautiously diluted with water and the pH was adjusted to >7 by the addition of 2 M aqueous sodium carbonate, causing a precipitate to be deposited. The solid was collected by filtration and washed sequentially with water, dichloromethane and diethyl ether to afford 4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenol as a colorless solid in 73% yield (1.26 g): 1H NMR (300 MHz, DMSO-d6) δ10.41 (s, 1H), 7.72-7.55 (m, 2H), 7.55-7.28 (m, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.91 (d, J=6.9 Hz, 1H); MS (ES+) m/z 245.0 (M+1), 247.0 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=2)[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1cnc(Br)c(Cl)c1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
A mixture of 2-bromo-3,5-dichloropyridine (2.72 g, 12 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.78 g, 6 mmol)), 2N Na2CO3 (9.0 mL, 18 mmol), Pd(PPh3)4 (0.35 g, 0.3 mmol) in toluene/ethanol (30 mL/6 mL) was sealed and heated at 90° C. for 12 hrs. The mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine and was dried over MgSO4. After filtration and concentration, purification by silica gel chromatography eluting with ethyl acetate/hexane (5/95) gave 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.8 g). MS (M+H)+: 315.6, tR=8.505 min (method 2)
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](OC)=[O:25].[H-].[Na+]>C(OCC)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:24][OH:25])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1OCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C(=CO)c1ccccc1OCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.3 %

Procedure:
A mixture of 30 g (0.10 mole) of methyl 2-(4-phenoxybut-1-yloxy)-phenylacetate, 12.5 g (0.21 mole) of methyl formate and 100 ml of diethyl ether is added dropwise at room temperature to a suspension of 3.4 g (0.14 mole) of sodium hydride in 50 ml of diethyl ether. The mixture is stirred for 12 hours at room temperature and is then hydrolyzed by adding ice. The aqueous, alkaline phase is extracted with diethyl ether, acidified with dilute HCl and again extracted by shaking with diethyl ether. After the organic phase has been evaporated down, 21 g (71%) of methyl alpha-[2-(4-phenoxybut-1-yloxy)-phenyl]-β-hydroxyacrylate are obtained.
Reaction SMILES: [F-].[K+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[C:25][Si](C)(C)C)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CN(C)C=O>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[CH:25])[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C2(C#C[Si](C)(C)C)CCCC(=O)C2)cc1OC1CCCC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reaction time: 18 h

Procedure:
A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-trimethylsilylethynylcyclohexan-1-one (0.3 g, 0.78 mmol) were stirred in dry N,N-dimethylformamide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate provided a clear colorless oil. Anal. (C20H24O3.1/10 H2O) calcd: C 76.45, H 7.76; found: C 76.32, H 7.60.
Reaction SMILES: [Cl:1][CH:2]([Cl:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].[CH2:13](O)[CH2:14][CH2:15][OH:16].C[Si](C)(C)Cl>>[CH2:15]1[O:16][C:8]2([CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]([Cl:1])[Cl:12])[CH2:10][CH2:9]2)[O:11][CH:14]1[CH3:13]
Reactant: OCCCO
Reactant: O=C1CCN(C(=O)C(Cl)Cl)CC1
Agent: C[Si](C)(C)Cl
Product: CC1COC2(CCN(C(=O)C(Cl)Cl)CC2)O1
Yield: 66.3 %

Procedure:
A mixture of 19 g (0.09 mol) of N-dichloroacetyl-piperid-4-one, 7.5 g (0.099 mol) of propane-1,3-diol and 22.4 g (0.21 mol) of trimethylchlorosilane was boiled under reflux for 12 hours, while stirring. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was then subjected to brief incipient distillation under gravity reduced pressure. The resulting brown oil, which slowly crystallized completely, was recrystallized from 200 ml of toluene. 16 g (66.6% of theory) of N-dichloroacetyl-piperid-4-one propylene ketal of melting point 115° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole (79 mg, 0.22 mmol) and 1,2,4-benzenetricarboxylic anhydride (42 mg, 0.22 mmol) the title compound was obtained (22 mg, 19%). 1H NMR (DMSO) δ 8.55(dd, 1H), 8.44(m, 3H), 8.22(d, 1H), 8.14(m, 1H), 7.90(m, 3H), 7.65(m, 3H), 4.00(s, 3H), 2.45(s, 3H). MS 527 m/z (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>O1CCCC1>[CH2:37]([N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:23][CH:22]=2)[C:18]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:19]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2Cc1ccccc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Potassium t-butoxide (0.04 g.) was added to a stirred solution of methyl 4-(5-hexanamidoindol-3-ylmethyl)-3-methoxybenzoate (0.15 g.) in dry tetrahydrofuran (5 ml.), under an atmosphere of nitrogen. The resulting dark-green mixture was stirred for 30 minutes. Benzyl bromide (0.062 g.) was added, causing the color to change to light brown. After 1 hour, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2×25 ml.). The combined extracts were dried (MgSO4) and evaporated. The brown oil obtained was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.04 g, 17%) as an oil; NMR: 0.86(t,3H, CH2.CH3), 1.27(m,4H, CH2.CH2.CH3), 1.57(m,2H, CH2.CH2.CON), 2.24(t,2H, CH2.CH2.CON), 3.82(s,3H, CO.OCH3), 3.91 (s,3H, OCH3), 3.99(s,2H, CH2.Ar), 5.32 (s,2H, NCH2Ph), 7.21(m,10H), 7.44(m,2H), 7.75(d, 1H), 9.64(s,1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]([O:18]C)=[O:17])[C:3]=1[Cl:20].[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(Oc2ccccc2)c(Cl)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1c(Cl)c(Oc2ccccc2)nc(C(=O)O)c1Cl
Yield: 90 %

Procedure:
To a solution of methyl 4-amino-3,5-dichloro-6-phenoxypyridine-2-carboxylate in methanol (10 mL) and water (100 mL) was added sodium hydroxide (0.5 g excess) and the solution heated under reflux for 3 hr. The solution was cooled and concentrated hydrochloric acid (2 mL) added. The solid was collected to give 4-amino-3,5-dichloro-6-phenoxypyridine-2-carboxylic acid (1.1 g, 90%); mp 158-60° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][NH2:13].CO>C1COCC1>[F:1][C:2]1[C:3]([C:9]([NH:13][CH3:12])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN
Reactant: O=C(O)c1ncc(F)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ncc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (600 mg) was added to a solution of 3,5-difluoropyridine-2-carboxylic acid (500 mg) in THF (10 ml), followed by stirring at 50° C. for one hour. The reaction solution was returned to room temperature, a 40% methylamine/methanol solution (1 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100 linear gradient) to obtain 3,5-difluoro-N-methylpyridine-2-carboxamide (293 mg) as a colorless solid.