Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH2:22]O)[CH:16]=4)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1>S(Cl)(Cl)=O>[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH2:22][Cl:1])[CH:16]=4)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1
Reactant: Cl
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(CO)c3)c(F)cc2c1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(CCl)c3)c(F)cc2c1=O
Yield: 85.9 %

Procedure:
Ethyl 1-cyclopropyl-6-fluoro-7-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate hydrochloride (6.68 g) in 40 ml thionyl chloride was heated at reflux for two hours. The excess thionyl chloride was removed in vacuo and by repeatedly adding ethanol and concentrating. The residue was crystallized from ethanol to give 5.50 g ethyl 1-cyclopropyl-7-[2-(chloromethyl)-6-methyl-4-pyridinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate as its hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:10](OCC)(=[O:13])[CH:11]=[CH2:12].CC(N=NC(C#N)(C)C)(C#N)C>CS(C)=O.O>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH2:12][CH2:11][C:10](=[O:13])[NH:7]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(Cl)ccc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2ccc(Cl)cc2N1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-2-iodoaniline (14.0 g, 0.0552 mol) in dimethyl sulphoxide, ethyl acrylate (30.38 mL, 0.276 mol) and n-tributyltinhydride (22.3 mL, 0.0828 mol), AIBN (3.6 g, 0.022 mol) was added at room temperature. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction mixture was cooled to room temperature; the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×500 mL), the combined organic layer was washed with cold water, saturated aqueous sodium chloride solution and dried over sodium sulphate, the solvent was evaporated under vacuum and the residue was purified with silica gel (60-120 mesh) silica gel column chromatography by 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.17-7.15 (d, J=7.6 Hz, 1H), 6.93-6.91 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 2.85-2.81 (t, J=7.2 Hz, 2H), 2.44-2.41 (t, J=8 Hz, 2H); MS (M+1): 181.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:29])[F:31])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)=[O:24])[CH2:41][CH2:40]1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccccc2Cl)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.07 minutes.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[N:24]1([CH2:29][CH2:30][OH:31])[CH:28]=[CH:27][CH:26]=[N:25]1>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:31][CH2:30][CH2:29][N:24]1[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: OCCn1cccn1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(OCCn2cccn2)c2cc(C3OCCO3)ccc21
Temperature: 140 °C

Procedure:
The title compound was prepared from 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-([2-(trimethylsilyl)ethoxy]methyl)-1H-indazole (Example 6A) in analogy to the procedure described in Example 21A. The procedure was modified by using 5 equivalents of 2-(1H-pyrazol-1-yl)-ethanol as the alcohol reactant and by switching to toluene as solvent. The reaction mixture was heated to 140° C. for 2 h using microwave irradiation, after which time the same amounts of catalyst and ligand were added again. This cycle was repeated one more time. The crude product thus obtained was purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 153 mg (52% of th.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].Cl.C(O)(=O)C>O>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Yield: 96.8 %

Procedure:
To 0.6 g of ethyl 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added 4 ml of a 3N hydrochloric acid/acetic acid mixture. The solution was heated at reflux for 2 hours. Distilled water (3 ml) was added to the solution, which was refluxed for 5 minutes. The precipitate was collected by filtration and washed with ethanol to give 0.54 g of the title compound.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][CH:2]=1.[H-].[Na+].[CH2:14]([I:16])[CH3:15]>C1COCC1>[CH2:6]([N:1]([C:15]1[CH:10]=[CH:9][CH:8]=[CH:7][C:14]=1[I:16])[C:2]1[O:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=1)[CH3:5]
Reactant: CCI
Reactant: O=c1ocnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1nc2ccccc2c(=O)o1)c1ccccc1I
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-(2-Iodo-phenyl)-amino]-benzo[d][1,3]oxazin-4-one (0.308 g, 0.00085 mol) was dissolved in THF (5 mL), and NaH (0.040 g, 0.0010 mol) was added. The reaction was stirred for 30 minutes and ethyl iodide (0.312 g, 0.0020 mol) was added. The reaction was heated to 60° C. and stirred for 24 hours under a nitrogen atmosphere. The reaction mixture was partitioned between H2O (200 mL) and ethyl acetate (200 mL). The ethyl acetate layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was chromatographed on a silica gel column eluted with petroleum ether:ethyl acetate (7:3). The product was recrystallized from ether/hexanes to produce the target compound as a white solid, mp 129°-130° C.).
Reaction SMILES: COC1C=C(N2CCC(C3C=CC=CC=3N)C2)C=CC=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1cccc(N2CCC(c3ccccc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Agent: COc1cccc(N2CCC(c3ccccc3N)C2)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCN(c2cccc(OC)c2)C1

Procedure:
Synthesized from 2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (180 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl{2-[1-(3-methoxyphenyl) pyrrolidin-3-yl]phenyl}amine (153 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (140 mg).
Reaction SMILES: [C:1](Cl)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[Cl:13][C:14]1[C:23]([OH:24])=[C:22]([OH:25])[C:21]([Cl:26])=[C:20]2[C:15]=1[CH2:16][CH2:17][NH:18][CH2:19]2.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[C:23]([OH:24])=[C:22]([OH:25])[C:21]([Cl:26])=[C:20]2[C:15]=1[CH2:16][CH2:17][N:18]([C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:19]2
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
trans-Cinnamoyl chloride (79 mg, 0.476 mmol) was suspended in DMF (7 mL) together with 5,8-dichloro-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.476 mmol) followed by triethylamine (133 μL, 0.952 mmol). The resulting mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL). The resulting mixture was washed twice with saturated sodium bicarbonate (2×40 mL), dried (MgSO4) and evaporated into a yellowish mass. Purification with column chromatography (petroleum ether/ethyl acetate 1/1→1/2) yielded 69 mg (40%) of the title compound as a yellowish solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[S:19]1[C:23]([CH:24]=[O:25])=[CH:22][N:21]=[CH:20]1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:24]([C:23]2[S:19][CH:20]=[N:21][CH:22]=2)[OH:25])[CH:14]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cncs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cncs1
Yield: 44.6 %

Procedure:
According to Reference Example 8-68, a 1.55 mol/L solution of n-butyllithium in hexane (2.24 mL, 3.48 mmol) was added to toluene (6 mL), and the mixture was stirred with a toluene solution (2 mL) of 3-bromopyridine (500 mg, 3.16 mmol), tetrahydrofuran (2 mL), thiazole-5-carbaldehyde (0.329 mL, 3.79 mmol) and 4 mol/L hydrochloric acid (2.37 mL, 9.48 mmol). Then, purification by preparative thin-layer chromatography (chloroform/methanol=12/1) was performed to give pyridin-3-yl(thiazol-5-yl)methanol (Compound EQ) (271 mg, yield: 45%).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Br:13][C:14]1C=C(C#N)[CH:17]=[CH:16][C:15]=1C.CC(C[AlH]CC(C)C)C.Cl>CCOC(C)=O.CCCCCC.C1COCC1>[Br:13][CH2:14][C:15]1[CH:3]=[CH:2][C:1]([CH:5]=[O:4])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C#N)cc1Br
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1ccc(CBr)cc1
Reaction time: 1.5 h

Procedure:
To a THF-toluene (2.4 L -0.24 L) solution of α bromo p tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature below 0° C. was added DIBAL-H in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred, in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying, the title compound was obtained (210 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:28])=O>>[Cl:28][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 1-(4-carboxyphenyl)-3-(difluoromethyl) -5-[4-(methylthio)phenyl]pyrazole (2 g) and thionyl chloride (20 ml) was refluxed for 3 hours, and concentrated in vacuo, giving 1-[4-(chloroformyl)phenyl]-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole. A solution of diethyl malonate (1.4 g) and ethanol (0.3 ml) in diethyl ether (15 ml) was added dropwise to a stirred mixture of magnesium (0.16 g), ethanol (0.2 ml) and carbon tetrachloride (0.36 ml) in diethyl ether (5 ml). The resulting mixture was refluxed for 1 hour. A solution of the above acid chloride in tetrahydrofuran (15 ml) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 1 hour and refluxed for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. A mixture of the residue (4 g), acetic acid (40 ml), and 20% sulfuric acid (20 ml) was refluxed for 3.5 hours and then concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give crystals of 1-(4-acetylphenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:16][CH3:17])([CH2:13][CH2:14][OH:15])[C:9]([NH:11][NH2:12])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:34]=[CH:35]/[C:36](=[NH:40])OCC)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.C(OCC)(=O)C.O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:16][CH3:17])([C:9]2[NH:11][N:12]=[C:36](/[CH:35]=[CH:34]/[C:24]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:22]([O:21][CH3:20])[CH:23]=3)[N:40]=2)[CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: COC(CCO)(C(=O)NN)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A solution of 2-(4-fluorophenyl)-4-hydroxy-2-methoxybutyric acid hydrazide (40 mg) in ethanol (1.6 mL) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (65 mg) and TEA (0.12 mL) in ethanol (0.7 mL), and the reaction solution was stirred at 75° C. for two days. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-methanol system) to obtain 38 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12]Br)=[CH:2]1.N1C=CC=CC=1.CN(C)C1C=CC(N=[O:29])=CC=1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.C(O)C.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]=[O:29])=[CH:2]1
Reactant: CN(C)c1ccc(N=O)cc1
Reactant: BrCc1ccccc1-c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccccc1-c1ccsc1
Reaction time: 0.5 h

Procedure:
To a solution of Compound 2b (1.98 mmol) in chloroform (5 mL) was added pyridine (9.88 mmol) and the reaction mixture heated at reflux for 1 hour under nitrogen. The solvent was removed in vacuo and the residue triturated with diethyl ether to give a white solid. The solid was dissolved in 95% aqueous ethanol (10 mL ) and N,N-dimethyl-4-nitrosoaniline (1.98 mmol) was added with stirring followed by the addition of sodium hydroxide (4.0 mmol) in water (3 mL). The reaction mixture was stirred for 16 hours at ambient temperature and then 6N hydrochloric acid (3 mL) was added. After 30 minutes, the solvent was removed in vacuo and the residue was diluted with water (10 mL) and extracted with diethyl ether (2×30 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate, brine and the solvent removed in vacuo to give crude Compound 2c as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 66.1 g (0.341 mole) of methyl 5-acetyl-2-hydroxybenzoate, 7.26 g (0.511 mole) of methyl iodide and 47.0 g (0.341 mole) of potassium carbonate in 400 ml of sieve-dried dimethylformamide is stirred at room temperature for 65 hours. The mixture is poured on 1.5 liters of N hydrochloric acid, extracted 6 times with ethyl ether, washed extract with water, NaHCO3 solution and cold 1 N NaOH, dried over Na2SO4, and evaporated solvent. Methyl 5-acetyl-2-methoxybenzoate, 51.3 g (72%) m.p. 95°-96° C., is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([OH:60])=[N:51][N:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([O:60][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:51][N:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: O=C(OCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(COC(=O)c5ccccc5)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.68 g), {4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate hydrochloride (0.73 g), potassium carbonate (0.45 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 10 min. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (10:90-30:70, v/v) to give {4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate as colorless crystals (0.55 g, yield 44%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(-c4ccccc4)cc32)cc1
Yield: 47 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 4-methoxyphenyl boronic acid. The title compound (70 mg) was obtained as a white solid, (yield=47%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:18][N:17]3[C:19]3[CH:23]4OC(C)(C)OC4C(=O)C=3)=[CH:15][C:10]=2OC1>O1CCOCC1>[CH:16]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:15]=2[CH:23]=[CH:19][NH:17][CH:18]=1
Reactant: CC1(C)OC2C(=O)C=C(N3CC3c3ccc4c(c3)OCO4)C2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C1=Cc2ccccc2C=CN1
Temperature: 100 °C
Yield: 171.7 %

Procedure:
Cesium carbonate (3.2 g, 9.8 mmol, 4.0 equiv) was added to a stirred solution of aziridine 54 (770 mg, 2.4 mmol, 1.0 equiv) in 1,4-dioxane (350 mL) at 25° C. The reaction vessel was sealed under argon and heated to 100° C. via oil bath for 18 h. The reaction mixture was gravity filtered and concentrated by rotary evaporation. The residue was purified by passage through a plug of silica gel (ethyl acetate) to afford 55 (590 mg, 76% yield) as a tan foam. Rf=0.27 (50% ethyl acetate in benzene); 1H NMR (500 MHz, CDCl3) δ 7.82 (br s, 1H, ArH), 6.54 (s, 1H, ArH), 5.93 (d, 1H, J=1.5 Hz, OCH2O), 5.91 (d, 1H, J=1.5 Hz, OCH2O), 5.77 (br s, 1H, NH), 4.97 (d, 1H, J=6 Hz, CH(OR)), 4.65 (d, 1H, J=6 Hz, CH(OR)), 3.80-3.85 (m, 1H, ArCH2CH2N), 3.60-3.65 (m, 1H, ArCH2CH2N), 2.95 (br t, 2H, J=4 Hz, ArCH2CH2N), 1.44 (s, 3H, CH3), 1.43 (s, 3H, CH3); 13C NMR (125 MHz, C6D6) δ 195.02, 165.26, 146.76, 146.28, 133.02, 126.24, 113.71, 109.55, 109.10, 109.00, 100.84, 78.98, 76.30, 47.65, 36.87, 27.89, 26.87; IR (neat film) 3266 (w), 2924 (s), 2855 (m), 1705 (w), 1585 (s) cm−1; HRMS (ESI) m/z: Calcd for C17H18NO5 (MH+) 316.1185; observed 316.1189.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH3:16])[CH3:15]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,3-dimethylpiperidine. Yield 0.7 g (75%), C7H16N2, m/z 129 (M+1), PMR (CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).