Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:17]2[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)=[O:12].CC(=CC)C>O.C(O)(C)(C)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:13]([C:11]([OH:6])=[O:12])[C:14]=2[CH:15]=[C:16]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1cc2c(C=O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1cc2c(C(=O)O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.3 %

Procedure:
A solution of sodium chlorite (9.70 g) and sodium dihydrogen orthophosphate (13.02 g) in water (50 ml) was added dropwise to a solution of ethyl 4-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate (4.47 g) and 2-methylbut-2-ene (50 ml) in tert-butyl alcohol (100 ml) and the mixture stirred for 72 hours at ambient temperature, then concentrated in vacuo and the resulting precipitate was filtered and dried to give the product as an off-white solid (4.16 g. 89%); NMR δ(CD3SOCD3) 1.25 (t, 3H), 4.30 (q, 2H)) 5.85 (s, 2H), 6.85 (m, 1H), 7.35 (m, 1H), 7.40 (q, 1H), 7.50 (m, 1H), 7.80 (m, 3H); M/z (−) 390.1 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.BrCC1C=CC=C(CBr)C=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][CH:65]=1)[CH2:42][N:43]1[CH2:47]C(=O)N(C2C=NN(CC3C(C)=NOC=3C)C=2)[C:44]1=O.CNC.[H-].[Na+]>CN(C=O)C.C1COCC1.C(O)C>[CH3:44][N:43]([CH2:42][C:41]1[CH:40]=[C:39]([CH:65]=[CH:64][CH:63]=1)[CH2:38][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19])[CH3:47]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CBr)c3)C2=O)cn1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: BrCc1cccc(CBr)c1
Agent: CNC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CN(C)C)c3)C2=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol) 1,3-bis(bromomethyl)benzene (263 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were dissolved in 2 mL DMF and irradiated in the microwave reactor at 165° C. for 5 minutes. The reaction was cooled to room temperature, and salt precipitate was removed by filtration. The clear solution containing crude product was concentrated and redissolved in ethyl acetate. The organic solution was washed with water twice followed by brine. The organic layer was dried over sodium sulfate and evaporated to give the crude product which was carried forward to the next step without further purification or characterization. 1-(3-(bromomethyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 42a) (152 mg, 0.3 mmol), dimethylamine (2 M solution in THF) (1.5 mL, 3 mmol), and sodium hydride (9 mg, 0.36 mmol) were dissolved in 1 mL anhydrous THF. The reaction was placed in a microwave reactor for 5 minutes at 120° C. The crude product was redissolved in 2 mL ethanol and was purified by HPLC (10-95% Acetonitrile/Water, 25 minutes) to afford 1-(3-((dimethylamino)methyl)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (16 mg, 13%). MS M+H calculated 423.1; found 423.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.2 uM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11]Br)[C:5]([OH:7])=[O:6].Cl.[OH2:14]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][OH:14])[C:5]([OH:7])=[O:6]
Reactant: O
Reactant: O=C(O)c1ccc(CBr)c(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CO)c(Br)c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of yield 3-bromo-4-(bromomethyl)benzoic acid (1.0 equiv.) in Water (0.56 M) at 95° C. was added potassium carbonate K2CO3 (5.0 equiv.). The homogenous reaction mixture was stirred at 95° C. in an oil bath for 1 hr. The reaction mixture was COOLED OFF TO RT, neutralized with 6 M HCl. diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude was used in next step. LC/MS (m/z)=294.8 (MH+), Rt=0.80 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][CH2:49][CH2:50][O:51][CH2:52][O:53][C:54]1[CH:63]=[C:62]2[C:57]([CH:58]=[CH:59][CH:60]=[C:61]2[NH:64][CH3:65])=[CH:56][CH:55]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:10])[C:11]([N:64]([C:61]1[C:62]2[C:57](=[CH:56][CH:55]=[C:54]([O:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH3:47])[CH:63]=2)[CH:58]=[CH:59][CH:60]=1)[CH3:65])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNc1cccc2ccc(OCOCCOC)cc12
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc2cccc(N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C)c2c1
Reaction time: 48 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)alanine (1.09 g, 5.78 mmol) in dry CH2Cl2 (4 mL) under argon were added PYBOP (3.01 g, 5.78 mmol), 7-[(2-methoxyethoxy)methoxy]-1-(methylamino)naphthalene, as described above in Step B, (302 mg, 1.16 mmol), and N,N-diisopropylethylamine (1.00 mL, 5.75 mmol). The reaction mixture was stirred for 48 hrs, then partitioned between CH2Cl2 (500 mL) and 10% aqueous citric acid (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of hexane −10% to 60% EtOAc to yield the desired product.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].[OH-].[NH4+:23]>>[NH2:23][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: [NH4+]
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Agent: [OH-]
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(N)=O

Procedure:
Three g of the product of Example 65 was reacted with 0.7 g of 35% ammonium hydroxide, substantially as shown in Example 60, to obtain 2 g of the desired product, m.p. 178°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH3:24].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH3:24])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CNC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added dimethylamine in THF (0.65 ml, 1.29 mmol, 2.0M THF) and T3P (50 wt % solution in EtOAc, 0.62 m, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (112 mg, 52% yield). Rf=0.65 (20% MeOH/CH2CH2+0.2% NH4OH); LRMS m/z Calcd for C18H25ClN2O2, 336.8, found, 337.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ (d, J=1.7 Hz, 1H), 7.46, 7.40 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 3.68 (s, 2H), 3.06-2.96 (m, 1H); 2.92 (s, 6H), 2.78-2.68 (m, 2H), 2.62-2.46 (m, 6H): 1.76-1.68 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 175.5, 146.2, 135.5, 133.9, 130.7, 126.5, 123.7, 72.9, 56.8, 54.3, 40.9, 37.4, 36.1, 28.5, 23.7.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]=1[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:13]([NH:12][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:35])=[O:2])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a suspension of (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic acid methyl ester (100 mg, 0.21 mmol) in THF (1 mL) and methanol (0.29 mL) was added a solution of lithium hydroxide monohydrate (25.4 mg, 1.0 mmol) in water (0.74 mL) added and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (92 mg, 95%) which was obtained as a white solid. MS: m/e=470.1 [M−H]−.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[N:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+].Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)Cl.O>[C:18]1([S:15]([C:12]2[N:13]=[N:14][C:9]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=34)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)nn1
Reactant: N[n+]1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
A two-phase mixture of 6-(2-phenylethynyl)-3-phenylsulfonylpyridazine (23.3 g), 1-aminopyridinium iodide (90%; 26.9 g), sodium hydroxide (11.6 g), and benzyltrimethylammonium chloride (1.35 g) in a mixture of methylene chloride (233 ml) and water (233 ml) was stirred for 2 hours at room temperature. Water (233 ml) was added to the reaction mixture, and the mixture was acidified with 36% hydrochloric acid (20 ml). The organic layer was separated, washed twice with water and once with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with hot ethanol (300 ml) to give 3-(3-phenylsulfonylpyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (20.8 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:22][CH:23]1[CH2:25][O:24]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCC1CO1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(F)c(F)c2)CCN1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC2CO2)CC1

Procedure:
In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and 2-bromomethyl-oxirane gave the title compound as yellow oil. MS: 337.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:6][CH:7]=1.[OH-].[Na+].CO.[Cl-].[Cl-].[Ca+2:33]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:25])([F:24])[F:26])[CH:9]=2)=[CH:6][CH:7]=1.[Ca:33]
Reactant: [Ca+2]
Agent: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: [Ca]

Procedure:
To celecoxib (100 mg; 0.262 mmol) was added a solution of 1 M NaOH in methanol (0.29 mL; 0.29 mmol). The mixture was gently warmed with occasional swirling until all the solids were dissolved resulting in a colorless solution. To the solution was added a 3 M CaCl2 solution in methanol (0.131 mL; 0.393 mmol). A solid formed within minutes. The precipitate was filtered and the powder was dried overnight with flowing nitrogen gas. Characterization of the product mixture was achieved via TGA (FIG. 25), Raman spectroscopy (FIG. 26), and PXRD (FIG. 27) and showed the presence of celecoxib Ca salt and NaCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C2C(=CC=1OC)C(=O)CC2.N1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:11](=[O:12])[C:13](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:14]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: COc1cc2c(cc1OC)C(=O)CC2
Agent: O=Cc1ccncc1
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2

Procedure:
U.S. Pat. No. 5,606,064 disclosed a process for the preparation of donepezil. 5,6-dimethoxy-1-indanone was condensed with pyridin-4-aldehyde to give 5,6-dimethoxy-2-(pyridin-4-yl)methyleneindan-1-one, reacted with benzyl bromide to give 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpyridinium bromide and then, hydrogenated in the presence of platinum oxide catalyst to yield donepezil.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.[NH2:23][C:24]1[CH:29]=[CH:28]C(I)=[CH:26][N:25]=1>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.O>[C:1]1([C:7]2[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(I)cn1
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: OB(O)c1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 41 %

Procedure:
A mixture of toluene (80 mL) and water (20 mL) was degassed with argon for 5 minutes. Sodium carbonate (9.63 g, 0.0909 mole) was added and the mixture was degassed with argon for 5 minutes. Phenylboronic acid (6.65 g, 0.05454 mole) and 2-amino-5-iodo-pyridine (10.0 g, 0.04545 mole) were then added and the mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.252 g, 0.00454 mole) was added was degassed with argon for 5 minutes. The resulting mixture was then heated to reflux for 3 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water followed by brine solution. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 3.2 g (41%) of 5-phenyl-pyridin-2-ylamine. LC-MS purity: 171.08 (M+1)+, 87%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:26]1([N:3]2[CH2:2][CH2:7][N:6]([CH2:12][CH2:13][CH2:14][NH:18][C:19]([NH:18][C:14]3[CH:13]=[C:12]([N:6]4[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:25])=[C:5]4[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][CH:15]=3)=[S:20])[CH2:5][CH2:4]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reactant: c1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCN(C3CCCCC3)CC2)c1
Yield: 92 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (500 mg, 1.4 mmol) was refluxed with 4-cyclohexyl-1-piperazine-1-propanamine (345 mg, 1.5 mmol) in 8 mL of benzene for 2 hours. Chromatographic purification (on silica gel, 100% methylene chloride first, followed by 10% (v/v) methanol in methylene chloride) of the residue after concentration in vacuo gave the title compound as a yellow foam (752 mg, 92%); 1H-NMR (CDCl3) δ 7.63 (br, 1H), 7.11 (t, 1H, J=8.0 Hz), 6.85 (br, 1H), 6.72 (br, 1H), 6.60 (d, 1H, J=8.2 Hz), 6.56 (dd, 1H, J=8.3, 2.2 Hz), 6.45 (br, 1H), 3.75 (s, 6H), 3.65 (m, 2H), 2.40 (s, 6H), 2.31 (t, 2H, J=6.6 Hz), 2.20-2.60 (m, 8H), 2.16 (m, 1H), 1.50-1.95 (m, 7H), 1.00-1.30 (m, 5H); 13C-NMR (CDCl3) δ 165.9, 152.5, 149.2, 130.1, 112.0, 108.8, 63.6, 53.2, 51.9, 48.7, 29.0, 26.2, 25.8, 25.3, and 18.0.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:52][O:53][C:54]1[CH:55]=[C:56]([CH:60]=[C:61]([O:65][CH3:66])[C:62]=1[O:63][CH3:64])[C:57](Cl)=[O:58]>CC(C)=O>[CH3:66][O:65][C:61]1[CH:60]=[C:56]([CH:55]=[C:54]([O:53][CH3:52])[C:62]=1[O:63][CH3:64])[C:57]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:58]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (3.95 g, 6.48 mmol) and acetone (20 mL), water (6 mL), and potassium carbonate (2.70 g, 19.5 mmol). Cool to 0° C. in an ice bath. After 30 minutes, add dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (1.71 9, 7.4 mmol) in acetone (20 mL). Warm to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.23 (silica gel, ethyl acetate). Analysis on HPLC using a CHIRALPAK AD (10 μm×4.6 cm×250 cm) column eluting with pentane/ethanol/methanol/triethylamine (80/15/5/0.1) with a flow rate of 1.5 mL/minute indicates an enantiomeric excess of 98%, (98% ee), retention time of 22.30 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13]C)=O)[CH2:5]2>C(N)CCC>[CH2:6]([NH:7][C:11]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7]1)=[O:13])[CH2:5][CH2:4][CH3:3]
Reactant: COC(=O)C1Cc2cc(Cl)ccc2N1
Solvent: CCCCN
Product: CCCCNC(=O)C1Cc2cc(Cl)ccc2N1

Procedure:
Methyl 5-chloroindoline-2(R/S)-carboxylate (0.63 g, 3 mmol) was dissolved in butylamine (25 ml) and refluxed for 4 h. The excess amine was removed and the residue was crystallized from ether to give a yellow solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([O:21]C)=[O:20].O.O[Li].O.Cl>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccc(Oc2cccnc2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Oc2cccnc2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(3-pyridyloxy)phenylacetate (0.45 g, 1.3 mmol) from Step 2 above in THF (4 mL) and water (1 mL) was added LiOH.H2O (0.065 g, 1.5 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-20% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoro-ethoxy)-4-(3-pyridyloxy)-phenylacetic acid as a gum (HPLC retention time=5.4 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19]>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: OCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCO)CC1
Yield: 78 %

Procedure:
In an atmosphere of argon, 4-(4-fluorobenzoyl)piperidine (2.07 g, 10 mmol) was dissolved in triethylamine (30 ml) to which was subsequently added dropwise 2-bromoethanol (1.1 ml, 14.7 mmol) at room temperature. After 1 hour of heating under reflux, triethylamine was removed by evaporation, and the resulting residue was mixed with saturated sodium carbonate aqueous solution (40 ml) and extracted with ethyl acetate. The resulting organic layer was dried on anhydrous sodium carbonate, the solvent was removed by evaporation and then the resulting residue was purified by subjecting it to a silica gel column chromatography (ethyl acetate-methylene chloride:methanol=10:1) to obtain 1.96 g (78.0%) of the title compound in the form of light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=1>CCO.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(OC)c3)c2cc1OC
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N

Procedure:
6,7-Dimethoxy-4-(3-methoxy-4-nitrophenoxy)quinoline was hydrogenated in EtOH/DMF using 10% Pd/C at 40 psi to yield 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine. LCMS m/z=327 (M+1); 1H NMR (DMSO) δ: 8.43 (d, 1H, J=6 Hz), 7.5 (s, 1H), 7.37 (s, 1H), 6.76 (d, 1H, J=2.6 Hz), 6.72 (d, 1H, J=9 Hz), 6.60 (dd, 1H, J=2.5, 8.5 Hz), 6.41 (d, 1H, J=5.6 Hz), 3.75 (s, 3H), 3.31 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C1C[O:18]CC1>[OH-].[Na+].O>[Cl:1][C:2]1[N:11]=[C:10]([OH:18])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(O)nc(Cl)nc2c1
Reaction time: 4 h
Yield: 63 %

Procedure:
2,4-dichloro-7-methoxyquinazoline (500 mg, 2.183 mmol) was suspended in 2% aqueous NaOH (6 mL). THF (1 mL) was added and the reaction was stirred for 4 h. The reaction was diluted with water and the solid that remained was filtered off. The aqueous phase was diluted with 1 N HCl. The precipitate that formed was filtered, washed with water and dried to give 2-chloro-7-methoxyquinazolin-4-ol (288 mg, 63% yield). MS: MS m/z 211.1 (M++1).