Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1NC=CN=1.C1(S([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](B(O)O)=N2)(=O)=O)C=CC=CC=1.P([O-])([O-])(O)=O.[Na+].[Na+]>O1CCOCC1.O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:2]1
Reactant: Brc1ncc[nH]1
Reactant: O=S(=O)(c1ccccc1)n1nc(B(O)O)c2ccccc21
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc2[nH]ccc2c1
Temperature: 110 °C

Procedure:
A mixture of bromoimidazole Int-22a (98 mg, 0.20 mmol), 1-(phenylsulfonyl)-3-indazole boronic acid (73 mg, 0.24 mmol) and sodium hydrogen phosphate (86 mg, 0.61 mmol) in 1,4-dioxane (4 mL) and water (2 mL) at r.t. was purged with nitrogen gas for 5 min in a microwave vial. Tetrakistriphenylphosphorous palladium was added. The mixture was heated in a microwave reactor at 110° C. for 1 h. Water and ethyl acetate were added, and the layers were separated. The separated aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (MgSO4) and filtered. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave indole Int-22b (112 mg, 84%) as a colorless oil.
Reaction SMILES: C(OCC(C)C)=C.C(Cl)(Cl)=O.[CH2:12]([OH:16])[CH:13]([CH3:15])[CH3:14].C(O[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])C(C)C>>[CH2:12]([O:16][C:23](=[CH2:22])[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC=CC(=O)OCC(C)C
Reactant: CC(C)CO
Agent: C=COCC(C)C
Agent: O=C(Cl)Cl
Product: C=C(OCC(C)C)C(=O)OCC(C)C
Temperature: 52.5 °C

Procedure:
100 g (1.0 mol) of isobutyl vinyl ether are initially charged in a 500 ml stirred apparatus and heated to 50-55° C. 113 g (1.15 mol) of phosgene are subsequently introduced over a period of 11 h. After an extra reaction time of 1.5 h, the reaction mixture is stripped phosgene free at 50-55° C. by introduction of nitrogen. The mixture is subsequently allowed to cool to room temperature, and and [sic] 60.7 g (0.82 mol) of isobutanol are added dropwise. After the addition has ended, the resulting reaction mixture is rectified. This gives 150.4 g (75%) of isobutyl 3-isobutoxyacrylate of b.p. 97° C. at 2.5 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1([CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=O)[CH2:23]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([CH3:32])([CH3:21])[CH2:23]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)c4ccccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 3,3-dimethyl-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=423.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Paraanisidine (136.34 g, 1.108 mol) was dissolved in dichloromethane (500 ml), triethylamine (234 ml, 1.66 mol) and acetic anhydride (114.8 ml, 1.22 mol) were added thereto, and the resulting mixture was stirred for 1 hour. After completion of reaction, the reaction solution was concentrated. Water (800 ml) was added to the residue and the resulting mixture was stirred and filtered to give 168.0 g (1.16 mol, Yield 92%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Na].[CH2:10]([OH:13])[CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCc1ccccn1
Reactant: OCCO
Agent: [Na]
Product: OCCOCc1ccccn1

Procedure:
2-Chloromethylpyridine is reacted with the sodium salt of ethylene glycol to give 2-(2-hydroxyethoxymethylpyridine. Treatment of 2-(2-hydroxyethoxymethyl)pyridine with thionyl chloride gives 2-(2-chloroethoxymethyl)pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:21]([C:22]1[CH:30]=[CH:29][C:27]([O:28][CH2:2][C:3]2[N:4]=[C:5]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]3)[S:6][C:7]=2[CH3:8])=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:20]
Reactant: CCOC(=O)C1CCN(c2nc(CCl)c(C)s2)CC1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(C=O)cc3OC)c(C)s2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A mixture of ethyl 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine-4-carboxylate (1.48 g), vanillin (0.75 g), anhydrous potassium carbonate (0.68 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl 1-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (1.70 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8].CC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=[CH2:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Dry tetrahydrofuran (80 ml) was added to a mixture of potassium t-butoxide (6.740 g, 60.06 mmoles) and methyltriphenylphosphonium bromide (24.276 g, 60.06 mmoles) and stirred at room temperature for 30 minutes. A solution of 3,5-di-t-butylbenzaldehyde (10.087 g, 46.20 mmoles) in dry tetrahydrofuran (30 ml) was then added and the reaction mixture was stirred at room temperature for 17 hours. Acetone (50 ml) was then added and then all of the solvent was removed under vacuum. Pet. ether (60-80, 150 ml) was then added to the residue and the mixture was stirred vigorously for 30 minutes. The solution was then filtered through silica, rinsing thoroughly with pet. ether (60-80) and the solvent removed under vacuum to give 3,5-di-t-butylstyrene (9.302 g, 93%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccncc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1
Yield: 83 %

Procedure:
3-Fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1, 612 mg, 1.7 mmol), tert-butyl 4-(aminomethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (amine intermediate “L”, 640 mg, 2.2 mmol), EDAC (649 mg, 3.4 mmol), HOBt (297 mg, 2.8 mmol) and diisopropyl-ethyl-amine (1.47 ml, 8.4 mmol) were dissolved in 15 ml NMP and stirred until LCMS showed complete consumption of acid starting material. (usually overnight) The product was precipitated out of the reaction mixture by addition of water, filtered, rinsed with water and dried. The title compound was isolated as a solid (1.01 g, 90% pure by HPLC, 83% yield). An analytical sample was purified by prep HPLC (C-18 reversed phase column, water/MeOH gradient, buffered with 0.1% TFA). Alternatively a water/acetonitrile gradient, buffered with 10 mM NH4OAc can be used. Product containing fractions were filtered through a cartridge filled with cation exchange resin (MCX from Waters or STRATA X-C from Phenomenex), rinsed with methanol, eluted with 2 M solution of ammonia in methanol and evaporated. The residue was dissolved in methanol, 1.0 equiv. aq. of 1.00 N HCl were added and the title compound was isolated as the mono-HCl salt by evaporation. LC/MS (M+H)+: 636. Ret. time: 1.66 min. (Condition M); analytical HPLC Ret. time: 16.74 min (Condition N).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[NH2:19])[CH:7]=[CH:6][CH:5]=1
Reactant: C#Cc1cccc(N)c1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 65 °C
Yield: 70.5 %

Procedure:
A multinecked round bottom flask fitted with a mechanical stirrer, reflux condenser, and thermometer was flushed and maintained under positive pressure of nitrogen. The flask was charged with 100.0 g (0.44 mol) of 3-bromobenzotrifluoride, 300 ml of dried, degassed triethylamine, 51.5 g (0.44 mol) of 3-aminophenylacetylene, 0.35 g (0.499 mmol) of bis(triphenylphosphine) palladium II chloride, 1.6 g (6.09 mmol) of (triphenylphosphine), and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature followed by the addition of 200 ml of ether. Removal of the triethylamine hydrobromide salt by-product by suction filtration followed by concentration of the filtrate under reduced pressure gave the crude product as a light off-white solid. Short path distillation of the crude product under reduced pressure gave 81.0 g (0.31 mol, 71% yield) of the product as a colorless liquid which crystallized on standing.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[C:32]([F:34])[CH:33]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)=[N:3][CH:4]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)cc(F)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3,5-difluorophenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.18 (1H, d, J=2.6 Hz), 7.95 (1H, dd, J=6.8, 1.8 Hz), 7.38 (2H, d, J=8.1 Hz), 6.83–6.69 (2H, m), 6.40–6.32 (2H, m), 6.25 (1H, br.s), 5.39–5.30 (1H, m), 1.60 (3H, d, J=6.2 Hz), 1.59 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:15][CH2:16][O:17][CH3:18])[CH2:6]1
Reactant: Brc1ccccc1OC1CCNC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(Oc2ccccc2Br)C1
Reaction time: 48 h

Procedure:
3-(2-Bromophenoxy)pyrrolidine (1.23 g), 1-bromo-2-methoxyethane (0.526 ml) and potassium carbonate (842 mg) were mixed with dimethylformamide (50 ml) and stirred for two days. The mixture was added to water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), washed with water (2×50 ml), brine (2×30 ml), dried (MgSO4) and concentrated in vacuo. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding product as a clear oil (0.8 g).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][C@@H:10]([C:18]([OH:20])=[O:19])[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:7])[C@@H:3]([CH3:5])[OH:4].ClCC(O)=O.[N:26]([O-])=O.[K+]>>[N+:1](=[C:2]([C@H:3]([OH:4])[CH3:5])[C:6]([O:8][CH2:9][C@@H:10]([C:18]([OH:20])=[O:19])[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:7])=[N-:26]
Reactant: C[C@@H](O)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=N[O-]
Agent: O=C(O)CCl
Agent: [K+]
Product: C[C@@H](O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of O-(L-threonyl)-N-(trifluoroacetyl)-L-serine (109 mg) were added aqueous 4M chloroacetic acid (20 μl) and aqueous 6M potassium nitrite (120 μl) and the solution was stirred at room temperature for 15 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.CS(O)(=O)=O.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Clc1ncc2cnn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.47 mmol) (Ark, Cat. No. AK-30782) in THF (10 mL) at r.t. was added methanesulfonic acid (84 μL, 1.3 mmol), followed by dihydropyran (1.77 mL, 19.4 mmol). The mixture was stirred at r.t. over weekend. The reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which was directly used in the next step reaction without further purification. LCMS (M-84+H)+: m/z=155.1/157.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.71 ml), 1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride (5 g) and potassium carbonate (8.83 g) in dimethylsulfoxide (50 ml) was stirred for 1 hour at 100° C. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and dried under reduced pressure to give 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc3c(c2)OCCO3)cc1
Reactant: Oc1ccc(F)cc1F
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc3c(c2)OCCO3)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(3,4-ethylenedioxyphenyl)-4-(4-methoxyphenyl)pyridazine (136 mg, 0.383 mmol) and 2,4-difluorophenol were reacted as starting materials at 120° C. for 8 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (113 mg, 65.7%). Melting point: 158.0-159.5° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al](Br)(Br)Br>ClC1C=CC(Cl)=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:24]=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccccc1
Agent: Br[Al](Br)Br
Solvent: Clc1ccc(Cl)cc1
Product: Clc1ccc2nc(-c3ccccc3)nc(-c3ccccc3)c2c1
Yield: 69 %

Procedure:
The preparation of 4-phenylquinazolines from an N-benzylideneaniline type of Schiff base that is formed from aniline and benzaldehyde, as shown in the reaction between p-chloro-(α-chlorobenzylidene)aniline and benzonitrile in 1,4-dichlorobenzene at 140° C. in the presence of AlBr3 that afforded 69% of 6-chloro-2,4-diphenylquinazoline [23], and the reaction between N-[o-(triphenylphosphoranylideneamino)benzylidene]-p-toluidine and p-nitrobenzaldehyde when refluxed in xylene for 12 hours that gave 70% of 6-methyl-4-p-nitrophenyl-2-phenylquinazoline [24]. The latter reaction would afford dihydroquinazolines as well if other benzaldehydes rather than p-nitrobenzaldehyde are used. In addition, the reaction between 3,4-diphenyl-1,2,4-oxadiazol-5(4H)-one and benzylideneaniline also afforded 2,4-diphenylquinazoline [25];
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][CH:38]=[CH:37]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[CH:37]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2ccc(OC[C@H]3CO3)cc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2ccc3ncccc3c2)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (100.0 mg; 0.264 mmol) is dissolved in ethanol (10 mL) at ambient temperature. (R)-6-Oxiranylmethoxy-quinoline (89) (53.0 mg; 0.264 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes, then 50%→70% acetone in hexanes) affording the desired product (50 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36 a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-fluorobenzaldehyde yields the (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow crystalline solid; MS: m/e=243 (M)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-methyl-2-(5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl) oxazole-2-carboxamido)butanoate (Example 1, 150 mg) in THF (3 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.6 ml) and the mixture was stirred for 4 hours at RT. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and then crystallized in EtOAc to give the title compound. Yield: 125 mg (85%); 1H NMR (DMSO-d6, 300 MHz): δ 12.93 (bs, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 8.64 (d, 1H), 8.03 (d, 1H), 7.81 (s, 1H), 7.8 (d, 2H), 7.64 (d, 2H), 7.58 (dd, 1H), 7.52 (dd, 1H), 7.34 (m, 1H), 4.28, (m, 1H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.C(Cl)(Cl)Cl>CN(C)C=O>[Cl:23][C:20]1[N:19]=[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(Cl)nc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-Methoxythiophenol (0.927 ml; 7.55 mmol) and 1.14 g (8.26 mmol) of potassium carbonate were added, at room temperature, to a solution (70 ml) of 1.70 g (6.86 mmol) of the resulting ester compound in N,N-dimethylformamide followed by stirring for 1 hour. Chloroform was added to the reaction solution followed by washing with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, drying and concentrating in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 743 mg (yield: 31%) of tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate as a colorless oily substance.