Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)CC)C>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Temperature: 110 °C

Procedure:
The mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine L (30 mg, 0.08 mmol), trans-1,4-cyclohexanediamine (49 mg, 0.43 mmol) and triethylamine (26 mg, 0.25 mmol) in 1.5 ml DMSO was heated in a reaction vesel at 110° C. in an oil bath for 16 h. Formation of desired product was confirmed by LC/MS. The reaction mixture solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Crude compound was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 444.2/446.2 (MH+), retention time=0.54 min.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC[O:30][CH2:31][CH2:32]Br.C(Cl)(Cl)Cl>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH2:32][CH2:31][OH:30])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCOCCBr
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OCCOc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) is suspended in DMF (5 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmol) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-methoxymethoxyethyl bromide (0.32 g, 2.0 mmol) under ice-cooling, and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added chloroform (100 ml), and the mixture is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (20 ml) and a 35% aqueous hydrochloric acid solution (2 ml), and the mixture is stirred at 60° C. for 30 minutes. The pH value of the reaction solution is adjusted to pH 10 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform (50 ml×2), washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.17 g), m.p. 129-132° C. (recrystallized from ethanol/isopropyl ether).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[N:11]([C:12]3[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=3[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[O:15])[CH:10]=[N:9][N:8]=2)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.[Cl:33]N1C(=O)C2=CC=CC=C2C1=O>>[Cl:33][C:10]1[N:11]([C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[O:15])[C:7]([CH2:6][N:5]2[C:4](=[O:27])[C:3]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]3[C:1]2=[O:32])=[N:8][N:9]=1
Reactant: O=C1c2ccccc2C(=O)N1Cl
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1Cl)c1ccccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with N-chlorophthalimide to form 2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2].[CH3:32][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (5.0 g, 11.7 mmol) was initially charged in absolute THF (500 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (13.5 ml, 13.5 mmol, 1.15 eq.) was added at −78° C. After 30 min of stirring, iodomethane (8.30 g, 58.5 mmol; 5 eq.) in THF was added, and the mixture was stirred with gradual warming from −78° C. to RT for 16 h. The reaction mixture was then concentrated under reduced pressure, and initially 1N hydrochloric acid (14.0 ml), and then MTBE (500 ml) were added. The organic phase was washed successively with water (2×), saturated sodium bicarbonate solution, saturated ammonium chloride solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (4.3 g, 83% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Br[C:34]1[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([C:34]2[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]3[S:40][CH:41]=[CH:42][N:43]=3)=[CH:37][CH:38]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.44 g, 13.9 mmol) synthesized in Example (1e) and t-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (5.21 g, 15.8 mmol) synthesized in Example (1g) were dissolved in a mixed solvent of 1,4-dioxane (200 mL) and water (50 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (564 mg, 0.691 mmol) and potassium carbonate (9.67 g, 70.0 mmol) were added, followed by stirring at 50° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (7.12 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)[CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.CC(=CC)C>O.CC(O)(C)C>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C@@H:19]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:1])=[O:32])=[CH:33][CH:34]=3)[CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=O)cc2)cc1OC1CCCC1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(=O)O)cc2)cc1OC1CCCC1
Yield: 101.8 %

Procedure:
A solution of NaClO2 (149 mg, 1.64 mmol) and NaH2PO4 ·H2O (227 mg, 1.64 mmol) in water (1 mL) was added to a solution of aldehyde from Step 3 (508 mg, 1.27 mmol) and 2-methyl-2-butene (0.94 mL, 8.9 mmol) in t-BuOH (6 mL). The reaction mixture was stirred at room temperature for 19 hours before 25% aqueous NH4OAc was added. The mixture was then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford the title compound as a white solid (540 mg). 1H NMR (400 MHz, CDCl3): δ 1.55 (m, 2H), 1.75 (m, 6H), 3.35 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.00 (d, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.45 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([NH2:15])=[N:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](O)(=O)[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[N:15]=[C:30]([CH3:31])[O:14][N:13]=2)[CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NC(=NO)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc(OCc3ccccc3)c(OCc3ccccc3)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3,4-bis-benzyloxy-N′-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) in dimethylformamide (5 mL) at room temperature was added 1,1-carbonyldiimidazole (0.494 g, 3.048 mmol) in one portion and the mixture was stirred at room temperature for ninety minutes. Thereupon, acetic acid (0.184 g, 3.067 mmol) was added dropwise and the mixture was allowed to stir for two hours at room temperature, then at 155° C. for three hours. The mixture was allowed to cool to room temperature, and poured onto ice-water (100 mL). Brine (10 mL) was added and the resulting precipitate was removed by filtration, washed with water and dried in air. The solid was then dissolved in dichloromethane (20 mL) and a spatula tip of activated charcoal was added. After stirring for twenty minutes, the suspension was filtered through celite and the filtrate was evaporated to leave a yellow oil that solidified on standing. After recrystallisation from dichloromethane/petroleum ether, 3-(3,4-bis-benzyloxy-5-nitrophenyl)-5-methyl-[1,2,4]oxadiazole was obtained as a pale yellow solid (0.537 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=3)[O:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: Oc1ccc(COCCn2ccnn2)c(F)c1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 201 mg (0.847 mmol) 3-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethoxylmethyl)-phenol in 5 ml dimethylformamide was treated with 22.5 mg ( 0.890 mmol) 95% sodium hydride and stirred at room temperature for 20 min, then 257 mg (0.847 mmol) 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued for 14 h. After addition of water, the precipitate was isolated, washed thoroughly with water, twice with ether and dried to give 1-[2-(2-fluoro-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
To a mixture of phenylsulfonamide (0.16 mol; 25.12 g) and potassium carbonate (0.2 mol; 27.6 g) in 500 mL dioxane is added dropwise 2,4-dichlorobenzoyl chloride (0.13 mole; 18.0 mL). The mixture is warmed to reflux under nitrogen for 16 hr. The reaction is then diluted with water (500 mL), neutralized to pH 5 with concentrated hydrochloric acid, and extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to a white solid. The solid residue is subjected to silica gel chromatography, eluting with dichloromethane containing from 0–5% methanol. Fractions containing the product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:21]=1[NH2:22].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][C:25]([I:27])=[CH:26][C:20]=1[F:19])[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: Nc1ccc(I)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)Nc1ccc(I)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (1.1 g, 4.06 mmol) and 2-fluoro-4-iodoaniline (800 mg, 3.38 mmol) in pyridine (15 mL) at −10° C. was slowly added phosphorus oxychloride (0.35 mL, 3.72 mmol) under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at −10° C. After removal of the solvent and the excess reagent by rotary evaporator, ice water was added. The mixture was extracted with dichloromethane and the organic layer washed with 1 M aqueous citric acid, brine, saturated aqueous sodium carbonate, brine and dried over sodium sulfate. The solvents were removed to give [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-thiophen-2-yl-ethyl]-carbamic acid tert-butyl ester as a yellow viscous oil for use in the next step (1.52 g, 92%).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:5]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCC1
Yield: 56.2 %

Procedure:
Cyclobutanecarbonyl chloride (2.37 g, 20 mmols) was added to a chloroform (30 ml) solution of benzyl alcohol (2.16 g, 20 mmols) and triethylamine (2.2 g, 22 mmols) with cooling with ice, and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ether. The organic layer was washed with 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate and the solvent was evaporated. The resulting oil was purified through silica gel column chromatography (developer:hexane/acetone=10/1) and distilled (110° C./1.2 mmHg) to obtain 2.14 g (yield: 56%) of benzyl cyclobutanecarboxylate as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1nc(Cl)nc2ccccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(O)c2c1

Procedure:
A cooled mixture of 70 ml of concentrated sulfuric acid and 35 ml of concentrated nitric acid was added dropwise to a cooled, stirred solution of 90 g of 2-chloro-4-hydroxyquinazoline [J. Chem. Soc., 1947, p. 775] in 270 ml of concentrated sulfuric acid at a rate such that the temperature remained at 5°-10° C. Stirring was continued until the reaction mixture reached room temperature, whereupon it was poured into crushed ice. The 2-chloro-4-hydroxy-6-nitro-quinazoline thus precipitated is filtered off, washed well with water and used directly in the next step.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.ICC.Cl>C1COCC1>[CH2:2]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCC1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of LDA (100 ml; 2.0 M THF solution) in THF (100 ml) was added dropwise over a period of 20 minutes under cooling with ice, a solution of cyclobutane carboxylic acid (10 g, 0.1 mol) in THF (15 ml) and the mixture was stirred at RT for 2 h. To the mixture iodoethane (15.6 g, 0.1 mol) was added dropwise and the mixture was stirred at RT overnight. To the reaction mixture was added 2N HCl and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine to afford the title compound as a light yellow oil (22.4 g), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
In an oven-dried 250 mL round bottom flask under nitrogen, ((3R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (2.181 mmol) dissolved in diethyl ether (5 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 mmol), 4-(dimethylamino)pyridine (0.218 mmol), and ethanol (4.8 mmol) at room temperature and the mixture was stirred overnight. The resulting white gummy precipitate was diluted with ether (100 mL) and washed with 1M aq sodium hydrogen sulfate solution (100 mL), saturated aq sodium bicarbonate solution (100 mL), and brine (100 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a clear oil (95%). MS(ES)+ m/e 258.1 [M+H]+, 280.0 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=[O:24].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:23]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:24])[CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCOc1cc(Br)ccc1OC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: CCOc1cc(C(O)c2cc(OC)cc(OC)c2)ccc1OC
Yield: 79.7 %

Procedure:
4-bromo-2-ethoxy-1-methoxybenzene (0.66 g, 2.86 mmol), n-butyl lithium (1.14 ml, 2.86 mmol), and 3,5-dimethoxybenzaldehyde (0.43 g, 2.60 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (20% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give (3,5-dimethoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (0.66 g, 80%): 1HNMR (CDCl3) δ 6.92-6.80 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.07 (q, J=6 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 2.19 (d, J=3 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:42]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[NH:44]1[C:48]([C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])=[N:47][CH:46]=[N:45]1>>[CH:52]([O:51][C:49]([C:48]1[N:44]([CH2:42][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]3=[N:34][C:33]=2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:45]=[CH:46][N:47]=1)=[O:50])([CH3:54])[CH3:53]
Reactant: CC(C)OC(=O)c1ncn[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CC(C)OC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and isopropyl 1H-1,2,4-triazole-5-carboxylate. m/e+ 430 for C20H18Cl2N5O2 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.41 (dd, J=0.9, 1.8 Hz, 1H), 8.01 (s, 1H), 7.82 (dd, J=2.1, 6.6 Hz, 2H), 7.64 (dd, J=0.9, 9.3 Hz, 1H), 7.46 (dd, J=2.1, 6.6 Hz, 2H), 7.28 (dd, J=1.8, 9.3 Hz, 1H), 6.21 (s, 2H), 5.38 (m, 1H), 1.50 (d, J=6.0 Hz, 6H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.353, 151.649, 146.894, 144.844, 144.190, 135.015, 132.017, 130.301, 129.199, 127.410, 122.448, 121.573, 118.355, 114.495, 71.973, 44.202, 21.946 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:23](=[O:25])[CH3:24])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.54 g, 2.42 mmol) in DCM (5 ml) at 0° C. was added pyridine (0.23 ml, 2.9 mmol). The reaction mixture was cooled to 0° C. and a solution of acetyl chloride (0.21 ml, 2.9 mmol) in DCM (4 ml) was added drop wise over 5 min. The reaction mixture was stirred at r.t. for 18 hrs, quenched with water (10 ml) and extracted in DCM (2×20 ml). The organic layer was dried over Na2SO4 and concentrated to afford the crude oil (0.64 g) which was used for the next step without purification.