Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 11 h
Yield: 42.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58.1 mg), 2′-hydroxyacetophenone (361 mg), and 4-dimethylaminopyridine (317 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 11 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue. The organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (36 mg, yield 43%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:29]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@H:30]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31](=O)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:13]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.C([BH3-])#[N:60].[Na+]>CO.ClCCl>[CH2:43]([O:42][C@H:30]1[C@H:29]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)[CH:13]=2)[NH:60][CH:31]1[CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CCOc1ccc(Cc2cc(C(=O)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)C(=O)COCc3ccccc3)ccc2Cl)cc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(C3NC(COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A solution of compound from step C (400 mg, 0.5 mmol), 7N ammonia in MeOH (1.0 mL) and freshly activated 4 Å molecular sieves (250 mg) in dichloromethane (20 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, then sodium cyanoborohydride (160 mg, 2.55 mmol) was added and refluxed for additional 2 h. The reaction mixture was filtered, diluted with dichloromethane (20 mL), washed with water, brine, dried (sodium sulfate), and concentrated under reduced pressure. Chromatography on silica gel (50 to 100% acetonitrile containing 0.1% ammonium acetate/water gradient) provided (3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)piperidine (136 mg, 34%).
Reaction SMILES: O[C:2]1([OH:11])[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]1[OH:10].[CH3:12][CH2:13][O:14]CC.C(#N)C.Cl>[Cl-].[Zn+2].[Cl-].O>[OH:11][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:13]([CH3:12])=[O:14]
Reactant: CCOCC
Reactant: OC1=CC(O)(O)C(O)C(O)=C1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1c(O)cc(O)c(O)c1O
Temperature: 0 °C
Reaction time: 13 h
Yield: 31.8 %

Procedure:
Under a stream of argon, 2.00 g (14.08 mmol) of 1,2,3,5-tetrahydroxyphenol (3) and 20 ml of ether were placed to form a suspension and 1.00 g (24.3 mmol, 1.73 equivalents) of acetonitrile was added to the suspension. While the resultant mixture was cooled with ice water, 0.70 g (5.14 mmol, 0.36 equivalent) of zinc chloride was added to the mixture and hydrogen chloride gas was bubbled at room temperature for four hours with stirring. The aeration of the mixture with the gas was stopped and the aerated mixture was left standing still at 4° C. for 13 hours. The ether layer was removed by decantation from the tarry precipitates consequently formed. The precipitates were stirred in an ice bath and 60 ml of water was added-to the stirred precipitates and they were heated under reflux for 4 hours. The product of the reflux, after adding a small amount of active carbon, was filtered while kept in hot. From the filtrate, yellow crystals were obtained as precipitates. By dissolving the crystals again in ether, removing the insoluble by filteration, and then concentrating the filtrate, 0.82 g (yield 31.8%) of the product (11) was obtained in the form of yellow platelike crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C[O-].[Na+].Cl[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.Cl>CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1
Reactant: ClCc1c[nH]cn1
Reactant: Cc1cccc(C)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(Cc2c[nH]cn2)cc(C)c1O
Yield: 54 %

Procedure:
To a solution of 12.2 g of 2,6-dimethylphenol in methanol are added 20 ml of 30% sodium methoxide solution, and the resultant mixture is warmed to 50° C. The mixture is maintained at that temperature while 5.8 g of 4-chloromethylimidazole in methanol are added, with stirring. After the addition is complete, the reaction mixture is stirred at 50°-60° C. for about 4 hours, then is cooled and poured into cold water. That mixture is acidified with hydrochloric acid and washed with ethyl acetate. The pH of the aqueous solution is then adjusted to 7-8, and the product is obtained by extraction with ethyl acetate. The desired 4-(3',5'-dimethyl-4'-hydroxybenzyl)imidazole is obtained in 54% yield. The free base is converted to the corresponding hydrochloride salt by treatment with HCl in a mixture of ethyl acetate and isopropanol. That salt melts at 210°-214° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:34]=CC(N)=C[CH:29]=1>>[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:34]=[CH:3][C:1]([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([B:14]3[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:12][CH:13]=2)=[O:6])=[CH:2][CH:29]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CN(C)CCOc1ccc(N)cc1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using 4-(2-(dimethylamino)ethoxy)aniline as the amine component.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:3][CH:18]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=O)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)co2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl (2R)-2-[4-(carbamoylamino)phenyl]propanoate (2.7 g, 9.95 mmol) in dioxane (50 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (1.03 ml, 10 mmol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (50 ml) and washed with a saturated NaHCO3 aqueous solution (3×30 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoate (2.5 g, 7.96 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 10.05 (bs, 1H, NH), 8.30 (s, 1H), 7.45 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=[O:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:25])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(O)cc2)N1CCN1CCOCC1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc(C2CCC(=O)N2CCN2CCOCC2)cc1
Yield: 52.3 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]pyrrolidin-2-one (0.99 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate (0.565 g) was added, the reaction mixture was stirred for 2 days and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, 1% triethylamine/1-10% methanol/ether) and (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to afford 0.62 g (52.3%) of product. Recrystallization from absolute ethanol/ether gave the analytical sample, mp 119°-120° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[C:25]([Cl:27])[N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:37]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[CH:39][CH:38]=1)[C:29]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([C:28]([O:21][CH2:20][C@H:19]2[O:22][C@@H:15]([N:14]3[C:23]4[N:24]=[C:25]([Cl:27])[N:26]=[C:10]([NH:9][C:1](=[O:8])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:11]=4[N:12]=[CH:13]3)[CH2:16][C@@H:17]2[OH:18])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=[CH:44][CH:43]=1
Reactant: O=C(Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)nc(Cl)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
Compound 123 was prepared from compound 122 as per the procedure of example 107 using compound 122 (2.5 g, 6.43 mmol), DMTCl (2.37 g, 7 mmol), dry TEA (0.71 g, 7 mmol) and dry pyridine (100 ml). The crude product was purified by flash chromatography using methylene chloride→ethyl acetate containing 18 TEA as the eluent to give 3 g (68%) of pure 123 as a foam.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH2:21].[H-].[Na+]>O=S(Cl)Cl.C1COCC1>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COc1ccc(Cl)c(N)c1Cl
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(Cl)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
A solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (1.6 g, 7 mmol, 3.0 eq) in SOCl2 (20 mL) was heated at reflux for 3 h. The excess thionyl chloride was removed in vacuo and the residue obtained dissolved in THF (10 mL) and added dropwise to a solution of 2,6-dichloro-3-methoxy-aniline (450 mg, 2.3 mmol, 1.0 eq) and NaH (85 mg, 3.4 mmol, 1.5 eq) in THF (10 mL). The reaction was stirred at room temperature for 2 h then quenched by addition of aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound (200 mg, 21%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH3:25])=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH3:25])=[CH:19][CH:18]=1
Reactant: CNCc1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Agent: BrB(Br)Br
Product: CNCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 28.7 %

Procedure:
Following General Procedure F, 8-methoxy-9-{4-[(methylamino)methyl]phenyl}thieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.29 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.7 mL, 1.7 mmol) to afford the desired product (28 mg, 30%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=8.1 Hz, 2H), 7.55 (d, J=5.4 Hz, 1H), 7.44-7.41 (m, 3H), 7.17 (d, J=8.9 Hz, 1H), 6.05 (d, J=5.4 Hz, 1H), 4.33 (s, 2H), 2.83 (s, 3H); ESI MS m/z 337 [C19H16N2O2S+H]+; HPLC >99% (AUC), tR=10.02 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1.[CH3:41][NH2:42].C1COCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15]([NH:42][CH3:41])[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1
Reactant: CN
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccc(Cl)nn12
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ccc2nc(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)c(Cc3cc(Br)ccc3OC)n2n1
Temperature: 150 °C
Yield: 24 %

Procedure:
A solution of 130 mg (0.2 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl]-6-chloro(imidazolo[1,2-b]pyridazin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in DMSO (3 mL) is treated with 2M methyl amine in THF 1.5 mL (3.0 mmol). The reaction mixture is heated to 150° C. in a sealed tube for 18 hr and following cooling partitioned between ethyl acetate and water. The organic extract is washed with 5×10 mL water, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 31 mg (24%) of the title compound. Mass Spec m/z (M++1) 646.
Reaction SMILES: O.[CH3:2][N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4]1.C(=O)([O-])O.[Na+].[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33](ON1C(=O)CCC1=O)=[O:34])#[N:24]>O1CCOCC1>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]([CH3:2])[CH:4]=1)=[O:34])#[N:24]
Reactant: N#Cc1ccccc1C=CC(=O)ON1C(=O)CCC1=O
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2C#N)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To water (60 mL)-dioxane (60 mL) suspension of 1-methyl-L-tryptophan (2.1 g) was added sodium hydrogencarbonate (0.8 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Dioxane (80 mL) solution of 2,5-dioxopyrrolidin-1-yl 3-(2-cyanophenyl)acrylate (2.5 g, 9.2 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, water was added thereto, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with a 10% aqueous citric acid solution, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (0.96 g, 27%) as an amorphous solid product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[O:21][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: Cc1cccc(C)c1O
Reactant: COc1ccc(C=O)cc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C=O)cc1COc1c(C)cccc1C
Yield: 91.1 %

Procedure:
To a solution of 3-(chloromethyl)-4-methoxybenzaldehyde (300 mg, 1.625 mmol, 1.0 equivalent) and 2,6-dimethylphenol (218 mg, 1.787 mmol, 1.1 equivalent) in 10 ml acetonitrile was added potassium carbonate (1.1 g, 8.12 mmol, 5.0 equivalents). The mixture was heated to 150 C in a microwave for 30 min. Upon completion, the mixture was filtered and dried down to give 3-[(2,6-dimethylphenoxy)methyl]-4-methoxybenzaldehyde (400 mg, 91% yield) as a yellow solid. A portion of which (100 mg, 0.370 mmol, 1.0 equivalent) was taken up in ethanol (4 ml), and to it was added 2-amino-N-(pyridin-3-ylmethyl)benzamide (92 mg, 0.407 mmol, 1.1 equivalent) followed by ytterbium(III) trifluoromethanesulfonate (45.9 mg, 0.074 mmol, 0.2 equivalent). The mixture was heated to 80 C for 2 h. Upon completion, the mixture was dried down and chromatographed on silica gel with 0-30% EtOAc (ethyl acetate)/hexanes gradient elution to give the desired 2-{3-[(2,6-dimethylphenoxy)methyl]-4-methoxyphenyl}-3-(pyridin-3-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one (110 mg, 62.0% yield) as a tan solid. 1H nuclear magnetic resonance (400 MHz, DMSO-d6) δ ppm 8.39-8.45 (m, 2 H), 7.60-7.67 (m, 2 H), 7.48 (d, J=2.35 Hz, 1 H), 7.15-7.35 (m, 4 H), 6.94-7.02 (m, 3 H), 6.84-6.93 (m, 1 H), 6.60-6.69 (m, 2 H), 5.82 (d, J=2.35 Hz, 1 H), 5.07 (d, J=15.65 Hz, 1 H), 4.64 (d, J=2.74 Hz, 2 H), 3.99 (d, J=15.45 Hz, 1 H), 3.73 (s, 3 H), 2.12 (s, 6 H); liquid chromatography mass spectrometry: (electrospray+ve), m/z 480.2 (MH)+ (mass of molecular weight plus 1); HPLC: tR=5.05 min, UV254=100%. High-resolution mass spectroscopy (electrospray ionization): m/z calculated for C30H30N3O3 [M+H]+480.2282, found 480.2291.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: Cc1ccc(Cn2cnc(NC(=O)c3ccc(F)cc3)c2C(N)=O)cc1
Yield: 64 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 2.30 g (9.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 87 and 4-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.26 g of 4-(4-fluorobenzoylamino)-1-(4-methylbenzyl)-5-imidazole carboxamide (yield 64%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:23](=[O:25])[CH2:22][O:21][C:18]1[CH:19]=[N:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Reactant: Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1ccccc1F

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 2-fluoroaniline. Yield: 9 mg.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1C=CN=[CH:27]1)=O.CNC>O1CCCC1>[CH3:24][N:26]([CH3:27])[C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.031 mole), 1,1'-carbonyldiimidazole (6.0 g, 0.037 mole), and dry tetrahydrofuran (200 ml) was stirred at room temperature for 2 hr. with a stream of nitrogen bubbling through it. The suspension was heated at 50° C. under nitrogen for 2 hr, cooled in ice and treated with a solution of dimethylamine in tetrahydrofuran (4.22 g of dimethylamine in 40 ml of tetrahydrofuran.) The solution was stirred at room temperature overnight, more dimethylamine (0.071 mole in 30 ml of tetrahydrofuran) was added, and the reaction mixture was heated at 45° C. for 3 hr. The reaction mixture was concentrated under reduced pressure; the resulting solid was triturated in water, filtered, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and cooled. Water was added and the solid filtered and dried at 80° C. under vacuum to yield 3.55 g (33%) of white solid, mp. 181°-183° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH3:24])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a solution of 0.7 g of 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 10 ml of dimethylformamide was added 0.13 g of sodium hydride. To this was added a mixture of 5.1 g of methyl iodide and 5 ml of dimethylformamide, dropwise under cooling, and immediately the resulting mixture was heated for 1.5 hour in an oil bath maintained at 100° C. After the reaction was complete, the solvent was distilled off under reduced pressure to leave a residue, to which was added ice-cold water. This residue was extracted with ether, washed and dehydrated. Separation and purification were accomplished by passing the solution through a column of alumina, and the eluate obtained was concentrated to give 0.6 g of 1-(m-trifluoromethylphenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 122° - 124° C.