Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH2:17][CH2:18][Br:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1>[BrH:19].[C:11]1([CH2:17][CH2:18][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]([CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[NH:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: BrCCc1ccccc1
Solvent: Cc1ccccc1C
Product: Br
Product: N=c1n(CCc2ccccc2)c2ccccc2n1CCc1ccccc1
Yield: 32.2 %

Procedure:
A mixture of 13.3 g of 2-aminobenzimidazole, 18.5 g of 2-phenylethyl bromide, and 300 ml of xylene is heated as in Example 1. Subsequently, the solution is concentrated to dryness, the residue is dissolved in boiling acetonitrile, and clarified by filtration. The crystalline product that separates in the cooled filtrate is filtered to give 6.8 g of 1,3-dihydro-1,3-bis(2-phenylethyl)-2H-benzimidazol-2-imine hydrobromide, m.p. 259°-260°.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][Si:13]([C:16]#[C:17][Si](C)(C)C)([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCC(=O)C#C[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To 500 ml of CH2Cl2 was added 53 ml (294 mmol) of nonanoyl chloride and 50 g (293.4 mmol) of bis(trimethylsilyl)acetylene. The reaction mixture was cooled in an ice bath and 40 g (300 mmol) of AlCl3 was added portionwise with stirring over 1/2 hour. After stirring for an additional hour the reaction mixture was quenched with ice. Water was added to the reaction mixture and it was extracted 3× with 200 ml aliquots of diethyl ether. The combined extracts were washed 2× with 50 ml aliquots of saturated NaHCO3, 1 × with brine, and then dried (MgSO4). The solvent was removed in vacuo to give a brown oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: CCCCCCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Agent: O=C(O)c1cc(O)ccc1O
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
11.5 g of 3-chloro-6-octanoyl-5,6,7,8-tetrahydropyrido(4,3-c]pyridazine, dissolved in 50 cc of dioxane, and 30 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 16 hours, and the mixture is worked up as described in Example 17. The gentisinate of the title compound has a M.P. of 164°-166° (decomp., from methanol).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3](I)[CH:2]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>>[CH3:19][Si:18]([C:16]#[C:17][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[CH:1][CH:2]=1)([CH3:21])[CH3:20]
Reactant: Ic1ccc(Cc2ccc(I)cc2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
In Step II of FIG. 1, 4,4'-diiododiphenylmethane [Compound (2)] was then coupled with ethynyltrimethylsilane [Compound (3)] to form an end-protected bis(4-trimethylsilylethynylphenyl)methane [Compound (4)] by forming a solution comprising 8.40 g (20.0 mmoles) of 4,4'-diiododiphenylmethane and 2.50 g (25.5 mmoles) of ethynyltrimethylsilane in 150 ml of 2:1 triethylamine toluene deaerated with argon. This solution was subsequently treated with a catalyst mixture comprising 50 mg of dichlorobis(triphenylphosphine)palladium[II], 150 mg of triphenylphosphine and 50 mg of copper[I] iodide. The yellow solution thus obtained was stirred and warmed to 80°-90° C. over 1 hour and kept in this temperature range for 4 hours. A copious white precipitate was formed which was filtered off after cooling to 25° C. and diluting with 150 ml of ether. The yield of triethylamine hydroiodide [Compound (5)] was quantitative. The filtrate was concentrated to a thick oil, dissolved in 200 ml of ether and washed with 200 ml each of 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water again. The ethereal phase was dried over magnesium sulfate and concentrated to an oil which crystallized on standing. The solid was taken up in 100 ml of 1:1 hexane/dichloromethane and filtered through a bed of silica gel. The filtrate was evaporated down to half of the original volume and cooled at -78° C. to precipitate 7.20 g (20.0 mmoles; 100%) of a crystalline solid. Recrystallization from hexane yielded pure, lustrous crystals in 81% recovery: mp 110°-111° C.; IR(KBr) 2790 (strong, sharp, SiCH3), 2160 (strong, sharp, C≡C), 1505 (strong, sharp, C=C), 1250 (strong, sharp, SiCH3) and 840 cm-1 (very strong, broad, Si-C bending); NMR(CDCl3) δ 0.28 (s, 18H, SiCH3), 3.92 (s, 2H, CH2), 7.37 and 7.40 ppm (q, 8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1O.[C:13]1(=[O:19])[O:18][C:16](=[O:17])C=C1.ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1.[C:35](OCC)(=[O:37])[CH3:36]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]3[CH2:36][C:35](=[O:37])[CH:5]([CH:6]4[C:16](=[O:17])[O:18][C:13](=[O:19])[CH:7]43)[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C1C=CC(=O)O1
Reactant: Oc1ccc2ccccc2c1O
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C1CC2c3ccc(O)cc3C1C1C(=O)OC(=O)C21
Temperature: 90 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of dihydroxynaphthalene (500 g, 3.125 mol) and maleic anhydride (765 g, 7.815 mol, 2.5 eq) in 1 L 1:1 1,2-dichlorobenzene:toluene were heated at 110° C. for 3 days. The reaction mixture was then cooled to 90° C., 1.5 L ethyl acetate added, and then further cooled to room temperature overnight. The mixture was then cooled over ice after another 0.5 L ethyl acetate was added and left stirring for 2 hours. The resultant solid was isolated by filtration, washed with 2×200 mL cold ethyl acetate and dried in oven at 40° C. to provide 130 g of the anhydride as a beige solid (16% yield). 1H NMR (acetone-d6) 7.33 (d, J=8.2 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.85 (dd, J=8.1, 2.4 Hz, 4.05 (d, J=3.9 Hz, 1H), 3.98 (dd, J=6.0, 2.9 Hz, 1H), 3.88 (dd, J=10.2, 3.9 Hz, 1H), 3.70 (dd, J=10.2, 2.7 Hz, 1H), 2.39 (br s, 2H). HRMS for MH+259.0600 (theoretical 259.0606).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][C:24]([F:23])([F:34])[F:35])[CH:27]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (495 mg) in DMF (5 mL) was added potassium carbonate powder (763 mg) and 3-(trifluoromethoxy)benzyl bromide (1.41 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([C:32]#[N:33])[CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([C:32]#[N:33])=[CH:24][C:23]=4[F:22])[CH:28]=[CH:29]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: N#Cc1cc(F)c2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C#N)cc(F)c43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 7-fluoro-1H-indole-5-carbonitrile (0.085 g, 44%),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][C:43]=1B(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][C:42]=3[C:41]([F:52])([F:51])[F:40])=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: OB(O)c1cnccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4cnccc4C(F)(F)F)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 4-trifluoromethylpyridine-3-boronic acid (61 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(4-trifluoromethyl-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert butoxycarbonylamino-propionic acid
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[N+:2]=[N-:3].[H-].[Na+].I[CH3:22]>O1CCCC1.O.C(OCC)(=O)C>[N:1]([CH2:4][C:5]1([O:18][CH3:22])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC1(CN=[N+]=[N-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 256 (0.123 g) in tetrahydrofuran (1.5 mL) was added sodium hydride (0.057 g) and iodomethane (0.089 mL) at room temperature. The mixture was stirred at room temperature overnight and then diluted with water and ethyl acetate. The organic layer was dried, evaporated in vacuo and purified by column chromatography on silica gel (5% methanol in dichloromethane) to obtain the title compound (0.071 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[O:11][CH2:6][C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a suspension of 4-chloro-2-hydroxybenzoic acid (10.0 g, 57.9 mmol) and K2CO3 (20.8 g, 151 mmol) in DMF (115 mL) is added benzyl bromide (14.5 mL, 122 mmol) and the mixture is stirred at 85° C. for 7 h. The mixture is allowed to cool to RT and is partitioned between EtOAc and 1N HCl. The organic phase is washed with 1N HCl and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC(C)([O-])C.[Na+:30].CC(C)=O>C(C(C)=O)C(C)C.CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:30]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)C
Solvent: CC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of esomeprazole (4.7 g, 13.6 mmol; 2.3% sulfone, 2.3% R-enantiomer) in methyl isobutyl ketone (30 mL) and methanol (2.1 mL) was cooled to 15° C. Sodium tert-butoxide (1.33 g, 13.8 mmol) was added in 5 min and the mixture stirred for 15 min. To the resulting solution, acetone (30 mL) was added slowly over 15 min and a solid started to crystallize. The mixture was heated to 25° C. and methyl tert-butyl ether (7.5 mL) was added dropwise. The slurry was stirred overnight. The solid was collected by filtration, rinsed with acetone (2×5 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 3.2 g (65%). Sulfone content: 0.26%. R-enantiomer content: 0.01%
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35][OH:36])[CH:12]=2)[N:7]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:36][CH2:35][C:28]1[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=1[C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH2:5])[N:15]=[C:14]2[C:16]([N:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)=[O:17])(=[O:3])[CH3:2]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
27 μl of acetyl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.[F-].[Cs+].Br[C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(COC)[O:32]C.CO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:15][C:12]1[N:13]=[CH:14][C:9]([O:32][C:20]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: COCCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)c1ccc(F)cc1Oc1ccc(N)nc1
Temperature: 80 °C

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.039 g), CsF (1.956 g), bis(triphenylphosphine)palladium(II) dichloride (0.301 g), and methyl 2-bromo-4-fluorobenzoate (1.0 g) in 50 mL dimethoxyethane-methanol (1:1) was heated at 80° C. for 2.5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, ad concentrated. The residue was chromatographed on silica gel with 25-80% ethyl acetate in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:23])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:33](=[O:35])[CH3:34])=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}methanamine (0.2 g) and triethylamine (0.08 g) in tetrahydrofuran (5 mL), acetyl chloride (0.05 g) was added dropwise and the mixture was stirred for one hour at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide (0.05 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[CH2:7][C:8]#N.[OH-:25].[Na+].[OH2:27]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[CH2:7][C:8]([OH:27])=[O:25]
Reactant: [OH-]
Reactant: O
Reactant: COc1cccc(Cn2c(-c3ccccc3)nc(Cl)c2CC#N)c1
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)c1

Procedure:
1.7 g of 4-chloro-1-(3-methoxybenzyl)-2-phenyl-5-cyanomethylimidazole was boiled in a mixed solution of 20 ml of ethanol and 10 ml of 1 N-sodium hydroxide for 10 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of water. After washing with 50 ml of chloroform, 10 ml of 1 N-hydrochloric acid was added to the water layer, resulting in the precipitate deposited. The precipitate was dissolved in 20 ml of 90% ethanol, and water was added little by little, thus yielding 1.3 g of 4-chloro-1-(3-methoxybenzyl)-2-phenylimidazole-5-acetic acid as colorless, needle-formed crystals, m.p. 135°-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]=[C:8]([CH3:11])[O:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].C(N(CC)C1C=CC=CC=1)C.[C:25](Cl)(=[O:28])[O:26][CH3:27]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:5]1[C:6]2[O:7][C:8]([CH3:11])=[CH:9][C:10]=2[C:2]([NH:1][C:25]([O:26][CH3:27])=[O:28])=[C:3]([F:13])[CH:4]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc2c(N)c(F)cc(Cl)c2o1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Nc1c(F)cc(Cl)c2oc(C)cc12
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of 4-amino-7-chloro-5-fluoro-2-methylbenzo[b]furan (3.4 g) and N,N-diethylaniline (2.6 g) was dissolved in tetrahydrofuran (20 ml), and methyl chlorocarbonate (1.6 g) was dropwise added thereto at room temperature. The resultant mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with 10% hydrochloric acid. After removal of N,N-diethylaniline, the reaction mixture was dried and concentrated. The residue was washed with hexane to give 7-chloro-5-fluoro-4-methoxycarbonylamino-2-methylbenzo[b]furan (3.8 g; yield, 87%). m.p., 168°-169° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:12]([CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:8]2)[CH3:13])=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCN(C2CCCCC2)C1
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)C1CCN(C2CCCCC2)C1
Reaction time: 2 h

Procedure:
4-Nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was prepared from 15 g. (0.085 mole) of 1-cyclohexyl-3-methylaminopyrrolidine and 15 g. (0.08 mole) p-nitrobenzoyl chloride. The 4-nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was converted to the fumarate salt (8.4 g., 24%) by precipitation with fumaric acid from isopropanol-isopropyl ether. The fumarate salt was dissolved in 95% ethanol and hydrogenated at three atmospheres of hydrogen over Raney Nickel for about 2 hours. The mixture was filtered, the filtrate concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried and concentrated and the residue treated wit hexamic acid in isopropanol-isopropyl ether. Recrystallization from the same solvent gave 5.2 g. (13.5% overall) of the salt melting 196°-199°C.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[C:19](S(C)(=O)=O)[N:18]=1>CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[NH2:16][C:17]1[N:18]=[C:19]([N:13]2[CH2:14][CH2:15][CH:11]([C:9]([NH:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12]2)[CH:20]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([NH2:32])=[N:28][NH:29]3)=[CH:25][CH:24]=2)[N:22]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: O=C(Nc1ccccc1)C1CCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC(C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 7.5 %

Procedure:
A mixture of N-phenyl-3-pyrrolidinecarboxamide hydrochloride (500 mg, 2.21 mmol), 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.6 mmol) in NMP (3 mL) and Hunig's base (1.5 mL) was heated at 160° C. for 1 hour under microwave conditions. The reaction mixture was concentrated and purified by SiO2 chromatography (eluent: 4.5:4.5:1 EtOAc:THF:NH4OH) to afford the title compound (50 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 2.05 (m, 2H), 3.30 (m, 1H), 3.4-3.7 (m, 4H), 5.36 (s, 2H), 6.03 (s, 2H), 6.31 (s, 1H), 7.03 (m, 1H), 7.31 (m, 2H), 7.57-7.74 (m, 4H), 7.94 (s, 1H), 10.10 (s, 1H), 11.49 (s, 1H).