Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C:6](=O)[CH3:7].[CH2:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>>[CH3:7][C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]#[N:18]
Reactant: N#CCc1ccccc1
Reactant: CC(=O)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCCC(C)=C(C#N)c1ccccc1
Yield: 23.9 %

Procedure:
To the mixture of 6-methyl-hept-5-en-2-one (90.86 g, 0.72 mol) and benzyl cyanide (46.8 g, 0.40 mol) is added dropwise a 4 N solution of KOH in MeOH (25.0 ml, 0.10 mol). The resulting suspension is heated to reflux during 4.5 h. Then methanol is removed by distillation and the residue is washed with 6 N aq. HCl-solution, then water, sat. aq. NaHCO3-solution and brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled twice over a Widmer column to yield 3,7-Dimethyl-2-phenyl-octa-2,6-diene nitrile (21.5 g, 24%, (E/Z) mixture) as a colourless oil (b.p. 122DC/0.1 mbar).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>FC(F)(F)C(O)=O.O>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Dibenzofuran (30 g, 178 mmol) was dissolved in 276 ml, trifluoroacetic acid (TFA) and cooled in ice water bath. Fuming nitric acid 15 g (˜17 mL) was diluted with 3 mL water and then dissolved in 25 mL TFA and added to dibenzofuran solution drop wise. Reaction takes place almost instantly and a thick light green color precipitate forms. At the end of addition, flask was stirred for 20 minutes more and then poured over ice. Light green precipitate was then filtered off, washed with 2 M NaOH, dried and recrystallized from boiling ethanol 30 g (76%) of product was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[CH3:16][NH:17][C:10]([N:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[CH:3]=2)[CH2:7]1)=[O:11]
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: -78 °C
Reaction time: 17 h
Yield: 18.2 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 2.4 g (0.03 mole) of 40% aqueous monomethylamine and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water. The reddish oil residue was cooled to -78° C. whereupon it crystallized (4.28 g). Recrystallization from benzene-ligroin gave 400 mg of fine white crystals, m.p. 143°-144° C. Addition of more ligroin yielded an additional 800 mg of "cream" colored crystalline product, m.p. 138°-142° C. The two fractions were combined and recrystallized from ethanol-isopropyl ether, yielding 600 mg (27.3%) of fine white crystals, m.p. 143°-144° C.
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=O)[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[CH3:14])[NH2:10]>C1C=CC=CC=1>[CH:3]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:7]([CH3:6])[CH:8]=1)([CH2:1][CH3:2])[CH3:5]
Reactant: CCC(C)=O
Reactant: Cc1ccc(N)cc1C
Solvent: c1ccccc1
Product: CCC(C)Nc1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Molecular sieves (Type 5A, 300 gm.) are added to 79.2 g. (1.0 mole) of methyl ethyl ketone and 121.0 g. (1.0 mole) of 3,4-dimethylaniline in 1 liter of dry benzene solvent. The reaction mixture is stirred at room temperature for 16 hours. The mixture is then filtered from the molecular sieves which are washed with dry benzene. The benzene solutions are combined and evaporated in vacuo leaving 198 g. (100%) of the desired product. The product is sensitive to hydrolysis and is therefore reduced immediately in a Parr hydrogenator using a 5% palladium on carbon catalyst to give N-sec-butyl-3,4-xylidine.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH2:1]([Sn:5]([C:2]#[C:1][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17][CH2:18][CH3:19])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1CCOC1
Product: CCCC[Sn](C#C[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC

Procedure:
In synthetic route `C1` of FIG. 1, an alternate two step process for preparing BFPE consistant with the route in Sutherlin et al., Macromolecules, v.19, p.1260-1265 (1986) is shown. The first step is coupling commercially available tri-n-butyltin chloride (Aldrich Chemicals, Milwaukee, Wis.) with lithium acetylide ethylenediamine complex. These precursors are heated to reflux in anhydrous tetrahydrofuran (THF) under an argon blanket to form bis(tri-n-butylstannyl)ethyne. The THF solution of bis(tri-n-butylstannyl)ethyne is subsequently washed and then dried over anhydrous sodium sulfate.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:12]1.C[Mg]Br.C1(C)C=CC=CC=1>[Cu]Cl.O>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: C1CCOC1
Agent: Cl[Cu]
Agent: C[Mg]Br
Solvent: O
Solvent: Cc1ccccc1
Product: CP(C(C)(C)C)C(C)(C)C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.025 g (0.25 mol (corresponding to 0.5% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, 55 ml (0.055 mol) of a tetrahydrofuran solution of methylmagnesium bromide having a concentration of 1 mol/liter was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 5 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 40 ml of toluene and 40 ml of water were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 750° C. to 810° C. under reduced pressure of 20 Torr were collected. As a result, 7.4 g (purity: 98.7%) of the aimed di-tert-butylmethylphosphine was obtained as an oily substance. The yield was 91.1%.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=3)[C:22]([OH:24])=O)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>CN(C=O)C>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=3)[C:22]([N:70]3[CH2:69][CH2:68][N:67]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:72][CH2:71]3)=[O:24])=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cncc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cncc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Reaction time: 0.03 h

Procedure:
To a solution of 5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid 19 (0.028 mmol) in DMF (1 mL) is added HATU (0.033 mmol) and DIEA (0.084 mmol) at rt. The resulting mixture is stirred for 2 min then N-boc-piperazine (0.03 mmol) is added. The reaction mixture is stirred at it for 12 h and directly purified by preparative LCMS to give tert-butyl 4-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinoyl)piperazine-1-carboxylate. The residue is treated with TFA (1 mL) at rt for 1 h, concentrated under vacuum, and directly purified by preparative LCMS to afford (5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)pyridin-3-yl)(piperazin-1-yl)methanone B3. NMR (400 MHz, d3-CH3CN) δ 9.32 (bs, 1H), 8.86 (s, 2H), 8.67 (bs, 1H), 8.41 (bs, 1H), 7.75 (d, J=12.0 Hz, 2H), 7.33 (d, J=12.0 Hz, 2H), 6.87 (t, J=73 Hz, 1H), 4.20 (bs, 4H), 3.30 (bs, 4H). MS (m/z) (M+1)+: 427.1.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[SH:5](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[O:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:4](=[S:24])[NH:3]1.[OH-].[Na+].Cl>O>[O:1]=[C:2]1[CH:6]=[SH:5](=[C:7]([CH3:23])[CH:8]=[CH:9][C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])[C:4](=[S:24])[NH:3]1
Reactant: CCOC(=O)COc1ccccc1C=CC(C)=[SH]1=CC(=O)NC1=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C=Cc1ccccc1OCC(=O)O)=[SH]1=CC(=O)NC1=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 0.85 g of ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetate, 5 ml of water and 1 ml of 5% sodium hydroxide solution was stirred at room temperature for one hour. 10% hydrochloric acid was added to the mixture and the precipitated crystals were collected by filtration and washed with methanol to give 2-[3-(4-oxo-2thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetic acid in the yield of 76%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3C)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
Methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (for a preparation see Example 173) (25 mg, 0.058 mmol) was dissolved in ethanol (1 mL) and treated with sodium hydroxide (1M in water, 0.291 mL, 0.291 mmol) and the resulting mixture was stirred at room temperature for 4 h then was concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave 4-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoic acid (2 mg, 8%) as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1)[CH3:21]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CNC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN(C)C)cc2s1

Procedure:
The title compound (24 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess dimethylamine. MS (m/z, ES+): 288.1 (M+1, 20%), 243.1 (M−(CH3)2N, 100%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:24](CC=C)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[S:14]2)[C@H:10]1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:23])[C:19]([F:20])([F:22])[F:21])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[S:14]2)[C@H:10]1[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(O)C(F)(F)F)O[C@@H]2S1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)(C)OC(=O)NC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(O)C(F)(F)F)O[C@@H]2S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 141 (1.6 g, 2.6 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (760 mg, 0.6 mmol), triethylamine (664 mg, 6.5 mmol) and formic acid (242 mg, 5.2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 60° C. for 20 minutes, and followed by addition of additional formic acid (605 mg, 26 mmol). After stirred overnight at 60° C., removal of volatiles gave a residue, which was dissolved into dichloromethane (50 mL) and neutralized with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography with 20%-30% ethyl acetate in petroleum ether to afford 142 as colorless oil (1.1 g, 77%). (ES, m/z): [M+H]+ 569.0; 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 10H), 6.17-6.13 (m, 1H), 4.62-4.46 (m, 2H), 4.43-4.00 (m, 4H), 3.91-3.73 (m, 3H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:33]3[CH:32]=[N:31][C:30]([O:29][CH3:28])=[N:35][CH:34]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)cn1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
Similarly to Example 56, a mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (148 mg, 0.374 mmol), 2-methoxy-5-pyrimidinylboronic acid (211 mg, 1.52 mmol), PdCl2(dppf) (40 mg, 0.05 mmol) and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 24 hrs. After cooling to room temperature, the mixture was diluted with H2O, and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4), and the solvents were removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), followed by recrystallization from CH2Cl2/MeOH/i-Pr2O gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-2′-methoxy-4,5′-bipyrimidine (61 mg, 35%): mp 238-241° C.; 1H NMR (CDCl3) δ 9.18 (s, 2H), 7.91 (d, J=8.1 Hz, 1H), 7.49 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.77 (s, 1H), 4.13 (s, 3H), 4.07 (s, 3H), 3.88 (dd, J=5.6, 3.7 Hz, 4H), 3.82 (m, 4H); Anal. Calcd. for C22H21F2N7O3: C, 56.3; H, 4.5; N, 20.9. Found: C, 56.1; H, 4.3; N, 20.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=C(O)C=C2C=1C(C)=C(CC1C=CC(Cl)=CC=1)C(C)=N2>CO>[Cl:8][C:6]1[CH:5]=[C:4]([OH:9])[C:3]2[C:17]([CH3:18])=[C:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)[C:20]([CH3:21])=[N:1][C:2]=2[CH:7]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Nc1cc(O)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc2cc(O)cc(Cl)c2c(C)c1Cc1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: Cc1nc2cc(Cl)cc(O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-5-chlorophenol (0.46 g), 3-(4-chlorobenzyl)pentane-2,4-dione (0.72 g), and p-toluenesulfonic acid monohydrate (0.26 g) was heated at 160° C. for 2 hours. The mixture was cooled to room temperature, diluted with methanol (5.0 mL) and sonicated. The resulting precipitate was collected by filtration, washed with methanol and dried to afford a 50:50 mixture of title compound and 5-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-7-ol as an off-white solid, 0.67 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 122.9 %

Procedure:
A mixture of 2-chloronitrobenzene (9.5 g, 60 mmol), 2-t-butyl phenol (9.04 g, 60.2 mmol) and potassium carbonate (10.6 g) in DMF was heated at 130° C. for 6 days. The reaction was cooled to rt and partitioned between diethyl ether (400 mL) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ether (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 1-tert-butyl-2-(2-nitrophenoxy)benzene (20 g). (M+H)+=216.23.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33][CH2:32]2>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH2:27][C@@H:23]5[CH2:24][CH2:25][CH2:26][O:22]5)[CH:30]=4)[C:35]3=[O:34])=[CH:15][C:14]=2[F:20])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1

Procedure:
[(R)-1-(4-Amino-2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was reacted with 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochroman-1-one by method AC. The product with the molecular weight of 525.63 (C29H36FN3O5) was obtained in this way; MS (ESI): 526 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1)=[O:6]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ccccn2)c(F)cc1Cl
Product: N#Cc1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 99 using 2-chloro-4-fluoro-5-(pyridin-2-yl)benzoic acid (Preparation 22) and 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53). The residue was purified using silica gel column chromatography eluting with 10% MeOH in EtOAc followed by a second chromatography eluting with 50% EtOAc in heptanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[C:11]([C:37]([C:36]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=3)=[O:38])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (10f) (6.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min. 3,4,5-Trimethoxybenzoyl chloride (7.2 mmol) was added at −78° C. and stirred for overnight. The reaction mixture was diluted with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 4:1) to give a white solid. Yield: 36.8%; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J=7.5 Hz, 2H), 7.77 (t, J=7.5 Hz, 1H), 7.62 (t, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.37 (s, 2H). MS (ESI): calculated for C25H21ClN2O6S, 512.1. found 513.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:19]([CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) and DMF (100 mL). The solution was cooled to 0° C. using an ice bath. NaH (60% dispersion in mineral oil, 2.54 g, 63.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (7.62 g, 63.5 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and water (900 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 66% yield (8.00 g) of 102a as an off-white solid: mp 65-67° C.; 1H NMR (300 MHz, CDCl3) d 7.72 (d, 1H, J=8.1), 7.44 (m, 3H), 7.25 (m, 1H), 5.62 (s, 2H), 4.42 (q, 2H, J=7.2 Hz), 1.43 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 229.1 (M+H).