Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([PH:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:31]=[CH2:32])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([P:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[C:23]([CH:31]=[CH2:32])[CH:22]=2)(=[O:17])[O:14][CH2:15][CH3:16])[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=1
Reactant: CCO[PH](=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1cc(P(=O)(OCC)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OC(C)C
Temperature: 70 °C
Yield: 2.8 %

Procedure:
To a degassed solution of ethyl 3,5-bis(trifluoromethyl)-phenylphosphinate (3.33 g, 15.24 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (3.33 mg, 13.8 mmol) in DMF (25 mL) were added the triethylamine (3.85 mL, 27.6 mmol) and tris(dibenzylideneacetone)dipalladium (2.53 g, 2.76 mmol). The mixture was heated in an oil bath at 70° C. overnight. The volatiles were removed in vacuo and the mixture was purified by column chromatography with 20 to 70% ethyl acetate in petroleum ether to afford compound BA3 (185 mg) as an oil in 2.8% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.38 (dd, J=6.1 and 1.4 Hz, 6H) overlapping 1.41 (t, J=7.1 Hz, 3H), 4.11-4.21 (m, 2H), 4.65 (sept., J=6.1 Hz, 1H), 5.33 (dd, J=11.2 Hz and 1.4 Hz, 1H), 5.80 (dd, J=17.9 and 1.2 Hz, 1H), 6.96 (dd, J=8.6 and 3.0 Hz, 1H) overlapping 7.00 (dd, J=18.0 and 11.4 Hz, 1H), 7.63 (ddd, J=11.9, 11.9 and 2.0 Hz, 1H), 7.90 (dd, J=12.7 and 2.1 Hz, 1H), 7.99 (s, 1H), 8.22 (s, 1H), 8.25 (s, 1H); 31P NMR (CDCl3, 161.8 MHz): δ (ppm) 28.59.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14]1[C:27]2[C:18](=[N:19][C:20]3[C:21](=O)[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[C:17](=O)[CH2:16][CH2:15]1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[C:17]1[C:18]2[C:27](=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[N:6][C:5]4[C:7]([CH:11]([CH3:12])[CH3:13])=[CH:8][CH:9]=[CH:10][C:4]=4[CH:1]([CH3:3])[CH3:2])[C:20]=3[N:19]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Product: CC(C)c1cccc(C(C)C)c1N=C1CCCc2cc3c(nc21)C(=Nc1c(C(C)C)cccc1C(C)C)CCC3

Procedure:
was synthesized by methods similar to those in Examples 3 and 4:: 2,6-di-iso-propylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[2,6-di-iso-propylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (4). The complexation of (4) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of the final complex was proved by direct probe GC. Exact mass direct probe calculated for C37H47Cl2FeN3: 659.25. Found: 659.25.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>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].O.O1CCOCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(Cl)c3)nc12
Yield: 32.2 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.430 g, 1.53 mmol), 2-chloropyridine-4-boronic acid (0.362 g, 2.30 mmol), potassium carbonate (0.782 g, 5.66 mmol), Pd(dppf)Cl2.CH2Cl2 (0.098 g, 0.12 mmol), 10 mL dioxane and 2.5 mL water was stirred at 160° C. in a microwave for 30 min. The resulting red mixture was partitioned between 80 mL of ethyl acetate and 150 mL of water. The aqueous layer was extracted with two 80 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->100% EtOAc/hexanes) afforded 0.155 g (32%) of 1-[2-(2-chloro-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a red solid.
Reaction SMILES: [CH:1]([CH:5]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[CH:2][CH2:3][CH3:4].F[B-](F)(F)F.[CH3:18][O+](C)C>>[CH3:18][O:12][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:1]=[CH:2][CH2:3][CH3:4])[N:11]=1
Reactant: C[O+](C)C
Reactant: CCC=CC1CCCCC(=O)N1
Agent: F[B-](F)(F)F
Product: CCC=CC1CCCCC(OC)=N1
Yield: 103.4 %

Procedure:
The product of Example 326 (1.34 g, 8 mmol) was reacted with trimethyloxonium tetrafluoroborate (1.63 g, 11 mmol) by the method of Example 26 to yield 1.5 g (100%) of the title material.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23]([I:30])[CH:22]=1>>[Br:19][C:13]1[C:12]2[C:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([Cl:20])=[CH:22][C:23]=3[I:30])=[C:10]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]3[C:17]=2[CH:16]=[C:15]([F:18])[CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1I
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1I)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (example 7, Step 8) and 4-chloro-2-iodobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(O)c(C)n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 140 °C

Procedure:
2,6-Dimethyl-pyridin-3-ol (3.0 g, 24.35 mmol) and cesium carbonate (15.87 g, 48.71 mmol) were added to a solution of 3,4-difluoronitrobenzene (3.87 g, 24.35 mmol) in DMF (30 ml). The mixture was heated at 140° C. for 2 hours. After cooling to room temperature it was filtered through diatomaceous earth and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 2% methanol/DCM as eluent) to yield intermediate D14 (5.88 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([O:16][C@H:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:34])[CH3:35])=[O:31])[CH2:28][CH2:29]2)[CH3:23])=[N:14][CH:15]=1
Reactant: CC(C)OC(=O)N1CCC([C@@H](C)OS(C)(=O)=O)CC1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cnc(O[C@@H](C)C3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Yield: 45 %

Procedure:
1-Methylethyl 4-[(1S)-1-({5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (0.334 g, 45%) was prepared as a yellow oil from 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.405 g, 1.71 mmol), crude 1-methylethyl 4-{(1R)-1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.70 g, 2.32 mmol) and K2CO3 (0.48 g, 3.43 mmol) in DMF (15 mL) in a manner similar to Example 166, Step 2. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.22 (d, 1H, J=1.3 Hz), 7.85 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.01 (dd, 1H, Ja=12.1 Hz, Jb=1.8 Hz), 5.15-5.05 (m, 1H), 4.89 (septet, 1H, J=6.2 Hz), 4.19 (bs, 2H), 2.80-2.65 (m, 2H), 2.50 (s, 3H), 1.85-1.65 (m, 3H), 1.40-1.15 (m, 11H); LRMS (ESI), m/z 434 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[NH2:26])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(S(N)(=O)=O)c1
Temperature: 92 °C
Yield: 90 %

Procedure:
A mixture of 3A, 3-bromobenzene sulfonamide (0.1 g, 0.4 mmol) in DME (6 mL) and 2.0 M Na2CO3 (0.8 mL) was degassed by bubbling argon for 5 min. To this solution, Pd(PPh3)4 (28 mg, 0.025 mmol) was added. The mixture was heated at 92° C. for 3 h. After cooling to rt, it was extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (hexanes/EtOAc=3/1) to give 3B (293 mg, 90% yield) as a semi-solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9H) 4.88 (s, 2H) 6.23 (m, 1H) 7.36 (m, 1H) 7.47 (t, J=7.69 Hz, 1H) 7.55 (m, 1H) 7.83 (d, J=8.35 Hz, 1H) 7.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O-:15][C:16]#[N:17].[K+].Cl[O-].[Na+]>C(O)(=O)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:11][C:10]1[NH:17][C:16](=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=2)[N:9]=1
Reactant: N#C[O-]
Reactant: CC=NNc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(Cl)c([N+](=O)[O-])c2)c(=O)[nH]1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a stirred mixture of 5.0 g (0.023 mole) of acetaldehyde 4-chloro-3-nitrophenylhydrazone in 50 ml of acetic acid was added dropwise a solution of 1.95 g (0.024 mole) of potassium cyanate in 5 ml of water. The resultant mixture was stirred at 15° C. for 1.5 hour. An additional 0.25 g (0.0031 mole) of potassium cyanate in 2 ml of water was added dropwise. This mixture was stirred for one hour. While maintaining a temperature of 15° C., 42.9 ml of an aqueous, 5% sodium hypochlorite solution was added dropwise. The resultant mixture was stirred at 15° C. for one hour. The solvents were removed by distillation under reduced pressure leaving a solid residue. This solid was stirred in 100 ml of toluene. The solvent was removed by evaporation under reduced pressure leaving a solid residue. The solid residue was dissolved in 150 ml of ethyl acetate. This solution was washed in succession with an aqueous, saturated sodium bicarbonate solution, water, and an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 5.77 g of 4,5-dihydro-3-methyl-1-(4-chloro-3-nitrophenyl)-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:27])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[N:13]=[CH:12][N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:44]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[O:42][N:41]=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:27])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:38](=[O:37])[NH:39][C:40]2[CH:44]=[C:43]([C:45]([CH3:47])([CH3:46])[CH3:48])[O:42][N:41]=2)[C:21]([CH3:26])=[CH:20]3)[N:13]=[CH:12][N:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2[nH]1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl]-methyl-carbamic acid tert-butyl ester (275 mg, 0.712 mmol) in THF (7 mL), NaH (85 mg, 2.13 mmol) is added under nitrogen at 0° C. The resulting mixture is stirred for 2 h. Then (5-tert-butyl-isoxazol-3-yl)-carbamic acid phenyl ester (370 mg, 1.42 mmol) is added to this mixture. The resulting mixture is allowed to warm to rt and stir for 18 h. The mixture is then quenched with saturated aqueous ammonium chloride. The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, dried over anhydrous sodium sulphate, concentrated and purified by FCC (0-70% EtOAc/heptane) to provide the title compound. MS (ESI) m/z 553.1 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:40]1[CH2:42][CH2:41]1)(=O)=O.[CH3:45][O:46][C:47]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)=[O:48].COC(C1C=CC(B(O)O)=CC=1)=O>>[CH:40]1([N:11]2[C:12]3[C:8](=[C:7]([C:51]4[CH:50]=[C:49]([CH:54]=[CH:53][CH:52]=4)[C:47]([O:46][CH3:45])=[O:48])[CH:15]=[C:14]([C:16]([N:18]4[CH2:23][CH2:22][C:21]5([CH2:32][C:31](=[O:33])[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([C:34]7[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=7)[CH:29]=6)[O:24]5)[CH2:20][CH2:19]4)=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:41][CH2:42]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(-c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc3c2ccn3C2CC2)c1

Procedure:
The intended compound was produced according to the procedure described in Example 28-1 but using 1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl trifluoromethanesulfonate and [3-(methoxycarbonyl)phenyl]boronic acid in place of 8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl trifluoromethanesulfonate and [4-(methoxycarbonyl)phenyl]boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:8]=[CH:9][C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH2:13][C:14](OC)=[O:15])[CH:12]=1)[CH3:6])=[O:4]>O>[O:15]=[C:14]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18][C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:3]([O:2][CH3:1])=[O:4])=[CH:12][C:11]=2[CH2:13]1
Reactant: COC(=O)Cc1cc(C(C)C(=O)OC)ccc1Sc1ccccc1
Solvent: O
Product: COC(=O)C(C)c1ccc2c(c1)CC(=O)c1ccccc1S2
Yield: 88.2 %

Procedure:
A mixture of 0.5 g of methyl 5-(1-methoxycarbonylethyl)-2-phenylthiophenylacetate [dicarboxylic acid ester] obtained in Example 1-(3) and 5.3 g of polyphosphoric acid (116%) was stirred at a temperature of 60°-80° C. for 6 hours. The mixture was cooled, and to this was added a mixture of ice and water to decompose excessive polyphosphoric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated and washed successively with saturated brine solution, aqueous saturated sodium hydrogen carbonate solution and saturated brine solution. The washed extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the dried extract under reduced pressure, and then the residue was recrystallized from a mixture of benzene and hexane to obtain 0.4 g of methyl 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionate (yield 89%), m.p. 81.0°-82.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=[N:16]O)[C:7]1=[C:6]2[CH3:18]>C(O)C.[OH-].[Na+].[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[C:7]1=[C:6]2[CH3:18]
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1=NO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c(C)c1n2CCCC1N
Temperature: 40 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
Raney alloy (10.2 g) was added portionwise (over 40 minutes) to a solution of 6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one oxime (6.2 g, 25.4 mmol) in ethanol (200 mL) and 10% aqueous sodium hydroxide (100 mL) at ~35° C. The reaction mixture was stirred at 40° C. for 12 hours, cooled to 25° C., and then poured into icy, saturated brine solution (500 mL). The product was extracted with ether (2×200 mL), and the combined extracts were washed with 5% hydrochloric acid (200 mL). Upon cooling the separated aqueous layer was rendered basic with 50% aqueous sodium hydroxide, and extracted with ether (3×150 mL). The ethereal extracts were dried over MgSO4, filtered, and evaporated to afford 5.8 g (99%) of the title amine as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: Nc1ccc[nH]c1=O
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: O=C(Nc1ccc[nH]c1=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3.3 g. (0.03 mole) of 3-amino-2-pyridone in 75 ml. of pyridine cooled in ice was added portionwise 6.3 g. (0.04 mole) of 2-fluorobenzoyl chloride over 5 minutes. After stirring for 15 hours at ambient temperature, the mixture was poured into ice-water. The resultant precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 3-(2-fluorobenzoylamino)-2-pyridone, m.p. 223° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[C:12]1([CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cc1ccncc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccccc1)c1ccncc1
Yield: 78.7 %

Procedure:
Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78%) was obtained as a crystalline solid: m. p. 101–103° C. Anal. Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:9][C:10]([CH:12]1[CH2:16][C:15](=O)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1)=O)[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([NH:9][CH2:10][CH:12]1[CH2:16][CH2:15][N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13]1)[CH3:8]
Reactant: CCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCC1CCN(Cc2ccccc2)C1
Yield: 88.1 %

Procedure:
To a suspension of 108.8 g (2.86 mole) lithium aluminum hydride in 800 ml tetrahydrofuran, was added a solution of 194.5 g (0.79 mole) of N-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in 600 ml tetrahydrofuran dropwise under nitrogen. The reaction was then refluxed four hours. The reaction flask was cooled in an ice bath and 108 ml of water, 108 ml of 15% sodium hydroxide, and 324 ml of water were added. The precipitated solids were filtered and washed with hot ethanol. The combined filtrates were concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to give 151.9 g of N-ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:38]O)=[NH:37])[CH:34]=2)[N:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:28]=1>CN(C=O)C>[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[N:37]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:38]=3)[CH:34]=2)[N:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:28]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3-Chloro-4-hydroxybenzoic acid (commercial) (240 mg, 1.40 mmol) in dry DMF (8 ml) was treated with EDC (292 mg, 1.52 mmol) and HOBt (208 mg, 1.52 mmol) and stirred for 5 minutes. Added ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (432 mg, 1.40 mmol) and stirred at RT for 30 minutes. The reaction mixture was heated at 80° C. for 7 hours. Added EtOAc (70 ml) and washed with water (70 ml), sat. aq, sodium hydrogen carbonate (70 ml) and water (70 ml). Dried over MgSO4 and evaporated off the solvent. The residue was subjected to chromatography using a biotage (EtOAc/hexane 1:2) to obtain the title compound as 200 mg of white solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 2.91 (2H, t), 4.04 (2H, q), 4.50 (2H, t), 7.67-7.70 (2H, m), 7.75 (1H, s), 7.80-7.81 (2H, m), 7.94 (1H, dd), 8.22-8.25 (1H, m), 10.95 (1H, broad s). MS (ES) C21H1735Cl2N3O4 requires 445; found 446 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[CH:11]2[CH2:12][C:7]3([OH:14])[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[CH2:15]([O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29](F)=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[CH2:15]([O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:14][C:7]34[CH2:12][CH:11]5[CH2:10][CH:9]([CH2:13][CH:5]([CH:4]5[NH2:3])[CH2:6]3)[CH2:8]4)=[C:30]([Cl:33])[CH:31]=2)[CH:26]=[CH:25][N:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NC1C2CC3CC1CC(Oc1cc4ccnc(OCc5ccccc5)c4cc1Cl)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 417 mg, 10.4 mmol, 3 eq.) in dimethyl acetamide (7 mL) was added a solution of 4-amino-adamantan-1-ol (640 mg, 3.82 mmol, 1.1 eq.) in dimethyl acetamide (7 mL). After stirring for 60 min at room temperature, a solution of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (1, 1.0 g, 3.48 mmol) in dimethyl acetamide (7 mL) was added and stirring was continued at room temperature until the reaction went to completion. The reaction was quenched by addition of water (15 mL) and the reaction mixture was extracted twice with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated, water was added and the mixture was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to yield 473 mg of the title compound as diastereomeric mixture. Rt=1.35 min, 1.55 min (Method 3). Detected mass: 435.2 (M+H+).