Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3]C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>O>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][CH2:11][C@H:10]([CH:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH2:15][CH2:14]1
Reactant: Fc1cccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1

Procedure:
First, 5.85 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone ethylene ketal, 0.5 g of p-toluenesulfonic acid monohydrate, 35 ml of dioxane, and 105 ml of water were placed in a 200 ml flask. The mixture was stirred under reflux for 2 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1), distilled under reduced pressure, and recrystallized from hexane to obtain 2.2 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone (Y: 55.8%). The compound thus obtained had a purity of 98.1% by GC and a b.p. of 165° C./0.5 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:9]2[CH:13]=[C:12]([N+:14]([O-])=O)[N:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][O:2][C:3]([C:5]1([N:9]2[CH:13]=[C:12]([NH:14][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(n2cnc([N+](=O)[O-])c2)CCC1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2(C(=O)OC)CCC2)cn1

Procedure:
1-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 463.0 m/z (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>O1CCCC1.[Ni](Cl)Cl.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 198 %

Procedure:
(4-bromophenyl)(4-chlorophenyl)methanone (10.0 g, 12.3 mmol) and bis(diphenylphosphino)propane nickel(II) chloride (0.4 g, 0.7 mmol) were dissolved in purified tetrahydrofuran (200 mL) under a nitrogen atmosphere, and isopropyl magnesium chloride (18.7 mL, 37.4 mmol) was slowly added thereto at 0° C. The reaction mixture solution was stirred at room temperature for 24 hours. The reaction mixture solution was subjected to extraction with dichloromethane and distilled water, and the extracted material was subjected to column chromatography (hexane:ethylacetate=8:2). The reaction solvent was removed, and then the residue material was dried in vacuum to thereby obtain a white solid (6.3 g, yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:43][NH:44][CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](=[O:28])[N:44]([CH3:45])[CH3:43])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N(C)C
Reaction time: 5 h
Yield: 76 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol) prepared in Example 62h, dimethylamine hydrochloride (13.5 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 mL) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (40 mg).
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39](C=O)[CH:38]=2)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>ClCCl>[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH:1]([O:4][CH3:5])[O:2][CH3:3])[CH:38]=2)=[N:29][CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
50 ml of trimethyl orthoformate were added to 40.0 g of montmorillonite K-10 in 250 ml of anhydrous dichloromethane, after which a solution of 20.0 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine in 50 ml of dichloromethane was added dropwise while stirring and cooling in ice. After stirring at 23° C. for 20 hours, the clay was removed and thoroughly washed with dichloromethane. The dichloromethane phase was concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (10:1). Yield: 22.1 g (96%) of a colorless oil.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 54.7 %

Procedure:
A mixture of 2.0 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 3.0 g of 2-(tributylstannyl)toluene and 200 mg of tetrakis(triphenylphosphine)palladium(O) in 200 ml of toluene is refluxed for 16 hours. The reaction mixture is evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 1.0 g of the desired product as a solid. Mass spectrum: M+H:379.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.Cl[Si](C)(C)C.CO[CH:31](OC)[N:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[N:32]1([CH:31]=[N:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: COC(OC)N1CCCCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(N=CN3CCCCCC3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred solution of 1.2 g (5 mmoles) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) of triethylamine and 30 ml of dichloromethane, cooled to 0° C., is added 0.54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0.86 (5 mmole) of 1-(dimethoxymethyl)hexahydroazepine (British Pat. No. 1,293,590) is added, and stirring is continued for a further 1 hour. The volatile components are removed by evaporation in vacuo, and then the residue is extracted with 25 ml of acetone. The insoluble material is filtered off, and the acetone is evaporated in vacuo to a yellow foam, which changes to a white powder on trituration with ether. This affords 1.44 g (82% yield) of 6-([hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1795 cm-1 (β-lactam), 1706 cm-1 and 1645 cm-1. The NMR spectrum (CDCl3) shows absorption bands at 8.00 ppm (singlet, 1H, N--CH=N), 5.90 and 5.60 ppm (two doublets, 2 H, J=4 Hz, C-5 and C-6 hydrogens), 5.40 ppm (singlet, 1H, C-3 hydrogen), 3.90-3.50 (multiplet, 4H, CH2 --N--CH2), 2.00-1.50 ppm (multiplet, 11H, C-2 methyl hydrogens and [CH2 ]4) and 1.20 ppm (singlet, 3H, C-2 methyl hydrogens). Examination of the product by thin-layer chromatography (0.2 M NaOAc: acetone; 1:6) showed a single spot (Rf 0.23).
Reaction SMILES: [Si](OI)(C)(C)C.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.OS(O)(=O)=O.[CH3:27][CH2:28]O>CS(C)=O>[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:27][CH3:28])=[O:18])=[CH:13][CH:12]=1
Reactant: CCO
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Agent: C[Si](C)(C)OI
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1
Temperature: 90 °C
Yield: 96 %

Procedure:
Compounds 100, 105, 107, and 106 were synthesized under the Corey-Chaykovsky cyclopropanation reaction conditions (TMSOI, NaH, DMSO). A mixture of trans-4-methoxycinnamic acid (18 g, 101 mmol) and concentrated H2SO4 (0.5 mL) in absolute EtOH (100 mL) was refluxed at 90° C. (bath temperature) for 16 h. After the excess EtOH was removed by a rotary evaporator, the residue was treated with H2O (100 mL), and the resulting mixture was extracted with ether (3×120 mL). The combined extracts were washed with 1N aq. NaOH (2×50 mL), H2O (80 mL) and brine (80 mL), and dried (anhydrous Na2SO4). The solvent was evaporated to dryness to give ethyl trans-4-methoxycinnamate (20 g, 96% yield) as light yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[O:10][C:9](=[O:11])[C@@H:8]([NH:12]C(=O)OCC2C=CC=CC=2)[CH2:7][O:6][CH2:5][C@H:4]([O:23][CH2:24][C:25]([CH3:27])=[CH2:26])[C@H:3]1[O:28][CH2:29][C:30]([CH3:32])=[CH2:31]>CCOC(C)=O.[Pd]>[NH2:12][C@H:8]1[CH2:7][O:6][CH2:5][C@H:4]([O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C@@H:3]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C@H:2]([CH3:1])[O:10][C:9]1=[O:11]
Reactant: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)COC[C@@H]1OCC(=C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCC(C)C
Temperature: 50 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
Benzyl (3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-1,5-dioxonan-3-ylcarbamate (265 mg, 0.592 mmol) was dissolved in EtOAc (8 mL) in a 50 mL high pressure reactor with a stir bar and Pd/C (5%, 30 mg) was added. The reactor was sealed and purged with H2 (4×), then charged to ˜600 pounds per square inch (psi) with H2. The reactor was warmed to 50° C. and stirred at 50° C. for 12 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to afford the title compound as a white solid (170 mg, 91%): mp 144-146° C.; 1H NMR (400 MHz, CDCl3) δ 4.82 (dq, J=8.5, 6.3 Hz, 1H), 3.97-3.84 (m, 1H), 3.78 (t, J=7.0 Hz, 1H), 3.72-3.53 (m, 3H), 3.44-3.29 (m, 2H), 3.29-3.12 (m, 4H), 1.82 (ttd, J=13.4, 6.5, 2.5 Hz, 2H), 1.42 (d, J=6.3 Hz, 3H), 0.99-0.78 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 175.66, 84.70, 83.85, 80.55, 77.57, 74.90, 72.72, 72.70, 29.11, 28.87, 19.58, 19.48, 19.45, 19.38, 18.61; ESIMS m/z 318.8 ([M+H]+).
Reaction SMILES: [K:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:12]1COCC1>>[K:1].[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:12][C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH2:4]
Reactant: C1CCOC1
Agent: [K]
Solvent: c1ccc2ccccc2c1
Product: C=C(C)c1ccccc1

Procedure:
The procedure of Example 17 was repeated, but an initiator was employed that was prepared by reacting, at ambient temperature, the naphthalene potassium solution which was the result of the preliminary addition of potassium to naphthalene in THF, with α-methylstyrene. The molar ratio of the ligand to the initiator was 10. The solvent employed was THF. The results obtained are reported in Table 3:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3=[O:35])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:38][N:37]=[N:36][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3=[O:35])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[S:10][C:9](B(O)O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:27]1[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>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>[CH:1]1([NH:4][CH2:5][C:6]2[S:10][C:9]([C:15]3[CH:16]=[C:17]4[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:27]3[CH2:28][CH2:29][N:30]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])[CH2:31][CH2:32]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(CNC2CC2)s1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CC5)s4)cc23)CC1

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 63 mg of crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give impure title compound. The impure title compound was purified again with the Agilent MDAP and isolated as the free base according to the procedure shown in Example 5 to give 6.8 mg of the title compound (7.2%).
Reaction SMILES: CN1C(C)(C)C(=O)N(C)C1=O.[F:12][C:13]1[CH:30]=[C:29]2[C:16]([S:17](=[O:32])(=[O:31])[NH:18][C:19]3[C:28]2=[CH:27][CH:26]=[C:25]2[C:20]=3[N:21]=[CH:22][CH:23]=[CH:24]2)=[CH:15][CH:14]=1.C(Cl)(Cl)[Cl:34]>>[Cl:34][C:26]1[CH:27]=[C:28]2[C:19](=[C:20]3[C:25]=1[CH:24]=[CH:23][CH:22]=[N:21]3)[NH:18][S:17](=[O:31])(=[O:32])[C:16]1[C:29]2=[CH:30][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(F)ccc21
Reactant: ClC(Cl)Cl
Agent: CN1C(=O)N(C)C(C)(C)C1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Temperature: 70 °C
Yield: 69 %

Procedure:
1,3-dimethyl-5,5-dimethylhydantoin (0.73 g, 36.7 mmol) was added to a solution of 9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 187 (1.0 g, 33.3 mmol) in chloroform (40 ml) and the reaction was heated at 70° C. until the starting material was consumed (LCMS). After cooling, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with sodium metabisulfate, water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (0.8 g, 69%).
Reaction SMILES: ClC1N=[C:4]([NH:18][C:19]2[C:24]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]([CH3:31])=[CH:21][N:20]=2)[C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH:7]=[C:26]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:25]3[C:24]4[C:19]([NH:18][C:4]=3[C:5]2=[O:17])=[N:20][CH:21]=[C:22]([CH3:31])[CH:23]=4)=[CH:10][CH:11]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Temperature: 130 °C
Reaction time: 94 h
Yield: 89.9 %

Procedure:
In a 2 L round bottom flask, 5-chloro-1-(4-methoxybenzyl)-3-(5-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-ylamino)pyrazin-2(1H)-one (35.2 g, 77.85 mmol) was taken up with anhydrous toluene (880 mL), attached a reflux condenser and transferred to an oil bath that was heated to 130° C. The reaction was stirred in the oil bath for 94 h and concentrated in vacuo to afford a brown solid. The crude was suspended in ethyl acetate (200 mL) and heated to a mild boil. The solids were collected by filtration, washed with additional ethyl acetate, diethyl ether and dried in vacuo to provide the title compound as a pale yellow powder (27.4 g, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 (s, 9H) 2.56 (s, 3H) 3.80 (s, 3H) 5.30 (s, 2H) 6.89 (d, J=8.59 Hz, 2H) 7.11 (s, 1H) 7.35 (d, J=8.84 Hz, 2H) 8.22 (s, 1H) 8.52 (d, J=1.52 Hz, 1H). ESI-MS: m/z 392.4 (M+H)+.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6]C)=O.[NH2:18][C:19]([CH2:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22]>C1(C)C(C)=CC=CC=1>[CH2:25]([C:19]1[NH:18][C:2]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:3][C:4](=[O:6])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:26]
Reactant: COC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(N)=CC(=O)OC
Solvent: Cc1ccccc1C
Product: CCc1[nH]c(-c2ccc(C(F)(F)F)cc2)cc(=O)c1C(=O)OC

Procedure:
1.00 g (3.84 mmol) of methyl 3-oxo-3-[4-(trifluoromethyl)phenyl]propanoate and 546 mg (4.23 mmol) of methyl 3-aminopent-2-enoate [Pena et al., J. Am. Chem. Soc. 124., 14552-14553 (2002)] were taken up in 4 ml of xylene, 1.50 g molecular sieve (4 Å) which had been dried by heating were added and the mixture was reacted at reflux temperature overnight. The molecular sieve was removed by filtration and washed with methanol/chloroform (1/1). The combined organic phases were concentrated on a rotary evaporator and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 270 mg (21% of theory) of the target compound.
Reaction SMILES: NC1N=CC=CC=1C(O)=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[NH:17][C:16](=O)[C:15]2=[O:23].[NH:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=[O:28])C1=O>>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]1[C:16](=[N:24][C:34]3[C:29]([C:27]1=[O:28])=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:15]2=[O:23]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C1Nc2c(F)cc(F)cc2C1=O
Agent: Nc1ncccc1C(=O)O
Product: O=C1c2cc(F)cc(F)c2-n2c1nc1ccccc1c2=O
Yield: 4.7 %

Procedure:
Using the procedure in Example 56 and substituting 2-aminobenzoic acid for 2-aminonicotinic acid and 5,7-difluoroisatin from Example 3 for isatin gave the title compound in 4.7% yield: mp 287°-290° C,; 1H NMR (300 MHz, CDCl3) δ 8.47 (d, 1H) 8.02 (d, 1H) 7.84-7.92 (m, 1H) 7.66-7.76 (m, 1H) 7.48-7.54 (m, 1H) 7.30-7.40 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][C:22]=1Br)(=[O:18])[CH3:17]>[Cu]I.COCCOC>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])=[CH:23][CH:24]=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: [Cu]I
Solvent: COCCOC
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 167e (301 mg, 1.47 mmol), 2,6-dibromobenzyl acetate 104g (1.1 g, 3.0 mmol), CuI (140 mg, 0.7 mmol) Cs2CO3 (961 mg, 3.0 mmol), N′,N′,N′,N′-tetramethylethylenediamine (0.22 mL, 1.5 mmol) and 1,2-dimethoxyethane (4.1 mL). The mixture was heated in microwave to 150° C. for 3 h. After this time, the mixture was filtered and the resulting solid was washed with 9:1 CH2Cl2/MeOH (50 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of hexanes-ethyl acetate to afford a 32% yield (200 mg) of 167f.