Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([OH:28])=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][O:19][CH3:20])[CH:15]=2)[N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]=1)=[O:7].[OH-].[Li+]>O1CCOCC1>[C:24]([O:23][C:21]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=2)[C:8]([C:6](=[O:7])[CH:5]=[C:4]([OH:28])[C:3]([OH:29])=[O:2])=[CH:9]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COCOc1ccc2c(c1)c(C(=O)C=C(O)C(=O)OC)cn2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCOc1ccc2c(c1)c(C(=O)C=C(O)C(=O)O)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 0.345 g (0.85 mmol) of the ester derivative obtained in above (1) in dioxane (7 ml) was added 1.7 ml of 1 N lithium hydroxide. The mixture was stirred for 1.5 hours at room temperature. The solvent was removed under reduced pressure at room temperature and the residue was dissolved in water. The aqueous layer was washed twice with ethyl acetate and neutralized with 1 N hydrochloric acid (1.7 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried. The solvent was removed and the obtained crystal was washed with ethyl acetate to give 0.28 g of the titled compound. Yield: 84%. m.p.: 165-170° C. (decomposition)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:12][CH2:13][CH:14]([CH2:17][O:18][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of Intermediate 14c (470 mg, 1.88 mmol) and Et3N (390 μL, 2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (607 μL, 2.26 mmol) and the mixture stirred at RT for 0.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound (565 mg, 74%). LCMS (Method 3): Rt 5.21 min, m/z 407 [MH+].
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[CH2:11]2
Reactant: CCCCc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 4-butyl-benzylamine (0.088 mL, 0.5 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-butyl-benzyl)-2,3-dihydro-isoindol-1-one (0.063 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.88 (t, 3H), 1.34 (m, 2H), 1.56 (m, 2H), 2.58 (t, 2H), 4.16 (s, 2H), 4.76 (s, 2H), 7.14-7.36 (m, 6H), 7.85 (d, 1H). GC-MS: m/z 405 (M)+, 348(M−57)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[CH3:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:16]=[CH:15][C:14]=1C(O)=O>ClCCl.O>[CH3:12][C:13]1[N:17]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[N:16]=[CH:15][C:14]=1[C:9]([NH2:8])=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (3.8 ml) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 23 in dichloromethane (50 ml) and stirred at room temperature for two hours. The solvent and an excess amount of oxalyl chloride were evaporated, tetrahydrofuran (50 ml) was added to the residue, 28% aqueous ammonia was added under ice-cooling, and stirred at room temperature for two hours. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with 1N hydrochloric acid aqueous solution, 4N aqueous solution of sodium hydroxide, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated to give 5-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (2.92 g) as a pale brown solid.
Reaction SMILES: [Na].C[C:3]([CH3:13])([CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[C:4]#N.O1CCCC1.[Cl-].[NH4+]>C(O)C>[CH3:13][C:3]1([CH3:4])[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH:9]1[NH2:10]
Reactant: CC(C)(C#N)CCC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 35 g. (0.61 mole) of 40% sodium dispersion in mineral oil. The oil was removed by washing with ethyl ether and decantation. The sodium was then mixed with 400 ml. of ether and a mixture of 32.8 g. (0.20 mole) 2,2,5,5-tetramethyladiponitrile, prepared by the method of Coffman et al., J. Am. Chem. Soc., 80, 2868 (1957), and 400 ml. of tetrahydrofuran was added slowly. The resulting mixture was stirred at room temperature for 4 hours, the excess sodium decomposed by dropwise addition of saturated aqueous ammonium chloride, the organic layer washed with water, dried (Na2SO4) and evaporated to afford 25.1 g. of crude 2,2,5,5-tetramethylcyclopentylimine. The imine was dissolved in 75 ml. of ethanol and added dropwise to a flask containing 23.3 g. (1 mole) sodium shot. An additional 75 ml. ethanol was added and the mixture heated at reflux until the remaining sodium metal was consumed. The reaction mixture was diluted with water, acidified to pH 1 with concentrated hydrochloric acid, the aqueous phase washed with ether then made strongly basic by addition of sodium hydroxide. The organic layer was extracted with ether, washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was distilled in vacuo to afford 6.6 g. (23%) of the desired amine, B.P. 60°-61° C. (20 mm.).
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O-:27])=[O:26])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:15][S:16][C@H:11]12)=O.CN(C)C1C=CC=CC=1.C[Si]([Cl:43])(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.C(O)CC(O)C>C(Cl)Cl>[ClH:24].[ClH:43].[NH2:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O-:27])=[O:26])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:15][S:16][C@H:11]12
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(Cl)c3)CS[C@H]12
Reactant: C[Si](C)(C)Cl
Agent: CC(O)CCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cl
Product: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(Cl)c3)CS[C@H]12
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 177.6 %

Procedure:
To a mixture of 7-(2-thienylacetamido)-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate (22.5 g) and N,N-dimethylaniline (60.0 g) in methylene chloride (400 ml) was added dropwise trimethylsilylchloride (50.0 g) at ambient temperature under stirring, which was continued for 15 minutes at the same temperature. The reaction mixture was cooled to -30° C. and phosphorus pentachloride (31.2 g) was added thereto under stirring, which was continued for one hour at -30° to -25° C. The reaction mixture was added to a cold solution of 1,3-butanediol (45 g) in methylene chloride (400 ml) under cooling in an ice-bath and stirring, which was continued for one hour at ambient temperature. The resulting precipitate was filtered, washed with methylene chloride and redissolved in methanol (50 ml). After the solution was treated with activated charcoal (1 g), the filtrate was poured into acetone (500 ml) under stirring, which was continued for 30 minutes at ambient temperature. The resulting precipitate was filtered, washed with acetone and dried to give 7-amino-3-(3-chloro-1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrochloride (17.7 g), mp. 160° to 165° C. (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].CO.O.O[Li].O>C1COCC1>[C:10]1([C:8]2[O:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(-c2ccccc2)on1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (3.86 g, 0.01754 mole) in methanol (78 mL) was added hydroxylamine hydrochloride (3.657 g, 0.0526 mole) at ambient temperature. The resulting mixture was then heated to reflux overnight. Volatiles were then removed by evaporation and the resulting residue was diluted with water and the product extracted with chloroform. The chloroform layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 2.8 g (79%) of 5-phenyl-isoxazole-3-carboxylic acid methyl ester. LCMS: 204.06 (M+1)+, 97.58%. To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid methyl ester (2.8 g, 0.01379 mol) in a mixture of THF (10 mL), methanol (10 mL) and H2O (10 mL) was added LiOH.H2O (0.87 g, 0.02073 mol) and the resulting mixture was stirred at ambient temperature for 2.5 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.2 g (85%) of 5-phenyl-isoxazole-3-carboxylic acid. LCMS: 190.04 (M+1)+, 96.4%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[N:12][CH2:13][C:14]#[CH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].O>C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:1][CH:2]1[CH2:11][CH:10]([NH:12][CH2:13][C:14]#[CH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: C#CCN=C1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CCNC1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a solution of (2-methyl-4-prop-2-ynylimino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (0.5 g) in acetic acid (20 ml), sodium triacetoxyborohydride was added in small amounts (1.75 g) under stirring at room temperature. The reaction mixture was then stirred at room temperature for one hour and poured on 100 ml of cold water under stirring. The desired compound was filtered after precipitation. The compound was dissolved in ethyl acetate and washed with water. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduce pressure to give a brown oil which was purified by flash chromatography with cyclohexane/ethyl acetate (95/5) as eluent and then cyclohexane/ethyl acetate (90/10) to give a mixture of diastereoisomere cis-trans (50–50) of (2-methyl-4-prop-2-ynylamino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (0.06 g, 17.6% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.B.C1COCC1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:3]12
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccc(O)cc2C2CCC(NCc3ccccc3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (14.0 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A solution of 1M borane/THF in THF (145 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back to 0° C. and trifluoroacetic acid was added in a dropwise manner. The solution was stirred for 15 minutes, neutralized with 10% NaOH (Aq), extracted with CH2Cl2, dried (Na2SO4) and concentrated to give 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][CH:17]([CH2:34][OH:35])[CH2:18][C:19]([CH3:33])([CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:21].[C:36]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([NH:46][C@H:47]([C:51]([O:35][CH2:34][CH:17]([OH:16])[CH2:18][C:19]([CH3:32])([CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)=[O:21])=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)CO)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a mixture of DCC (14.8 g, 72 mmol), DMAP (0.88 g, 7.2 mmol) and 4-methoxybenzyl 4,5-dihydroxy-2,2-dimethyl-valerate (20.3 g, 72 mmol) in CH2Cl2 (400 mL) at 0° C., was added dropwise a solution of N-CBz-L-valine (16.2 g, 65 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 22.4 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26](Br)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([C:45]6[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=6)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(-c6cccc(C#N)c6)ccc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
100 mg (0.18 mmol) {1-[4-(9-Bromo-3-phenylpyrimido[1,2-b]indazole-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-0), 51.6 mg (0.35 mmol) (3-cyanophenyl)boronic acid, 14.3 mg (0.02 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 55 mg (0.53 mmol) sodium carbonate in 1.8 mL dioxane and 0.3 mL water were heated in a microwave vial which had been sealed with a microwave cap for 18 hours at 105° C. (heating block). After the usual work up, the crude mixture (131.2 mg) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=4[CH:18]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: [O-]B([O-])Oc1ccc(N2CCCCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-piperidinophenyl borate (0.55 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethyl acetate to give yellow crystals of methyl 7-(4-piperidinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.85 g).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24]
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: Cc1ccc(CNc2ccc3c(Nc4cccc(S(C)(=O)=O)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=408.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 3-methylsulfonylaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[Cl:11][C:12](Cl)([Cl:17])[C:13]([Cl:16])([F:15])[F:14].C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[ClH:35].CNC>C(#N)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]([Cl:35])[CH2:7][C:12]([Cl:17])([Cl:11])[C:13]([Cl:16])([F:15])[F:14]
Reactant: Cl
Reactant: FC(F)(Cl)C(Cl)(Cl)Cl
Reactant: C=CC(C)(C)CC(=O)OC
Agent: CNC
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CC#N
Product: COC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)C(F)(F)Cl

Procedure:
37.5 g of 3,3-dimethyl-4-pentenoic acid methyl ester, 102 g of 1,1,1,2-tetrachloro-2,2-difluoroethane, 22 g of acetonitrile, 325 mg of FeCl3.6H2O, 255 mg of benzoin and 200 mg of dimethylamine hydrochloride were heated to 100°-120° C. in a 250 ml VA autoclave under 6 bars of nitrogen for 7 hours. Distillation of the mixture gave 3,3-dimethyl-4,6,6,7-tetrachloro-7,7-difluoroenanthic acid methyl ester of boiling point 129°-134° C./0.7-0.9 m bar. Refractive index: nD20 =1.4680. ##STR8##
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[CH2:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:31]#[N:32].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[CH3:13][C:12]1[C:4]([CH2:3][C:2]2[NH:36][C:35]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[N:27]=2)=[C:5]2[C:9](=[C:10]([CH:14]=[CH2:15])[CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:17])=[O:18])[CH:7]=[CH:6]2
Reactant: C=Cc1cc(C)c(C=C(Br)Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: C=Cc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Temperature: 25 °C

Procedure:
A solution of 4-(2,2-dibromovinyl)-5-methyl-1-tosyl-7-vinyl-1H-indole (57 mg, 0.115 mmol) and 3,4-diaminobenzonitrile (23 mg, 0.173 mmol) and DABCO (38.7 mg, 0.345 mmol) in NMP (0.5 mL) was stirred at 110° C. After 80 minutes the mixture was slowly cooled to room temperature overnight, and then heated again at 110° C. for 4 hours. The reaction was cooled to room temperature and loaded onto silica gel and purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 467.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8](F)[C:7]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].[Li+].C[CH:17]([N-:19]C(C)C)C.[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[C:1]([O:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([CH:24]2[CH2:25][CH:23]2[CH2:27][C:17]#[N:19])[C:7]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(F)ncc(F)c1OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Product: Cc1c(C2CC2CC#N)ncc(F)c1OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A sample of 4-t-butoxy-2,5-difluoro-3-methylpyridine (40.8 mmol) was dissolved in 50 mL of THF and cooled to -78° C. To this was added a freshly prepared solution of LDA (0.103 mmol) in 50 mL of THF at -78° C,, and the reaction was stirred for 1 hour. The reaction was then stirred at 0° C. for 1 hour, quenched with saturated NH4Cl solution and extracted with ether. The extracts were washed with saturated NaCl solution, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 1:4 ethyl acetate:hexane, to yield 10.33 g of 2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile after removal of the solvent. MS 263 (M+H)+ ; 1H NMR (CDCl3)∂: 0.50 (m, 2H), 0.63 (m, 1H), .73 (m, 1H), 1.60 (m, 1H), 1.43 (d, 9H, J=2 Hz), 2.29 (s, 3H), 3.76 (d, 1H, J=8 Hz), 8.30 (d, 1H, J=3 Hz). IR (neat) 2240, 1580, 1470 cm-l.