Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(CC2[C:16]([OH:17])=[C:15](C(O)=O)[C:14]3[C:9](=[C:10]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=CC=1.C(C1C=CC=C2C=1NC(=[O:40])C2=O)C.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C.ClC1C=CC(CC2C(O)=C(C(O)=O)C3C(=C(CC)C=CC=3)N=2)=CC=1>>[C:21]1([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[NH:8][C:16](=[O:17])[C:15]3=[O:40])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Reactant: CCc1cccc2c1NC(=O)C2=O
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Agent: CCc1cccc2c(C(=O)O)c(O)c(Cc3ccc(Cl)cc3)nc12
Product: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Yield: 25 %

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-ethyl-1H-indole-2,3-dione (1.00 g, 5.71 mmol) with intermediate 2 (1.62 g, 7.14 mmol). The crude acid was purified as described above for Compound 3 to give product as a bright yellow powder (Compound 7, 0.488 g, 25% yield): 1H NMR (400 MHz, DMSO-D6) δ 1.21 (t, J=7.5 Hz, 3H) 3.11 (q, J=7.3 Hz, 2H) 4.32 (s, 2H) 7.34 (s, 4H) 7.40 (d, J=7.1 Hz, 1H) 7.46 (t, 1H) 8.32 (d, J=8.1 Hz, 1H); HRMS (ESI+) calcd for C19H17ClNO3 (MH+) 342.0892, found 342.0890.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)C.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH3:12][S:13]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCc1ccccn1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccn1

Procedure:
2-Methylpyridine of general structure III is prepared by α-methylation of substituted pyridine II using the method of Kray and Reinecke (J. Am. Chem. Soc., 1964, 86, 5355). Oxidation with m-chloroperbenzoic acid gives substituted 2-methylpyridine N-oxide IV. Treatment of the latter with phosphoryl chloride gives the 2-chloromethyl substituted pyridine VII. Alternatively, refluxing IV in acetic anhydride gives the 2-(acetoxymethyl) pyridine VII which is hydrolysed with aqueous base to the corresponding alcohol VII. When this hydroxymethyl derivative is treated with methanesulfonyl chloride in the presence of triethylamine, the 2-(methanesulfonyloxymethyl)pyridine is obtained, whereas treatment with brominetriphenylphosphine gives the 2-(bromomethyl)pyridine VII. When either the bromomethyl, chloromethyl, or the mesyloxymethyl pyridine derivative VII is refluxed in acetonitrile in the presence of triphenylphosphine, the corresponding phosphonium salt VIII is formed.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([NH2:15])=[N:10]1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33].[OH-].[Na+]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])=[N:10]1
Reactant: C=C(C)C(=O)Cl
Reactant: NC1=NN(c2cccc(Cl)c2Cl)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)NC1=NN(c2cccc(Cl)c2Cl)C(=O)C1
Reaction time: 0.5 h

Procedure:
Forty grams (0.16 mole) of 1-(2,3-dichlorophenyl)-3-amino-2-pyrazoline-5-one, 30.4 ml (0.38 mole) of pyridine, and 4.0 ml of nitrobenzene were added to 600 ml of tetrahydrofuran, and to the mixture, cooled by ice, were added dropwise 39.2 g (0.38 mole) of methacryloyl chloride, and the liquid was stirred for 30 minutes, and then poured into 4 liters of water, extracted with use of ethyl acetate, then dried with use of anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure at a temperature of from 25° to 35° C. To the remaining oily substance were added 80 ml of ethanol and 80 ml of water and then a solution containing 22.4 g (0.56 mole) of sodium hydroxide. This mixture was stirred for 30 minutes at room temperature, and neutralized with acetic acid. The deposited crystals were filtrated, and recrystallized from methanol, whereby 32.4 g (64%) of Coupler Monomer (1 ) were obtained.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH:8]([O:10][CH2:11][CH:12](CC)[CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:9]>>[C:4]1(=[O:6])[NH:5][C:1](=[O:7])[CH:2]=[CH:3]1.[CH:8]([O:10][CH:11]([CH2:1][CH3:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:9]
Reactant: C=COCC(CC)CCCC
Agent: O=C1C=CC(=O)N1
Product: C=COC(CC)CCCCC
Yield: 59 %

Procedure:
A polymer was prepared in the manner of Example 1, except the comonomer to maleimide was 2-ethylhexyl vinyl ether. The polymer yield was 59%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=3)=[CH:14][N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.[C].[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[O:10])=[CH:31][CH:32]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 4-[2-(4-methanesulfonylbenzoylamino)pyridin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (83 mg, 0.18 mmol) in methanol (2 mL) was added 10% palladium-carbon (8.3 mg). The mixture was hydrogenated at room temperature for 4 hours and filtered through Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/3) to give the title compound as a white crystal (47 mg, yield 57%).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][C:6]2([CH2:11][CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2)[CH2:5]1)[CH3:3].[OH-].[Li+].O>C1COCC1>[CH2:2]([N:4]1[CH2:5][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:18][C:19]([CH3:21])([CH3:22])[CH2:20]1)[CH3:3]
Reactant: CCN1CC(C)(C)OC2(CCN(C(=O)C(F)(F)F)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC(C)(C)OC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To 1-(8-ethyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone hydrochloride salt (47 mg, 0.14 mmol) and lithium hydroxide (10 mg, 0.42 mmol) was added water (0.15 mL) and THF (0.6 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, partitioned between DCM (10 mL)/1:1 brine:NH4OH (2 mL), extracted with DCM (5×10 mL), dried over MgSO4 and concentrated in vacuo to give 4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane (24 mg, 81%). ESI-MS m/z calc. 212.2. found 213.5 (M+1)+; Retention time: 0.19 minutes (3 min run).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].CO>O1CCCC1.O>[C:3]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]([N:13]2[CH2:17][CH:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(COC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC1CN(C(=O)OCc2ccc(C(=O)O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 13, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-benzyl ester (50 mg, 0.08 mmol) was heated with aqueous LiOH (19 mg, 0.8 mmol) in tetrahydrofuran (3 mL), water (3 mL), and methanol (1 mL) at room temperature for 18 h to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-carboxy-benzyl ester as a white solid (Yield, 35 mg, 71%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][NH:6][CH2:5]1.CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[ClH:1].[NH2:3][C@:4]1([C:15]([OH:17])=[O:16])[C@@H:8]([CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[CH2:7][N:6]([C:33](=[O:34])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:5]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N[C@@]1(C(=O)O)CNC[C@@H]1CCCB(O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@]1(C(=O)O)CN(C(=O)Nc2ccc(F)cc2)C[C@@H]1CCCB(O)O
Reaction time: 1.5 h
Yield: 26.8 %

Procedure:
While under nitrogen, a stirred mixture of (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]pyrrolidine-3-carboxylic acid dihydrochloride (0.225 g, 0.623 mmol) in dry DMF (9 mL) was treated with Et3N (0.521 mL, 3.74 mmol) and 4-fluorophenyl isocyanate (92.1 uL, 0.810 mmol). After stirring for 1.5 h, the reaction mixture was diluted with water (5 mL) and acidified to pH˜1 with 3M aqueous HCl (5 mL). The aqueous phase was washed with methylene chloride (2×25 mL) and ethyl acetate (25 mL), concentrated and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[(4-fluorophenyl)carbamoyl]pyrrolidine-3-carboxylic acid hydrochloride (racemate) (65 mg, 27%) as a white amorphous solid. MS (ESI+) m/z 336 (M−H2O+H+), 3.18 (M−2 H2O+H+) and MS (ESI−) m/z 334 (M−H2O+H+).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]([F:28])([F:27])[CH2:25]I>CN(C=O)C.O>[C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:25][C:24]([F:28])([F:27])[F:23])[CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)CI
Reactant: O=c1[nH]cnc2occ(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(-c3ccccc3)coc2ncn1CC(F)(F)F
Temperature: 70 °C
Yield: 26.3 %

Procedure:
To a solution of 5-phenylfuro[2,3-d]pyrimidin-4(3H)-one (2 g, 9.42 mmol, prepared as described in WO2006/004658) in DMF (20 ml) was charged cesium carbonate (6.76 g, 20.7 mmol) and 1,1,1-trifluoro-2-iodoethane (1.86 ml, 18.9 mmol). The reaction was heated at 70° C. for 18 h under a nitrogen atmosphere. A further 1 eq. of 1,1,1-trifluoro-2-iodoethane was charged to the reaction mixture. The reaction was heated to 100° C. for 5 h before being cooled to RT, diluted with water and extracted twice with ethyl acetate. The organic extracts were washed with brine (3×50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by silica gel chromatography (SiO2, 0 to 50% EtOAc in cyclohexane) affording the title compound as a beige solid (730 mg, 26%). LCMS RT=1.27 min, M+H+=295.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2].[CH2:22](O[Si](C)(C)C)[CH2:23][CH2:24][CH3:25].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C([SiH](CC)CC)C.Cl>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:20][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCCCO[Si](C)(C)C
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCOC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
6 g of oxo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid ethyl ester and 2.6 g of butoxytrimethylsilane were dissolved in 200 ml of methylene chloride. The solution was cooled to 0° C., treated with 400 mg of trimethylsilyl triflate and stirred at 0° C. for 1.5 hours. After the dropwise addition of 2 g of triethylsilane, the reaction mixture was stirred at room temperature for 26 hours, then diluted with 500 ml of water, acidified with 2N hydrochloric acid and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated. The oily residue was purified with flash chromatography (silica gel, eluent hexane/tert.butyl methyl ether 3%) and preparative HPLC (YMC CN 60 Å5-15 μm, hexane) to give 3.5 g of the title product as colorless oil.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][CH2:38][CH2:39][CH2:40]C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([CH2:40][CH2:39][CH2:38][OH:37])[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(CCCO)ccc3c1)n2C1CCCCC1
Yield: 90 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-hydroxy-pentan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (96 mg, 90% yield). MS: 430.23 (M+H+); HPLC Procedure A, retention time=6.84 min, 82.48% purity.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylate (0.4 g., 0.0014 mol) and N-chlorosuccinimide (0.9 g., 0.0014 mol) in pyridine (4 ml) is heated on a steam bath for 18 minutes. The reaction mixture is cooled and poured into a large volume of ice water. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol gives the product (0.2 g.) mp 188°-190° C.
Reaction SMILES: CC(C)[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].BrC1C=C2C(=CC=1)C(=O)N(CC(OC)=O)C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>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].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:16][N:8]1[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 363 was prepared analogous to compound of example 360 by reaction of the compound of example 362, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=2[CH2:15][CH3:16])[C:7](=[O:20])[CH:6]2[CH2:21][CH:3]1[CH2:4][CH2:5]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1.[Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][CH3:16])=[C:9]([CH:8]3[C:2](=[O:1])[CH:3]4[CH2:21][CH:6]([CH2:5][CH2:4]4)[C:7]3=[O:20])[CH:10]=2)=[N:32][CH:33]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCc1ccc(B(O)O)cc1C1C(=O)C2CCC(C2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCc1ccc(-c2ccc(Cl)cn2)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a microwave vial containing 3-(2,4-dioxobicyclo[3.2.1]oct-3-yl)-4-ethylphenylboronic acid (0.15 g, 0.52 mmol) and potassium phosphate (0.667 g, 3.15 mmol) is added 2-bromo-5-chloropyridine (0.121 g, 0.63 mmol), palladium acetate (4.0 mg, 0.016 mmol) and tris(3-sulfophenyl)phosphine trisodium salt (21 mg, 0.038 mmol). A degassed solvent mixture of water/acetonitrile (1.6 ml, 2:1 ratio) is then added, followed by flushing with nitrogen, then stirring at ambient temperature for 5 minutes before heating at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction is partitioned between 2M aqueous hydrochloric acid and dichloromethane, and the organic phase is separated. The aqueous phase is further extracted with dichloromethane and all organic fractions are combined then evaporated. The residue is purified by preparative reverse-phase HPLC to give 3-[5-(5-chloropyridin-2-yl)-2-ethylphenyl]bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24][S:35]([CH3:34])(=[O:37])=[O:36])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCCC1Nc1nc(-c2c[nH]c3ncccc23)ncc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncccc23)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine, 16b, (0.009 g, 0.027 mmol) was dissolved in an 8:2 mixture of CH2Cl2/DMF (1 mL) and treated with iPr2NEt (0.019 mL, 0.110 mmol) and methanesulfonyl chloride (0.006 mL, 0.083 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and the residue was purified by HPLC with 10%-90% acetonitrile/water with 0.03% TFA to provide compound 337.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 85 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.08-3.17 (m, 4H), 3.73-3.86 (m, 4H), 4.13 (s, 3H), 7.00-7.65 (m, 7H), 7.74 (d, J=8.0 Hz, 1H).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]1[C:25]2[C:20](=[C:21]([C:28]3[CH:33]=[CH:32][C:31](F)=[CH:30][C:29]=3F)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[CH2:19][CH2:18][C:17]1=[O:36].C(Cl)[Cl:38]>>[Cl:38][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][C:17](=[O:36])[N:16]2[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:15]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reaction time: 16 h

Procedure:
A solution of 5 in 100 mL of CH2Cl2 was added Et3N (4.28 mL, 30.72 mmol) and 2 (26.88 mmol) in 27 mL of CH2Cl2. After 16 h at rt, it was loaded on silica gel and eluted with EtOAc:hexane=1:3 give 6 (16.62 g). Mass spectrum (ESI) for 6, 703 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[CH3:22][C:23]1[N:24]=[C:25]([NH2:29])[S:26][C:27]=1[CH3:28]>>[CH3:22][C:23]1[N:24]=[C:25]([NH:29][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:19])[S:26][C:27]=1[CH3:28]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1nc(N)sc1C
Product: Cc1nc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)sc1C
Yield: 56 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4,5-dimethyl-2-thiazolamine with a yield of 56% of theory.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:37][CH2:38][CH2:39][OH:40])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and 3-bromo-1-propanol (0.03 ml) were added to the supension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (32 mg, yield 68%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH:2]=[CH2:3].C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1OCC=C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)c1cc(N)ccc1OCC=C

Procedure:
Reduction of the above nitro compound by the method of Example 2, except that the solvent was methanol, and NaHCO3 solution was used to basify, gave allyl 2-allyloxy-5-aminobenzoate. Nmr (CDCl3): δ 3.23 (br, 2H); 4.53 (dt, 2H); 4.79 (d, 2H); 5.21-5.49 (m, 4H); 5.93-6.14 (m, 2H); 6.80 (m, 2H); 7.16 (d, 1H).