Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Cl[CH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[N:3]=1
Reactant: CN(C)C(=O)c1cccc(CCl)c1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: CN(C)C(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
To a flask was added 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and CH3CN (6 mL) followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.523 ml, 2.59 mmol). The mixture was stirred for 5 minutes, and then 3-(chloromethyl)-N,N-dimethylbenzamide (0.479 g, 2.42 mmol) was added as a CH3CN (4 mL) solution. The reaction was stirred at ambient temperature for 5 hours. The mixture was concentrated and diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (EtOAc) to provide 0.567 g (72%) of the desired product as an orange foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[O:14].[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH3:38])=[CH2:25].C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:14]2)=[C:30]1[CH3:38])=[CH2:25]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: C=COCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C=COCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A mixture of 15.6 g of 2-(2-methyl-4-dietylaminophenyl)carbonylbenzoic acid, 12.5 g of 1-(2-vinyloxyethyl)-2-methylindole, and 50.0 ml of acetic anhydride was maintained at approximately 70° C. for approximately four hours. The resulting solution was cooled to ambient temperature and slowly poured into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed successively once each with water and saturated sodium chloride solution and evaporated to dryness. The residue that remained was heated in a 1:1 mixture of isopropyl alcohol:hexane. The liquid was decanted from a gummy residue. The residue was dissolved in 100.0 ml of acetone and the resulting solution was added dropwise to 1500.0 ml of 2 percent aqueous ammonium hydroxide. The solid which precipitated was collected by filtration, washed with water and dried to obtain 18.86 g of 3-[1-(2-vinyloxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula I: R1 =CH2 =CHOC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a tan-colored solid which melted over the range 135°-141° C. Significant infrared maxima appeared at 1760 (C=O; s) and 1120 (C--O; s)cm-1. A toluene solution of the product spotted on an acid clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: O[CH:2]([C:4](=[CH2:7])[C:5]#[N:6])[CH3:3].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[CH3:29][N:30]=[C:31]=[O:32].[N-]=C=O>>[C:5]([C:4]([CH:2]([C:31](=[O:32])[NH:30][CH3:29])[CH3:3])=[CH2:7])#[N:6]
Reactant: CN=C=O
Reactant: C=C(C#N)C(C)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [N-]=C=O
Agent: [Sn+2]
Product: C=C(C#N)C(C)C(=O)NC
Reaction time: 6 h

Procedure:
2-Cyano-3-(N-methyl carbamyl)-1-butene was prepared through the following reaction. A three-necked 250 ml round bottom flask equipped with an overhead stirrer, N2 inlet, water condenser and dropping funnel was charged with 47.5 parts 2-(1-hydroxyethyl) acrylonitrile and 0.71 parts stannous octoate. To this stirred mixture, 28.5 parts methyl isocyanate was added through the dropping funnel. The mixture was maintained below 35° C. during addition by cooling and adjustment of the addition rate of the isocyanate. After the addition was complete, the mixture was stirred for an additional six hours. The product was then subjected to reduced pressure to remove any unreacted methyl isocyanate. The product was obtained as a viscous oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)=[C:21]([C:34]([O:36]C)=[O:35])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:9]=2[CH3:10])=[O:32])=[C:21]([CH:20]=1)[C:34]([OH:36])=[O:35]
Reactant: CCNc1cc(-c2ccc(F)cc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCC(=O)O
Product: CCN(C(=O)CCCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccc(F)cc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-4′-fluoro-4-methylbiphenyl-3-amine was reacted with the 5-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-5-oxopentanoic acid to give 5-chloro-2-((5-[ethyl(4′-fluoro-4-methylbiphenyl-3-yl)amino]-5-oxopentanoyl)amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH3:18])[C:11]([OH:17])=[CH:12][CH:13]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][O:4][CH2:3][CH2:2][O:17][C:11]1[C:10]([CH3:18])=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([CH3:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1C
Yield: 16.9 %

Procedure:
1-Bromo-2-methoxyethane (0.64 g, 4.6 mmol), 2,8-dimethylquinolin-7-ol (1.0 g, 2.3 mmol) and potassium carbonate (0.96 g, 6.9 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-2,8-dimethylquinoline (90 mg, 17% yield) as an oil
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:26]=[CH:27]/[CH3:28])=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:26]=[CH:27]/[CH3:28])=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C=C/c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 305/306 Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate and to replace cyclopropylboronic acid with trans-propenylboronic acid pinacol ester, tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate was obtained as a yellowish oil (1.20 g, quant.). To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.30 g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the title compound as a yellowish residue (0.260 g, quant.) which was used without further purification: MS (ES+) m/z 345.2 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][C:13]([CH3:23])=[C:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C1(C)C=CC=CC=1.Cl[CH2:39][CH2:40][N:41]([CH2:46][CH2:47][O:48][CH3:49])[CH2:42][CH2:43][O:44][CH3:45]>CN(C=O)C>[F:30][C:4]([F:29])([F:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:23])[N:14]([CH2:39][CH2:40][N:41]([CH2:46][CH2:47][O:48][CH3:49])[CH2:42][CH2:43][O:44][CH3:45])[C:15]([CH3:22])=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COCCN(CCCl)CCOC
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)N(CCN(CCOC)CCOC)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride (5.2 gms.; 0.11 mole) (50% suspension mineral oil) in 100 ml of dry distilled DMF is added a solution of diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (39.7 gms.; 0.1 mole) in 150 ml of DMF. After the gassing has ceased, the reaction mixture is heated on a water bath for 1 hour and then is cooled to 50° C. and to the hot solution is added a toluene solution of 2-chloro-N,N-bis(methoxyethyl)ethylamine. The reaction mixture is heated at 100°-110° C. for a period of 8 hours and then cooled. The unreacted NaH and NaCl is filtered off and the solvent removed from the filtrate. The residue is extracted with hot hexane which, on cooling, affords the desired product. Recrystallization from heptane yields the pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:38])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][NH2:29])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]([NH:29][CH2:28][C@@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25][CH2:24][NH:23][C:22]([O:21][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:38])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.10 g (0.45 mmol) of N-[(benzyloxy)carbonyl]beta-alanine and 0.185 g (0.58 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.112 g (0.58 mmol) of EDC and 0.018 g (0.134 mmol) of HOBt are added. The mixture is warmed slowly to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH2:39])=[O:38].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:39][C:37]([C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[NH:34][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:38]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)c1csc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.9 %

Procedure:
2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate VI.1 is obtained as a solid (1.4 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14])=[CH:4][C:3]=1[I:24].N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:16])[CH3:17])[CH2:13][O:14][C:32]([O:34][CH3:35])=[O:33])=[CH:4][C:3]=1[I:24]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 16 (13.4 g, 29.9 mmol) and pyridine (9.7 mL, 120 mmol) in anhydrous chloroform (60 mL) at 0° C. was added dropwise a solution of methyl chloroformate (9.2 mL, 120 mmol) in chloroform (30 mL). The mixture was stirred 1 h at 0° C., and then was washed with 2 N HCl (2×60 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil (mixture of 16 and 17) was treated with pyridine (5 mL, 62 mmol) and methyl chloroformate (4.6 mL, 60 mmol) under the same conditions above another four times to achieve approximately 90% conversion. The crude product, a yellow oil, was purified on an AnaLogix chromatography system with 33-50% EtOAc/heptanes to give 7.6 g (50%, greater than 98% purity) of 17 as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.C1COCC1.CO.Cl>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.45 g, 7.47 mmol) in THF (11 mL) was added BH3.THF (1 M solution in THF, 60 mL) at rt and the mixture was stirred at 75° C. After 3.5 h, the mixture was cooled to rt. To the cooled mixture was added MeOH (30 mL) and mixture was stirred at rt. After 30 minutes, the mixture was treated with concentrated HCl (6 mL, 72 mmol) and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL×4), washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as a reddish-orange solid: Mass Spectrum (ESI) m/e=181.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[C:25]1([CH2:31][C:32]#[CH:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.CN(C=O)C.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.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:33]#[C:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-1-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. Further 3-phenyl-1-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100° C. for further 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+1); Rt: 2.43 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(OC(C)(C)C)C(OC)=O)C=1C.[NH2:60][C:61]1[CH:66]=[CH:65]C(B(O)O)=[CH:63][N:62]=1>>[NH2:60][C:61]1[N:62]=[CH:63][C:23]([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:12]([CH:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([OH:9])=[O:8])[C:21]=2[CH3:22])=[CH:65][CH:66]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Agent: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(N)nc1

Procedure:
2-(4-(6-Aminopyridin-3-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (143) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-aminopyridin-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 8.06-7.86 (m, 4H), 7.76-7.68 (m, 2H), 7.56-7.37 (m, 5H), 7.26 (d, J=8.6 Hz, 1H), 7.17-7.13 (m, 1H), 5.13 (s, 1H), 2.33 (s, 3H), 0.96 (s, 9H). 19F-NMR: (377 MHz, DMSO-d6): δ-74.2 (s). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H28ClN2O3: 475.2; Found: 475.2.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH2:6]([O:8][SiH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH3:7]>C1C=CC=CC=1>[CH3:2][CH2:1][O:3][CH2:4][CH2:5][Si:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:8][CH2:6][CH3:7]
Reactant: C=COCC
Reactant: CCO[SiH](OCC)OCC
Solvent: c1ccccc1
Product: CCOCC[Si](OCC)(OCC)OCC
Yield: 91 %

Procedure:
390 g vinylethylether, 600 g triethoxysilane, 3 g of a catalyst prepared according to Example 1 and 1000 ml of benzene were introduced into a reaction vessel and the mixture heated for 1.5 hours to boiling. After distillation, 786 g of CH3CH2OCH2CH2Si(OC2H5)3 were obtained (90% of the theoretical amount).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:69][CH:70]1[CH2:75][CH2:74][N:73]([CH2:76][CH2:77][NH2:78])[CH2:72][CH2:71]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:78][CH2:77][CH2:76][N:73]2[CH2:74][CH2:75][CH:70]([F:69])[CH2:71][CH2:72]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: NCCN1CCC(F)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (156 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 110 mg (57%) of the titled compound. MS m/z 645 [M−1].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40](I)[S:41][C:34]=12.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.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>[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:18]3[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:19]=3)[S:41][C:34]=12
Reactant: COCCN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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
Solvent: ClCCl
Product: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C

Procedure:
A mixture of 78 (369.3 mg, 0.93 mmol), 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (466.6 mg, 1.12 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol) and Na2CO3 (305 mg, 2.8 mmol) in DME (1.9 mL) was heated to reflux overnight under nitrogen. It was then diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluents EOAc/Hex 1:1, EtOAc, 5% MeOH in DCM affording title compound 79 (203 mg, 39%) as brown syrup. MS (m/z): 558.2 (100%) (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([I:16])[CH:15]=1)[N:12]=[CH:11][C:10]([C:17]([O:19]CC)=O)=[C:9]2[OH:22])(=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCOCC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:17]([C:10]2[CH:11]=[N:12][C:13]3[C:8]([C:9]=2[OH:22])=[CH:7][C:6]([CH2:5][OH:4])=[CH:15][C:14]=3[I:16])=[O:19])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cc(COC(C)=O)cc2c1O
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Temperature: 180 °C
Yield: 73 %

Procedure:
A suspension of ethyl 6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate (0.90 g) and 4-chlorobenzylamine (2.6 mL) is heated at 180° C. for 1 h. The reaction is cooled to room temperature and diluted with Et2O. The resulting solid is filtered and triturated with acetone to yield 0.74 g (73%) of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide, m.p. 283-286° C.