Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=O.C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:14][N:15]([CH3:32])[S:16](=[O:31])(=[O:30])[O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH:28]=[CH:5][C:3]#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=CC#N)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: -10 °C
Yield: 80 %

Procedure:
Add 3.1 g (0.0773 mol) of sodium hydride in portions to a solution at 0° C. of 11.9 ml (0.0736 mol) of diethyl cyanomethylphosphonate in 400 ml of THF. Cool the mixture to −10° C. and add dropwise a suspension of 21.3 g (0.0736 mol) of 2-formyl-4,5-dimethoxyphenyl dimethylsulphamate in 200 ml of THF. Stir for 30 minutes and hydrolyse with 600 ml of a solution of sodium hydrogen carbonate and water (50/50) and then extract the solution twice with 300 ml of toluene each time. The organic phase is washed with 100 ml of water and 100 ml of saturated aqueous NaCl solution and then dried over MgSO4, filtered and evaporated to dryness. The residue obtained is crystallised in 80 ml of diisopropyl ether at ambient temperature and then filtered and washed with 20 ml of diisopropyl ether and dried in vacuo. 18.4 g of title product are obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([Cl:21])=[CH:13][CH:12]=1>>[Br:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([Cl:21])=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=1
Reactant: COC(=O)c1nc(Br)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(Br)cc([N+](=O)[O-])c1Cl
Temperature: 70 °C

Procedure:
To a solution of fuming nitric acid (10 mL) and fuming sulfuric acid (10 mL) was added methyl 6-bromo-3-chloropyridine-2-carboxylate, N-oxide and the reaction was heated to 70° C. in an oil bath for 4 hr. The mixture was poured over ice water (100 mL) and extracted with ethyl acetate (3×75 mL) and the combined extracts were backwashed with brine, dried (Na2SO4) and concentrated. The dark oil was chromatographed over silica in 4:1 EtOAc/hexane to give methyl 6-bromo-3-chloro-4-nitropyridine-2-carboxylate, N-oxide (0.007 mol, 2.2 g). 1H NMR (CDCl3): δ 4.1 (3H, s), 8.4 (1H, s).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[NH:21][N:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>C1COCC1.CO>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:22]2[NH:21][N:20]=[C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:34])=[O:5])=[CH:12][CH:13]=3)[CH:23]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)[nH]n3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)[nH]n3)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of {6-[5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (5 mg, 10 μmol) in THF/methanol 2/1 (750 μl) was added 1 N aqueous LiOH solution (600 μl). The reaction mixture was stirred for 14 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (3 mg, 7 μmol, 68%) as brown crystals.
Reaction SMILES: [CH:1]1([N:4]([CH:41]2[CH2:43][CH2:42]2)[C:5]([C:7]2[N:38]([CH2:39][CH3:40])[C:10]3=[N:11][C:12]([N:19](CC4C=CC(OC)=CC=4OC)C(=O)OC(C)(C)C)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:19][C:12]1[N:11]=[C:10]2[N:38]([CH2:39][CH3:40])[C:7]([C:5]([N:4]([CH:41]3[CH2:43][CH2:42]3)[CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:8][C:9]2=[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl 7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1I, 2.66 g, 4.51 mmol) in dichloromethane (33.8 mL) was added TFA (11.28 mL). The reaction mixture was stirred at rt 45 min and was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2 x) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography using an Isco 40 g column eluting with 4-10% MeOH/CH2Cl2 to yield 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (1.2 g, 3.55 mmol, 79% yield) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:17]([C:12]3[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=4)[N:11]=3)=[CH:18][CH:19]=[N:20]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=415.2 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[N:7]=1.[H-].[Na+].[CH3:19]I>CN(C)C=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][N:14]([CH3:19])[N:13]=2)[N:7]=1
Reactant: c1cc(-c2cc[nH]n2)nc(C2OCCO2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2cccc(C3OCCO3)n2)n1
Reaction time: 1 h

Procedure:
2.50 g of 2-[1,3]dioxolan-2-yl-6-(1H-pyrazol-3-yl)pyridine (11.5 mmol) dissolved in 4 ml of N,N-dimethylformamide are added dropwise to a suspension of 0.48 g of sodium hydride (20 mmol) in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred for 1 hour under a nitrogen atmosphere and then 0.93 ml of methyl iodide (15 mmol) diluted in 1 ml of N,N-dimethylformamide is added dropwise to the reaction mixture. The solution is stirred for 12 hours at room temperature and then the mixture is poured in ice-cold water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 99:1). 0.83 g of a white solid is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[F:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(O)CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1cc(C(=O)CCC(=O)O)ccc1F

Procedure:
A stirred mixture of 3-(4-fluoro-3-nitrobenzoyl)propionic acid, cyclohexene, palladium on charcoal, and ethanol, was heated under reflux for 18 hours. Evaporation of the filtered solution gave 3-(3-amino-4-fluorobenzoyl)propionic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:24])[CH3:23])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28]C1C(=O)C=CCC1(C)C)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:23])[CH3:24])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28][CH:9]1[C:2](=[O:1])[CH:3]=[C:4]([CH3:10])[CH2:5][C:6]1([CH3:8])[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: COc1cc(CC2C(=O)C=C(C)CC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Yield: 60 %

Procedure:
This compound was prepared from isophorone (0.168 g, 1.22 mmol) in the manner previously described for enone 13, affording 0.342 g (60%) of the alkylation product (Rf 0.40, 2:1 hexanes/ethyl acetate) as a colorless, oily solid. 1H NMR (400 MHz, CDCl3) δ0.20 and 0.22 [2s, 2×3H, Si(CH3)2 ], 0.99 [s, 9H, SiC(CH3)3 ], 1.00 and 1.02 (2s, 2×3H, geminal-CH3 's),b 1.91 (s, 3H, 3-CH3), 2.18 and 2.28 (ABq, 2H), 2.42 (dd, 1H), 2.82 (dd, 2H), 3.70 (s, 3H, OCH3), 5.82 (sl d, 1H, 2-H), 6.71 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:16]2[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=2)=[CH:7][N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ncc(Br)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnn(C)c2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-bromo-2,4-bis(methyloxy)pyrimidine (commercially available from Aldrich, 500 mg, 2.283 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (132 mg, 0.114 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (commercially available from Maybridge, 997 mg, 4.79 mmol) and 1M/H2O sol. of NaHCO3 (5 ml, 5.00 mmol) were added. After 2 h stirring at 90° C., the reaction mixture was cooled at room temperature, diluted with water (5 ml) and extracted with DCM (3×10 ml). The obtained residue was purified by flash chromatography first eluting with cyclohexane/EtOAc 4:1 then with 1:2 cyclohexane/EtOAc. 483.7 mg of the title compound were obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:1]1[CH:2]=[C:3]([S:7]([O:21][C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[O:13][CH3:12])(=[O:9])=[O:8])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(C)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)ccc1OS(=O)(=O)c1cccc(C)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of m-toluenesulfonyl chloride (0.53 g, 2.78 mmol) and 2-methoxy-4-methylphenol (0.38 g, 2.75 mmol) in DCM (10 mL) was treated with triethylamine (0.5 mL, 3.6 mmol) and stirred at ambient temperature. After 18 hours the reaction was concentrated in vacuo, the residue dissolved in 1:1 hexane:DCM, filtered, and the filtrate evaporated under high vacuum giving the title compound as a white solid (0.79 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.72 (hr s, 1H), 7.66 (br d, 1H, J=7.2 Hz), 7.45 (br d, 1H, J=7.2 Hz), 7.38 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=8.1 Hz), 6.67 (m, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][S:39]([CH3:38])(=[O:41])=[O:40])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cc(CN)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNS(C)(=O)=O)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
To a solution of 5-aminomethyl-2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (0.382 g, 0.944 mmol) and Et3N (0.191 g, 1.89 mmol) in dry THF (20 mL) was added MsCl (0.162 g, 1.42 mmol) at room temperature. After the addition the mixture was stirred at room temperature for 2 h saturated aqueous NaHCO3 (20 mL) was added. THF was then removed, and the aqueous residue was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over MgSO4. After filtration the solvent was removed to afford 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-(methanesulfonylamino-methyl)-benzoic acid methyl ester as a pale yellow foam (0.460, 100%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[F:13][C:14]([F:30])([F:29])[CH:15]([NH2:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:28][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:17]=1)[C:14]([F:13])([F:30])[F:29])=[O:8]
Reactant: NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1F)NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2-fluorocinnamic acid (33 mg), 2,2,2-trifluoro-1-(3-morpholin-4-yl-phenyl)-ethylamine, Preparation 23 (52 mg), DMAP (24 mg), EDC.HCl (80 mg), and Et3N (80 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 65 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:19]([C:23]([F:26])([F:25])[F:24])[O:20]2)=[CH:15][C:14]=1[Cl:32]>>[Cl:32][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[CH2:12][N:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]1=[O:8])[O:20][CH:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cn3cc(Cl)ccc3=O)cc2OC1C(F)(F)F
Yield: 38.1 %

Procedure:
The formation of the ester was performed according to the procedure outlined in Example 157 Step 4 starting with 97 mg of 5-chloro-2-pyridinol, 20.7 mg of sodium hydride (60% dispersion in mineral oil) and 300 mg of the bromide from Example 157 Step 3. The compound was purified on the FlashMaster® chromatography system eluting with 25% EA/hexane then 50% EA/hexane to give 128 mg (38%) of the desired compound.
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16](F)[CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:21]C1C=C2C(C(C3CCCCC=3)=CN2)=CC=1>>[CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: Fc1ccc2c(C3=CCCCC3)c[nH]c2c1
Reactant: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Product: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 60 %

Procedure:
This compound was prepared in the manner as described above for (2a) by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal with 4-(6-fluoro-1H-3-indolyl)-cyclohex-3-en-isomer ethylene ketal (9.54 g) in 60% yield (5.83 g) as a white solid: mp 158-159° C.
Reaction SMILES: [CH2:1]([C:11]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]2[CH:22]=[C:21]([I:24])[CH:20]=[CH:19][C:18]=2C2C1=CC(I)=CC=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36]1([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:26]([C:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:45]2[CH:44]=[C:43]([N:42]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:48]=[CH:47][C:46]=2[C:18]2[C:23]1=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(I)ccc2-c2ccc(I)cc21
Reactant: c1ccc(Nc2ccccc2)cc1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(I)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 96 h

Procedure:
9,9-Didecyl-7-iodofluoren-2-yl)diphenylamine (15) (0.49 g, 0.66 mmol) was subjected to similar Ullmann condensation reaction with 9,9-didecyl-2,7-bis(phenylamino)fluorene (0.17 g, 0.27 mmol) to yield the desired product. (9,9-Didecyl-7-iodofluoren-2-yl)diphenylamine (15) was prepared by reaction of 9,9-didecyl-2,7-diiodofluorene (reported in Example 7) with one equivalent of diphenylamine. TLC analysis (60:40 hexanes/CH2Cl2) indicated condensation was complete after 4 days. The orange-brown oil was further purified by column chromatography on silica gel using first (70:30) hexanes/CH2Cl2 followed by (80:20) hexanes/CH2Cl2 resulting in 0.42 g of yellow solid (85% yd). Anal. Calcd for C135H174N4: C, 87.51%, H, 9.46%, N, 3.02%. Found: C, 87.37; H, 9.53%, N, 3.02%. 1H NMR (300 MHz. C6D) δ: 7.09 (d, 2H), 7.04 (s, 1H), 7.0 (dd, 5H), 6.93 (s, 1H), 6.85 (t, 6H), 6.73 (t, 6H), 6.53 (m, 3H), 1.33 (m, 4H), 0.87 (bd, 28H), 0.52 (bt, 10H). 13C NMR (300 MHz, C6D6) δ: 152.4, 148.5. 147.0, 136.6, 129.4, 124.2, 123.9, 120.2, 119.6, 119.1, 55.2, 40.3, 32.2, 30.4, 30.0, 29.8, 29.7, 29.6, 24.4, 22.9, 14.2. FT-IR (KBr, cm1): 3036 (vArCH), 2926; 2854 (valCH), 1593 (vArC═C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13].C(O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: C=C(C#N)CCC#N
Solvent: CO
Solvent: CCO
Product: N#CCCC(C#N)CSc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 3,4-dichlorobenzenethiol (3.00 ml), methyleneglutaronitrile (2.57 ml), ethanol (25 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 4 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give 6.14 g of 2-(3,4-dichlorophenylthiomethyl)glutaronitrile.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Yield: 50 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-30 by using (4-chloro-3-nitrophenyl)methanamine hydrochloride (0.700 g, 3.14 mmol), cyclopropylcarbonyl chloride (0.490 g, 4.71 mmol), DIPEA (3.0 mL) and THF (15 mL) to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (d, J=6.0 Hz, 2H), 1.55-1.61 (m, 1H), 4.33 (d, J=6.0 Hz), 7.55 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.68 (br s, 1H); MS (m/z): 255.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:8])[NH2:7].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:8][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:7]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3,4,5-Trimethoxybenzothioamide (2.5 g) and 90% ethyl bromopyruvate (2.62 g) were added to ethanol (20 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) and further recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][CH:2]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: COc1cc(C(O)c2ccccc2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(OC(C)=O)c2ccccc2)ccn1
Reaction time: 5 h

Procedure:
A mixture of 104 g of 4-(α-hydroxybenzyl)-2-methoxypyridine, 100 ml of acetic acid anhydride and 100 ml of pyridine was heated under stirring for 5 hours in an oil bath kept at 110° C. After the reaction solution was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5-20% ethyl acetate/hexane, to give 112 g of the target compound.