Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH:22]([C:27]3[C:35]([Br:36])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]=2[CH:18]=1)(C)(C)C>ClCCl>[Br:36][C:35]1[C:27]([CH:22]2[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]3[CH:18]=[C:17]([CH2:16][CH2:15][NH2:14])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:28][C:29]2[O:33][CH2:32][O:31][C:30]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Trifluoroacetic acid (1.2 mL) was added dropwise to a solution of {2-[4-(6-bromo-benzo[1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethyl}-carbamic acid tert-butyl ester (0.15 g, 0.3 mmol) in dichloromethane (1.5 mL), and stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (15 mL) and washed with cold saturated NaHCO3. Organic layer dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative silica gel chromatography using 20% MeOH/DCM and gave the product as a colorless solid (0.115 g, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([F:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(F)c1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(C(F)CCNC(=O)OC(C)(C)C)c1)CCC

Procedure:
Sonogashira coupling of tert-butyl 3-(3-bromophenyl)-3-fluoropropylcarbamate and 4-ethynylheptan-4-ol following the method described in Example 12 gives tert-butyl 3-fluoro-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[NH2:16][C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH2:8][OH:7])[C:6]([NH:16][C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:20]=[CH:21][CH:22]=1)=[O:10]
Reactant: CCOC(=O)C(Cc1cccc(N)c1)OC(C)C
Reactant: O=C1OCCC1Oc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(Cc1cccc(NC(=O)C(CCO)Oc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
20 mg of 3-(2,4-Dichlorophenoxy)dihydrofuran-2-one and 30 mg of ethyl 3-(3-aminophenyl)-2-isopropoxypropanoate were dissolved in 1 ml of toluene, and the solution was heated under reflux for 8 hours. After removing the solvent under a stream of nitrogen, the residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 2 ml of water and 0.14 ml of 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was collected, and the solvent was removed under a stream of nitrogen. The residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 6.8 mg of the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: Fc1cncc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68.1 %

Procedure:
To a −78° C. solution of LDA (2 M solution in heptane/THF, 14.2 mL, 28.4 mmol) in anhydrous THF (45 mL) was added a solution of the 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred at −78° C. for 45 minutes. Then, a solution of ethyl chloroformate (24 mL, 284 mmol) was added slowly over 10 minutes. After stirring for 20 minutes, the reaction mixture was quenched with a saturated solution of NaHCO3. The mixture was extracted into ethyl acetate (3×100 mL). The combined organic extracts were extracted with water (2×200 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 3-bromo-5-fluoropyridine-4-carboxylate (4.8 g, 69% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][O:13][CH3:14])=[CH:7][N:8]=1
Reactant: COc1ccc(O)cn1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OC)nc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol, 1 eq.) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (15.5 g, 0.19 mol, 1.2 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. 1H NMR (400 MHz; CDCl3) 7.97 (d, 1H), 7.35 (dd, 1H), 6.70 (d, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.51 (s, 3H). LRMS (M+H+) m/z 170.1
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[NH:11][C:12]=2[CH2:13]CCCN)=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][C:23](C2N=C(C)NC=2CCCCN2C(=O)C3C(=CC=CC=3)C2=O)=[CH:22]C=1.NN>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:18][CH2:22][CH2:23][CH2:24][NH2:25])[NH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)nc2)c(CCCCN2C(=O)c3ccccc3C2=O)[nH]1
Reactant: Cc1nc(-c2ccc(Cl)nc2)c(CCCCN)[nH]1
Agent: NN
Solvent: CCO
Product: Cc1[nH]c(CCCCN)nc1-c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 75 %

Procedure:
4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (1.0 g, 2.54 mmoles) in ethanol (25 ml) was added hydrazine (0.24 ml, 7.6 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×100 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butylamine (500 mg, 75%). MH+(265).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1)([CH3:14])[CH3:13]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)N
Product: Cc1nc(NC(C)C)ccc1[N+](=O)[O-]

Procedure:
6-Chloro-2-methyl-3-nitro-pyridine (0.5 g) was treated with isopropyl amine according to General Procedure U to give isopropyl-(6-methyl-5-nitro-pyridin-2-yl)-amine LCMS (m/z): 196. This was reduced under hydrogen atmosphere according to General Procedure Z to give N*2*-Isopropyl-6-methyl-pyridine-2,5-diamine (0.35 g), LCMS (m/z): 166. This was converted to 6-isopropylamino-2-methyl-pyridine-3-sulfonyl chloride according to General Procedure AA.
Reaction SMILES: C(O[CH:5]=[C:6]([Cl:9])[CH:7]=[CH2:8])(=O)C.[C:10]1([S:16]([C:19]#[N:20])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([S:16]([C:19]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:20]=2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C=CC(Cl)=COC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A tubular reactor (capacity:1 ml, voidage:100%) was heated to 100° C. To the reactor was fed a toluene solution of 2-chloro-1,3-butadienyl acetate (44 volume percent, 3.0 moles/L) at a flow rate of 6.4 ml/hour, and benzenesulfonyl cyanide (79 volume percent, 4.69 moles/L) at a flow rate of 4.1 ml/minute for 1 hour (residence time 5.7 minutes). The effluent was ice-cooled for recrystallization, the crystals were collected by filtration, washed with cold toluene and dried under reduced pressure using a vacuum pump to give 4.39 g of 2-benzenesulfonyl-5-chloropyridine (yield 90.1%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[C:21]([O:23][CH3:24])=[O:22]>CO.O>[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.9 %

Procedure:
0.15 g of sodium borohydride was added in one portion, at a temperature in the region of 20° C. and under an inert atmosphere, to a stirred solution of 1.6 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]-piperidine-3-carboxylate in 15 cm3 of methanol. The mixture was subsequently stirred for 2.5 hours at a temperature in the region of 25° C. 15 cm3 of distilled water were then added dropwise over approximately 10 minutes while maintaining at a temperature in the region of 15° C. The mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 20 cm3 of distilled water. The mixture was extracted with a total of 100 cm3 of dichloromethane. The organic phases were combined, dried over sodium sulfate, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The solid obtained was purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 20-45 μm; diameter 3 cm; height 35 cm), elution was carried out with a mixture of ethyl acetate and cyclohexane (8/2 by volume), and 15-cm3 fractions were collected. Fractions 38 to 59 were combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylate were thus obtained in the form of a foam.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:14]>O>[Br:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([Cl:14])=[CH:3][CH:4]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-amino-3-bromo-2-methylpyridine (239 g, 1278 mmol) in concentrated HCl (1.0 L) was cooled to −5° C. A solution of sodium nitrite (238 g, 3450 mmol) in water (1.0 L) was added dropwise over 1 hour while maintaining the temperature of the reaction between −5 and 5° C. After the addition was complete, the reaction was stirred for 1 hour, and then the cooling bath was removed and the reaction was warmed to r.t. and stirred for 16 hours. The reaction was then poured onto ice and 5N NaOH (1.7 L) was added to adjust the pH of the solution to 13. The mixture was extracted 3 times with EtOAc (3 L and 2×2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 100% methylene chloride afforded 3-bromo-6-chloro-2-methylpyridine. 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: NCCON
Reactant: CCOCCCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 4.6 mmol (1.20 g) of 3', 4'-dichloro-4-ethoxybutyrophenone (melting point 52°-54° C), 4.7 mmol (0.70 g) of 2-aminooxyethylamine dihydrochloride, 2.5 ml of pyridine and 5 ml of absolute ethanol was refluxed for 2.5 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in 40 ml of water. This solution was washed twice with 15 ml of petroleum ether (boiling point 40°-60° C), rendered alkaline with 10 ml of 2N sodium hydroxide solution and then extracted three times with 20 ml of ether. After washing the collected ether extracts with 10 ml of water and drying over sodium sulphate, the ether was evaporated in vacuo. The resulting base was then evaporated to dryness three times with 20 ml of toluene. Subsequently the hydrochloride was prepared by means of alcoholic hydrochloric acid. This was recrystallized from an ether/petroleum ether mixture. The melting point of the resulting above entitled compound was 92°-94° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][N:6]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:29]>C1COCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][N:6]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH2:29])=[O:21])=[CH:22][CH:23]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Reaction time: 2 h
Yield: 19.1 %

Procedure:
A solution of 76 mg (2.1 mmol) 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester in 2 ml THF/Methanol 1.1 was treated with 0.5 ml of 1N LiOH. After stirring for 3 h the reaction mixture was acidified with 1N HCL, taken up in EtOAc and washed with water to give 65.5 mg of pure 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid MS (API): 327.5 (M−H). A solution of 47 mg (1.3 mmol) 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid and 27 mg (0.16 mmol) of 1,1-carbonyl diimidazole in 1 ml of THF was stirred under reflux for 1 h, then 32 mg (0.4 mmol) of Ammonium acetate was added and the stirring under reflux was continued for another 2 h. The reaction mixture was taken up in EtOAc and washed with 1N HCL and water. The crude product was crystallized in Ether/Heptan to give 25 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzamide. MS (ESI): 328.4 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]([CH3:8])([OH:7])[C:5]#[CH:6].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]([CH3:8])([OH:7])[CH:5]=[CH2:6]
Reactant: C#CC(C)(O)C(OC)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(O)C(OC)OC

Procedure:
198 G. of 4,4-dimethoxy-3-methyl-but-1-yn-3-ol are dissolved in 960 ml. of high-boiling petroleum ether and, after the addition of 19.35% palladium catalyst and 19.3 g. of quinoline, hydrogenated under normal conditions. After the uptake of 33.5 l. of hydrogen, the hydrogenation is stopped. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-1-en-3-ol boils, after rectification, at 70°-72° C./18 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(Nc2ccc(F)cc2F)c1
Reaction time: 1 h
Yield: 22.3 %

Procedure:
A mixture of 3'-(2,4-difluorophenylamino)-4'-nitroacetophenone (8.5 g), iron powder (8 g), and ammonium chloride (0.8 g) in ethanol (100 ml) and water (50 ml) was refluxed with stirring for 1 hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. The residual oil was purified by column chromatography on silica gel (150 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give a powder of 4'-amino-3'-(2,4-difluorophenylamino)acetophenone (1.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O.O1CCCC1>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:21][CH:22]=1
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Yield: 65.4 %

Procedure:
A mixture of 37.8 g of 8-bromo-1-octanol, 30.77 g of 4-phenylphenol, 8.31 g of sodium hydroxide and 34 g of N-methyl-N,N-diocyl-1-octanaminium chloride in 100 ml of water and 175 ml of tetrahydrofuran was refluxed for 17 hours. The tetrahydrofuran was removed and the residue extracted with warm chloroform. The chloroform extract was washed with water, dried and the solvent removed. The residue was recrystallized from methanol, giving 35.26 g of the desired compound as a white solid, mp 101°-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:24]>CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:24])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c2cc(C(N)=O)[nH]c2c1
Yield: 46 %

Procedure:
20.0 g 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole (see preparation of the primary products in connection with Example 1) are heated together with 200 ml each of methanol and liquid ammonia in the autoclave for 16 hours, to 100° C. The solution is evaporated and the residue is chromatographed on silica gel (fluxing agent: chloroform/methanol 98:2). There is obtained 8.5 g (~46% of theory) 4-benzyloxy-2-carbamoyl-6-methyl indole; m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[N:5]([CH3:12])[N:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]([CH3:12])[N:4]=1
Reactant: COC(=O)c1cc(OC)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a solution of methyl 3-methoxy-1-methyl-1H-pyrazole-5-carboxylate (2.01 g, 11.8 mmol) in methanol (15 mL) was added 8N aqueous sodium hydroxide solution (3.00 mL), and the mixture was stirred at room temperature for 18 hr. 6N Hydrochloric acid (4.00 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration, washed with water and air-dried. The precipitate was suspended in diisopropyl ether, and the mixture was stirred at 80° C. for 15 min. After allowing to cool to room temperature, the precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (746 mg, yield 40%) as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][CH2:25][CH2:26][C:27]1[O:28][C:29]([CH2:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:31]=1)(C)C>C1COCC1>[OH:24][CH2:25][CH2:26][C:27]1[O:28][C:29]([CH2:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CCOCc2ccccc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCc1ccc(CCOCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0 h
Yield: 99.7 %

Procedure:
Tetrabutylammonium fluoride (1.0M in THF, 3.06 mL, 3.06 mmol) was added to the solution of compound 255D (1.1 g, 3.06 mmol) in 10 mL of THF at 0° C. The reaction mixture was stirred at rt for 0.10 minutes, quenched by sat. NH4Cl and extracted with ether (3×). The combined extracts were dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 10% EtOAc/90% CH2Cl2 gave 750 mg (3.05 mmol, 99.6%) of compound 255E as a light yellow oil.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29](O)[N:28]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[N:28]=[C:29]([O:5][CH2:6][C@@H:7]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:8])[CH:30]=[CH:31][CH:32]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](COc1cccc(Nc2cc(Br)cn(C)c2=O)n1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A mixture of 107a (964 mg, 5.5 mmol), 5-Bromo-3-(6-hydroxypyridin-2-ylamino)-1-methylpyridin-2(1H)-one 101a (4 g crude, 16.5 mmol), Cs2CO3 (5.38 g, 11 mmol) in DMF (20 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with DCM, washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give 107b (550 mg, 22%) as a brown solid. MS-ESI: [M+H]+ 453.1
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1>[Pt]>[CH:5]1([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCC1
Agent: [Pt]
Product: Cl[Si](Cl)(Cl)C1CCCC1
Yield: 19 %

Procedure:
The reaction was performed by agitating the reaction mixture, which was prepared from 19.1 g (0.141 mole) of trichlorosilane, 9.2 g (0.135 mole) of cyclopentene and 0.13 g of the catalyst I corresponding to 23 ppm by weight as platinum based on the total amount of trichlorosilane and cyclopentene, in a glass flask at 30° C. for 22 hours under normal pressure. Only about 22% of the starting reactants had been reacted after the end of this reaction time as determined by the gas chromatographic analysis. Treatment of the reaction mixture after the reaction was performed in the same manner as in Example 1 to give 5.2 g (0.0256 mole) of cyclopentyl trichlorosilane in a yield of 19% as isolated based on the theoretical value.