Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18]/[C:19](/[CH:27]=O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:18][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:27]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: C/C(C=O)=C\c1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Butyllithium (135 mL of 2.5 N solution) was added to 600 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (30.5 g) in 220 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 60 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of α-methyl-trans-cinnamaldehyde (23.2 g) in 100 mL of anhydrous THF was added to the reaction at −65° C. over a period of 70 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (125 mL) to a pH of 2.8. The aqueous layer was extracted with 100 mL of ether twice and with 100 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 100 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 25.8 g of the desired 4-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.53 (d, 1H), 7.43 (m, 4H), 7.37 (dd, 1H), 6.97 (broad s, 1H), 6.02 (d, 1H), 2.07 (s, 3H)
Reaction SMILES: C([Li])(CC)C.[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN(C)CCN(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(OCC)C.O>[N:6]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A 1.3 M solution of sec-butyl lithium in cyclohexanes (1642 mL, 2.13 mol) was added dropwise to a solution of 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (300 g, 1.37 mol) and N,N,N′,N′ tetramethyl-1,2-ethanediamine (248 mL, 1.64 mol) in dry diethyl ether (2.5 L) at −78° C. The reaction mixture was stirred for 2 hours at this temperature and ethyl chloroformate (143.9 mL, 1.50 mol) was added dropwise to the mixture at −78° C. After the addition, the reaction was allowed to warm to room temperature overnight. Water (1 L) was added carefully to the mixture and the organic layer was separated and dried (Na2SO4). The solution was concentrated and the residue was purified by silica-gel column chromatography (PE:EA=10:1), giving 150 g (38%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:45])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A solution of 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (236.1 mg, 0.65 mmol) in tetrahydrofuran (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.27 mL, 1.54 mmol) and nicotinoyl chloride hydrochloride (115 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/hexanes) afforded 6-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]phenyl}-propionylamino)-nicotinic acid methyl ester (219.6 mg, 72.3%) as a white solid: mp 110-1 15° C.; EI-HRMS m/e calcd for C27H28N4O4 (M+) 472.2110, found 472.2109.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Br:18]P(Br)Br>C(Cl)Cl.C1COCC1>[Br:18][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(NC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(Br)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl 3-(1-hydroxyethyl)phenylcarbamate (5.8 g, 24.44 mmol) in CH2Cl2 (30 mL) and THF (20 mL) at 0° C. was added tribromophosphine (1 M solution in CH2Cl2, 24.44 mL, 24.44 mmol). The reaction was stirred at 0-10° C. for 1.5 h and then quenched with water. The mixture was extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound (5.7 g, 78% yield) as a colorless oil. LCMS, [M+Na]+=322.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)—N—((R)-1-(4-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (5.4 g, 19.4 mmol) in methanol (150 mL) at 0° C. was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 19.4 mL, 77.6 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The solvent removed in vacuo, and the crude material was dissolved in saturated aqueous sodium bicarbonate and dichloromethane. The mixture was stirred for 45 min to give a clear solution. The phases were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (3.1 g, 92%, >96% ee, determined by Mosher's method).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13]Br>ClC(Cl)C>[Br:13][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]=1[OH:8]
Reactant: BrBr
Reactant: Oc1ccc(F)cc1C(F)(F)F
Solvent: CC(Cl)Cl
Product: Oc1c(Br)cc(F)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
9 g (500 mmol) of 4-fluoro-2-(trifluoromethyl)-phenol is dissolved in 100 ml of dichloroethane, the solution is stirred at 50° C. and a solution of 9.6 g (60 mmol) of bromine in 30 ml of dichloroethane is instilled in the course of 2 hours. When the instillation is completed, it is stirred for 1 more hour at 50° C. and then concentrated by evaporation in a vacuum. The oily residue is dissolved in 100 ml of dichloroethane and shaken out three times with 20 ml of water each. The organic phase is dried on magnesium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) ethyl acetate/hexane. 8.07 g (31.15 mmol)=62.3% of the theoretical yield is obtained as a partially crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I-:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][I:46])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: [I-]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To the solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (80 mg, 0.253 mmol) in DCM (2.5 ml), was added Ph3P (133 mg, 0.505 mmol), imidazole (34.4 mg, 0.505 mmol) and iodide (128 mg, 0.505 mmol) at 0° C., The mixture was stirred at 0° C. for 10 min, then at room temperature for 1 h. The reaction was quenched with sat. Na2SO3 solution. The aqueous phase was extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (50 mg, 46.4% yield) as colorless oil. LCMS: rt=4.47 min
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (82.2 mmol) trans-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 l CH2Cl2 was treated with 12.83 g (131.5 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 10.85 ml (98.6 mmol) N-methylmorpholine and at 0° C. with 18.91 g (98.64 mmol) EDCI and 12.62 g (82.2 mmol) HOBT. The reaction mixture was stirred 2 h at room temperature and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 24.25 g (quantitative) trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester, mp: 130-140° C., slowly dec.; MS: 287 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([F:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of 2-amino-5-fluoropyridine (8.6 g, 77 mmol) in conc. sulfuric acid (40 ml) was added dropwise (30 min) fuming nitric acid (3.25 ml, 77 mmol) at a temperature of +3° C. The reaction mixture was stirred at room temperature for 1 h and at +55° C. for 1 h. The mixture was poured onto ice and neutralized with 10 M sodium hydroxide and was extracted with methylene chloride. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel, using (i) methanol:methylene chloride (1:20) and (ii) diethyl ether:petroleum ether (1:1) as eluent to give the title compound (0.44 g, 3.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[C:10][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1
Reactant: C#Cc1ccc(NC)nc1
Reactant: Cc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(C#Cc2c(Cl)ccnc2C)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20 mg (0.08 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 11 mg (0.09 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine using 1.5 mg (0.01 mmol) CuI, 5.5 mg (0.01 mmol) PdCl2(PPh3)2 and 0.11 mL (0.8 mmol) triethylamine in 1 mL dry DMF. After completion of the reaction the product is purified by RP-HPLC using a ACN/H2O gradient (95:5 to 70:30). Yield: 20 mg (98%).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15]([NH:17][NH2:18])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([NH:17][N:18]=[C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCCCCCC1
Product: CC(C)(C)OC(=O)NN=C1CCCCCCC1

Procedure:
According to a published procedure, cyclooctanone Compound 21a was reacted with hydrazinecarboxylic acid tert-butyl ester to produce an intermediate N′-cyclooctylidene-hydrazinecarboxylic acid tert-butyl ester Compound 21b (as described in Ghali N K and Venton D L, J. Org. Chem., 1981, 46, 5413). According to the published procedure, Compound 21b was carried forward to provide cyclooctyl-hydrazine hydrochloride Compound 21c.
Reaction SMILES: CI.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[C:7]2[CH3:15].[C:16]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:16])[C:9](=[O:14])[CH:8]=[C:7]2[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)[nH]c2ccc(F)cc12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2ccc(F)cc12
Reaction time: 8 h
Yield: 68.6 %

Procedure:
MeI (130 mg, 0.914 mmol) was added into a suspension of 6-fluoro-4-methylquinolin-2(1H)-one (135 mg, 0.762 mmol) and Cs2CO3 (248 mg, 0.762 mmol) in DMF (10 mL). The reaction mixture was stirred overnight and partitioned between Na2CO3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was washed with hexanes and dried to give 6-fluoro-1,4-dimethylquinolin-2(1H)-one (100 mg, 68%) as a white solid which was used without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:8][C:7]=1[CH3:23])=O)C.[NH3:24]>CO>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[S:10][C:6]([C:4]([NH2:24])=[O:3])=[C:7]([CH3:23])[N:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reactant: N
Solvent: CO
Product: COc1cc(-c2nc(C)c(C(N)=O)s2)cc(OC)c1OC
Reaction time: 168 h
Yield: 71 %

Procedure:
Into 200 ml of methanol, 16.9 g (0.05 mol) of 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester produced in Example 3 was dissolved, and 25 ml of an aqueous 28% solution of ammonia was added to the solution. The mixture was left at room temperature for 7 days, and then condensed to dryness. The dried residue was recrystallized from a mixture of methanol and water to obtain the object amounting to 10.9 g (yield of 71%) consisting of colourless needle-like crystals melting at 196° to 197° C.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(OCC)C>ClC1C=CC=CC=1Cl>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[C:7]2[C:6](=[CH:12][CH:11]=1)[N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17](=[O:18])[NH:8]2
Reactant: Nc1cc(C(F)(F)F)ccc1-n1ccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2ccnc12
Yield: 75.4 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (17.00 g; 74.8 mmol; 1 eq) in anhydrous 1,2-dichlorobenzene (375 mL), commercially available carbonyldiimidazole (24.72 g; 149.7 mmol; 2 eq) is added under an argon atmosphere. This reaction mixture is allowed to stir under reflux for 2 hours. The expected quinoxalinone precipitates as a grey powder during the reflux. The initial crystal clear solution quickly turns black after heating and becomes non homogeneous. This crude reaction mixture is allowed to precipitate at 4° C. during 48 hours. The grey powder formed is then filtered off on a fritted glass. This solid is transferred in a 1 L flask, diluted in fresh ethyl acetate (500 mL) and heated to gentle reflux for two hours. Hot filtration and then several washings of the solid with diethyl ether afforded the title compound (14.28 g; 56.4 mmol; 75%) as a grey powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[NH:27][CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1c(OCCN(Cc2ccccc2)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1c(N)cccc1OCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a mixture of N-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg) in ethanol (40 mL) at 50° C. was added a solution of hydrazine hydrate (1.3 g) in ethanol (10 mL). The reaction was allowed to stir for 3 hr then the catalyst filtered through celite and the solvent removed. Purification by chromatography (30% ethyl acetate-hexane) afforded 380 mg (78.9%) of a clear oil; MS EI m/e 371 (M+); IR (film) 3400, 3350, 1680 cm-1.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].F[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>CN1CCCC1=O.O>[CH:5]1[CH:6]=[CH:7][C:2]([O:1][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: [O-]c1ccccc1
Reactant: Fc1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(Oc2ccccc2)cc1
Yield: 54.2 %

Procedure:
A stirred solution containing 14.8 g (0.112 mole) of potassium phenoxide and 13.1 g (0.10 mole) of p-fluorochlorobenzene in 100 ml of N-methyl-2-pyrrolidinone is heated at reflux for a period of time necessary to effect complete reaction, as determined by vapor phase chromotography techniques. The crude reaction mixture is cooled and diluted to a volume of 400 ml with water, whereupon it is extracted with several portions of ether. The combined organic extracts are washed with a 5% sodium hydroxide solution, water, and a saturated sodium chloride solution, dried (magnesium sulfate), and concentrated in vacuo. Distillation at reduced pressure affords 11.1 g (54%) of material, b(0.05 mm) 73.5°-75.5°, whose spectral properties are in agreement with the desired structure.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)s1
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: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 80 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g), 4-fluorophenylboronic acid (0.91 g) and tetrakis(triphenylphosphine)palladium (289 mg) in 1,2-dimethoxyethane (10 ml) was added aqueous solution of sodium carbonate (2M, 6.5 ml) followed by stirring at 80° C. for 6 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 30% dichloromethane in n-hexane to give 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.16 g, 98.3%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: Fc1ccc([S-])c(F)c1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Sc2ccc(F)cc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (5.5 g) in N,N-dimethylformamide (9 ml) was added dropwise to a solution of 4'-chloro-3'-nitroacetophenone (5 g) in toluene (50 ml). The mixture was stirred at room temperature for 2 hours, washed with water, dried and evaporated to dryness. The residue was washed with a mixture of hexane and ethanol to give crystals of 4'-(2,4-difluorophenylthio)-3'-nitroacetophenone (7.4 g).
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: CC(C)CCO
Product: CCCCCCCC[Sn](CCCCCCCC)(OCCC(C)C)O[Sn](CCCCCCCC)(CCCCCCCC)OCCC(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
972 g (2.7 mol) of di-n-octyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2100 g (23.9 mol) of 3-methyl-1-butanol were placed in a 5000 mL volumetric eggplant-shaped flask. The flask was attached to an evaporator to which was connected an oil bath equipped with a temperature controller, a vacuum pump and a vacuum controller. The purge valve outlet of the evaporator was connected to a line containing nitrogen gas flowing at a normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 145° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 3-methyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 3-methyl-1-butanol was distilled with the pressure inside the system at 74 to 35 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the flask was taken out of the oil bath, the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1176 g of reaction liquid were obtained in the flask. Based on the results of 119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-octyl-1,3-bis(3-methylbutyloxy)distannoxane was confirmed to have been obtained at a yield of 99% based on di-n-octyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 14120 g of 1,1,3,3-tetra-n-octyl-1,3-bis(3-methylbutyloxy)distannoxane.