Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[I:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
A solution of 1.15 g of 2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine in 40 ml of dioxan was treated with a solution of 0.28 g of sodium hydrogen carbonate in 10 ml of water and stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between chloroform and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with chloroform. The chloroform extracts were dried over sodium sulphate, concentrated to 30 ml in a vacuum and chromatographed over 50 g of silica gel. 1.05 g of the desired product were eluted with chloroform/ethanol mixtures containing 3 to 7% ethanol. After recrystallization from ethyl acetate/diethyl ether there was obtained 0.955 g of 8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C. which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH2:12][CH2:13]Br>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: Clc1cccc(Cl)c1CCBr
Product: CC(CCc1c(Cl)cccc1Cl)c1ccncc1
Yield: 55.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 2,6-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.45 g of the desired compound (yield: 55.3%). The resulting compound was identified as 1-(2,6-dichlorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 11) by the following analytical results.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1.[CH3:19][NH:20][O:21][CH3:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:20]([CH3:19])[O:21][CH3:22])=[O:14])=[CH:10][CH:11]=1
Reactant: CNOC
Reactant: O=C=Nc1ccc(OCc2ccccc2F)cc1
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccccc2F)cc1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of 4-(2-fluorobenzyloxy)phenyl isocyanate (24.3 g) in benzene (150 ml), a solution of N,O-dimethylhydroxylamine (20 g) in benzene (100 ml) is added dropwise at 20° to 30° C., and the resulting mixture is stirred at the same temperature for 30 minutes. The reaction mixture is concentrated in vacuo, and the residual crude crystals are recrystallized from ethanol to give N-[4-(2-fluorobenzyloxy)phenyl]-N'-methyl-N'-methoxyurea (Compound No. 1) (18 g) as white scales. M.P., 99° to 100° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[C:19]([F:29])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH+:9]([O-:36])[CH2:10][C@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Product: O=C1O[C@H](C[NH+]([O-])C(=O)c2ccc(Cl)s2)CN1c1ccc(N2CCOCC2)c(F)c1

Procedure:
is obtained by treating 5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide from Example 1 with the magnesium salt of monoperoxyphthalic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][O:24][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]nc(N)c(n1)c23
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc3ccc4c(=O)[nH]nc(N)c(n2)c34)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A mixture of 4-amino-2-(2-C-methyl-β-D-ribofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene-7-one (65 mg, 0.19 mmol) in DMF, tert-butyldimethylsilyl chloride (70 mg, 0.45 mmol) and imidazole (61 mg, 0.90 mmol) was stirred overnight at room temperature and then concentrated in vacuo. The oily residue was dissolved in CH2Cl2 (20 mL), washed with aq. HCl (0.1 N), sat.aq. NaHCO3, water, brine and dried (Na2SO4). The evaporated residue was purified on silica gel with hexanes/EtOAc (1/1)+0.5% Et3N and EtOAc+0.5% Et3N to yield the target compound 16.1 as colorless oil (38 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.Cl.[CH2:11]([OH:14])[CH2:12][CH3:13]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:9])[O:14][CH2:11][CH2:12][CH3:13])[CH:5]=[N:6][CH:7]=1
Reactant: CCCO
Reactant: N#Cc1cncc(N)c1
Agent: Cl
Product: CCCOC(=N)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
After 5-amino-3-cyanopyridine (380 mg, 3.19 mmol) was dissolved in 1-propanol (15 ml) and hydrogen chloride gas was passed into the solution at a temperature of 0°-5° C. for 15 minutes, the reactor was tight sealed for stirring the mixture at room temperature for 22 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the concentrated mixture to adjust the pH to alkaline. The mixture was extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (Wako Gel C-200, 25 g), and elution was conducted with chloroform: methanol (8:1) to give propyl 5-amino-3-pyridinecarboximidate (526 mg, yield 92%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:26]([OH:28])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:52][C:53]([F:64])([F:63])[O:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C@@H:10]([C:26](=[O:28])[NH:60][CH2:59][C:58]2[CH:61]=[CH:62][C:55]([O:54][C:53]([F:52])([F:63])[F:64])=[CH:56][CH:57]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Yield: 55.3 %

Procedure:
To a solution of the compound (168 mg) obtained in Step 2 in N,N-dimethylformamide (1.7 ml) were successively added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole hydrate (75 mg) and 4-trifluoromethoxybenzylamine (85 mg). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (132 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].Cl.[OH-].[Na+]>C1COCC1.O.CCOC(C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:13]([F:16])([F:15])[CH:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:10])[OH:9]
Reactant: O=Cc1c(I)ccnc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC(c1c(I)ccnc1F)C(F)(F)F
Temperature: 3.5 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
2-fluoro-4-iodo-pyridine-3-carbaldehyde (50 g, 199.2 mmol) was dissolved in dry THF (600.0 mL) and the mixture cooled to 3.5° C. Trimethyl-(trifluoromethyl)silane (102.0 g, 106.0 mL, 717.1 mmol) was added and the mixture was stirred for 10 minutes (temp held at 3.6° C.) then tetrabutylammonium fluoride (9.960 mL of 1 M, 9.960 mmol) (in THF) was added dropwise. The temperature increased rapidly to 23.6° C. on adding ca 0.5 ml. The remainder of the solution was added slowly over 10 minutes—the reaction temperature did not increase further. The reaction mixture became dark brown in colour, and was diluted by slow addition of 6M HCl (500 ml) with the ice bath still in place. The temperature increased to a maximum of 27.8° C. The mixture was stirred for 10 minutes and then re-cooled in an ice bath and sodium hydroxide (120 g total) was added partially as solid, then as a concentrated solution in water. The pH of the final mixture was 6-7. The mixture was diluted with EtOAc (500 ml) and the organic layer removed. The aqueous was extracted with EtOAc (2×500 ml) and the combined organics washed with brine (250 ml), dried (MgSO4), filtered and concentrated to a dark brown oil which was purified by filtration through a silica plug eluting with a 15%-30% EtOAc/Hexanes solvent system. The product was collected as a beige solid (45 g, 71% Yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:30]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:9]3[CH:10]=[C:5]([C:4]([F:3])([F:12])[F:13])[CH:6]=[CH:7][C:8]3=[O:11])=[CH:17][CH:18]=2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
73.6 mg (1.84 mmol, 60% pure) of sodium hydride were added to 300 mg (1.84 mmol) of 5-(trifluoromethyl)pyridin-2(1H)-one in 2.5 ml of DMF. After 30 min of stirring, 500 mg (1.42 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were added. After a further 2 h of stirring at RT, the reaction mixture was warmed to 40° C. for 1 h. Water and ethyl acetate were then added to the mixture, and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 4:1). This gave 522.0 mg (84.7% of theory) of the target compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12]([CH3:14])=O)[CH:5]=1)[CH3:2].Cl.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:5]=[C:6]2[C:7]([C:12]([CH3:14])=[CH:11][NH:10]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CC)c1cccc(NCC(C)=O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc2c(C)c[nH]c2c1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
An intimate mixture of 46.5 g of N,N-diethyl-N'-acetonyl-m-phenylenediamine and 46.5 g of zinc chloride is heated slowly, in which process it starts to melt from 70° C. upwards and from 115° C. upwards the exothermic reaction has to be controlled by external cooling. After maintaining the temperature of 130° C. for 30 minutes, 250 ml of 1N hydrochloric acid are added dropwise in the course of 20 minutes, in which process the temperature stabilised at approximately 90° C. The brown emulsion is stirred for a further 1.5 hours at this temperature and is then rendered alkaline with 100 ml of concentrated sodium hydroxide solution. Ethyl acetate is added to the resultant suspension and the latter is filtered. The organic phase is separated off, active carbon is added to it and it is stirred for 1 hour at room temperature. After filtering and evaporating down, 23 g of 6-diethylamino-3-methylindole is obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl.CN(C)C=O>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[C:8]([F:11])[CH:7]=2)=[O:6])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
2-Chloro-5-fluoro nicotinic acid (5.00 g, 28.48 mmol) (see Preparation 41), was dissolved in dichloromethane (200 ml) and N,N-dimethylformamide (1 drop) was added, followed by addition of oxalyl chloride (7.45 ml, 85.44 mmol). The reaction mixture was held at room temperature for 18 hours, after which the solvent was removed in vacuo. The residue was then suspended in dichloromethane (150 ml) and triethylamine (11.91 ml, 85.44 mmol) added followed by addition of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.85 g, 34.18 mmol). The reaction mixture was then stirred under an atmosphere of nitrogen at room temperature for 64 hours before being washed sequentially with water (2-fold 100 ml), a saturated aqueous solution of sodium chloride (100 ml) and a 10% solution of citric acid in water (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent was removed in vacuo giving 4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g) as an off-white solid.
Reaction SMILES: O[C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:28]([C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[N+:29]=[N-:30]
Reactant: COC(=O)c1ccc([C@H](C)O)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([C@@H](C)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (S)-methyl 4-(1-hydroxyethyl)benzoate (24.8 g, 138 mmol) in toluene (300 mL) was cooled in ice-salt bath (bath temp: −10° C.). DPPA (36.3 mL, 168 mmol) was then added dropwise over 15 min (Bath temp was kept at −10° C. during addition). After 5 min, DBU (25.3 mL, 169 mmol) was added over 8 min. The ice in the bath was allowed to melt and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc (200 mL), and washed with 0.1 N HCl aq. (300 mL). The aqueous layer was extracted with EtOAc (100 mL×2) and the combined organic phase was further washed with 0.1N HCl aq. (300 mL×2), 5% NaHCO3 (300 mL×2), and saturated NaCl (300 mL×2). The organic layers was dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on SiO2 (ISCO: hexane/CH2Cl2=3/1→3/7) to yield the title compound. MS (m/z): 206.2 (m+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:19]([C:21]([F:24])([F:23])[F:22])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 57 %

Procedure:
To a solution of 2,4-difluorophenol (1.9 g, 14.61 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. Then the reaction was quenched with water (200 ml) and extracted with ethyl acetate (3×100 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 2%˜5% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluoro-2-methylphenoxy)-2-nitroaniline as a yellow solid (1.3 g, 30%). Next, to a solution of 4-chloro-5-(2,4-difluorophenoxy)-2-nitroaniline (1.3 g, 4.32 mmol) in ethanol (20 ml) was added hydrogen chloride (conc. 1 ml) followed by the addition of Zn powder (1.7 g, 25.92 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (150 ml), adjusted pH to 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml), dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine as a light yellow solid (600 mg, 51%). Finally, a solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in hydrogen chloride (conc. 2 ml) and TFA (10 ml) was stirred overnight at 80° C. The solution was quenched with water (100 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (73.5 mg, 57%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C(OC(OCC)OCC)C.[C:37]([C@@H:42]([C@H:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])O)[OH:43])([O:39][CH2:40][CH3:41])=[O:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:49]([O:48][C:46]([C@H:44]1[C@H:42]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:43][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[O:26]1)=[O:47])[CH3:50]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C3O[C@@H](C(=O)OCC)[C@H](C(=O)OCC)O3)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of 0.706 g of 4'-(6-acryloxyhexyloxy)biphenyl-4-carboxaldehyde, 1 ml of orthoformic acid triethyl ester, 0.7 ml of diethyl L-tartrate, 27 mg of BHT, 6.8 mg of 4-toluenesulphonic acid monohydrate and 10 ml of toluene was allowed to stand for 1 hour at room temperature, then heated for 2.5 hours to boiling, the solvent being distilled off and replaced by fresh toluene. After the addition of 3 drops of triethylamine and cooling, it was diluted with diethyl ether, washed with water, dried over sodium sulphate, filtered and concentrated at 40° C. in vacuo. The oily residue was chromatographed on 45 g of silica gel with hexane/ethyl acetate 4:1. Recrystallisation from ethyl acetate resulted in 0.18 g (4R,5R)-2-[4-(6-acryloxyhexyloxy)biphenyl-4-yl]-1,3-dioxolane-4,5-dicarboxy acid diethyl ester; boiling point (C-I) 65° C.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].CI>CN(C=O)C>[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (2.6 g, 6.98 mmol) in dry DMF (75 ml) was added NaH (0.35 g, 8.38 mmol 60% in mineral oil) and the resulting mixture was stirred for 1 hr. Methyl iodide (521 μl, 8.38 mmol) was added and the stirring was continued for an additional 1 hr. The reaction mixture was quenched with water (50 ml) followed by extraction with diethyl ether (2×50 ml). The combined organic phases were washed with saturated aqueous ammonium chloride, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (40 ml) and TFA (25 ml) was added. The resulting mixture was stirred for 18 hrs. at room temperature and evaporated in vacuo. To the residue was added water (10 ml) and the pH was adjusted to 9 by addition of 1 N sodium hydroxide. The aqueous phase was extracted with diethyl ether (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo affording 2.5 g crude product which was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording a slowly crystallizing oil which was washed with diethyl ether (10 ml), filtered off and dried in vacuo at 50° C. afforded 0.9 g (45%) of the title compound as a solid.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[CH2:16]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
40 ml (0.516 mol) of mesyl chloride were added dropwise at 5° C. to 83.3 g (0.4 mol) of N-(4-nitrophenyl)-3-hydroxypyrrolidine dissolved in 625 ml of anhydrous THF and 72.7 ml (0.6 mol) of triethylamine. The mixture was allowed to return to room temperature and was then poured into ice to form a precipitate.