Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH2:15][CH2:14]2)[CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH2:27])[CH2:17][CH2:18]2)[CH:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(F)cc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(F)cc2n1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 7-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (0.046 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.04 g; 7 eq) and ammonium chloride (0.04 g; 7 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, with additional amounts of iron powder (total 0.04 g; 7 eq) and ammonium chloride (0.04 g; 7 eq) added in 3 portions during the reaction. The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure thus obtaining the title compound in 32% yield (0.012 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[CH3:8][N:9]=[C:10]=[S:11]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:10]([NH:9][CH3:8])=[S:11])[N:4]=[C:5]([CH3:7])[N:6]=1
Reactant: CN=C=S
Reactant: Cc1nc(N)n[nH]1
Solvent: CN(C)C=O
Product: CNC(=S)n1nc(C)nc1N
Yield: 29 %

Procedure:
The synthesis method of Example 1-(3) was applied. The compound (664 mg) obtained in (2) above, dimethylformamide (13 ml) and methyl isothiocyanate (600 mg) were used as reagents to give 340 mg of white crystals (yield 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[C:7]([NH:11][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[C:5]([NH:12][C:13]([O:14][CH3:15])=[O:16])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1c(Cl)cc(N)cc1NC(=O)OC
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1c(Cl)cc(NC(=O)OC(C)C)cc1NC(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Methyl N-(2-ethoxy-3-chloro-5-aminophenyl)carbamate (1.39 g) and N,N-diethylaniline (0.85 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-ethoxy-5-methoxycarbonylaminophenyl)carbamate (Compound No. 2) (1.73 g) in a yield of 92.0%. M.P., 140° C.-142° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2].[OH-].[K+].[I:23]I>CN(C=O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:23])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(I)n[nH]c2c1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1H-indazole (Preparation 15, 1.46 g, 5.4 mmol) in DMF (20 mL) was added KOH (1.14 g, 20.3 mmol) and the mixture was stirred for 5 minutes. A solution of iodine (2.75 g, 10.8 mmol) in DMF (5 mL) was slowly added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (2×100 mL) and saturated sodium metabisulfite aqueous solution (100 mL), dried over MgSO4 and concentrated in vacuo to furnish the title compound (1.94 g) in a 91% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2c(c1)CCO2
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of nitric acid (100%, 1.5 ml, 36 mmol) in acetic anhydride (18 ml) was maintained at room temperature for 0.5 hour. The mixture was added to a solution of 5-fluoro-2,3-dihydrobenzofuran (2.5 g, 18 mmol) in 10 ml acetic anhydride at 10° C. The reaction mixture was stirred at room temperature for 2 hours then poured into ice-water. The mixture was extracted with methylene chloride (3×60 ml), washed with 1N sodium hydroxide (5×100 ml) and brine (200 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford a yellow solid: mp 113-114° C.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][NH2:21]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:21][CH3:20])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In an argon atmosphere, 5.24 g (22.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding 25.0 mL (48.8 mmol) of a tetrahydrofuran solution (concentration: 1.95 mol/L) of methylamine, the mixture was stirred at room temperature for 1 hour. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./3.8×102 Pa) to obtain 1,3-di-tert-butyl-2-methylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHMe) as a pale yellow liquid (yielded amount: 4.41 g, yield: 86%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:36])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:21]=3)[CH:15]=2)[N:10]([C:32](=[O:34])[CH3:33])[C@@H:9]([CH3:35])[CH2:8]1)[CH3:3].[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[C:32]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][NH2:24])[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:36])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cn(CCN)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
A solution of 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-imidazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 79) (47 mg, 0.094 mmol) in 1,4-dioxane (0.5 mL) was treated with HCl (4M in 1,4-dioxane, 2 mL, 8 mmol) and the resulting mixture was stirred at room temperature for 4 h. Et2O (10 mL) was added and the resulting mixture stirred for 15 min. The solid formed was filtered off, washed with Et2O and dried under house vacuum to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-aminoethyl)-1H-imidazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (25 mg, 0.057 mmol, 61%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.Cl.[Cl-].[Na+]>N1C=CC=CC=1>[Cl:16][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: ClCCCCOCc1ccccc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 4-benzyloxybutanol (64.8 g, 0.36 mol) in dry pyridine (200 ml) is stirred and heated to 50°-60° C. A solution of thionyl chloride (43 g, 0.36 mol) in pyridine (100 ml) is added slowly, and the mixture is kept at 60° C. for one more hour. After cooling to room temperature, the reaction mixture is poured into a mixture of ice and 2 N HCl. The mixture is saturated with sodium chloride, extracted with ether, and washed successively with water, 10% sodium bicarbonate, and water. Evaporation of solvent gives a yellow oil (49.7 g) which is distilled under vacuum to give the pure title compound (47 g), bp0.03-0.05 85°-90° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([OH:15])=[O:14]>C(Cl)Cl>[CH3:10][C:11]1[C:19]([N+:6]([O-:9])=[O:7])=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 46 ml of concentrated sulfuric acid and 23.5 ml of concentrated nitric acid was added slowly to a stirred solution of 2,6-dimethylbenzoic acid (50.0 g, 0.333 mole) in 200 ml of methylene chloride at a rate such that a gentle reflux was maintained throughout the addition. After complete addition, reflux was maintained for 30 minutes. The reaction mixture was cooled, poured onto 300 g of ice and the organic phase separated. The aqueous phase was extracted with three 200 ml portions of diethyl ether, and the organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 2,6-dimethyl-3-nitrobenzoic acid (60.2 g) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: Oc1cccc(Cl)n1
Product: Oc1cccc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
To a stirring solution of morpholine (10 ml) was added 6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at 90° C. for 60 h. The reaction mixture was cooled to RT and concentrated under reduced pressure (while heating) to afford the title compound as a brown solid (85%. The crude material was used without further purification. MS (ESI) 181.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Reactant: CN
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The title compound was prepared from (2-chloro-6-nitro-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine and methyl amine by a procedure similar to example 14. 1H NMR (CDCl3): 8.11 (dd, J=9.3, 8.0, 1H), 7.73 (d, J=2.4, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 6.98 (m, 2H), 5.29 (s, broad, 1H), 3.86 (s, 3H), 3.55 (s, broad, 3H), 3.14 (d, J=4.8, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](N)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CC[N:15](CC)CC>>[C:2]1([NH2:1])[C:3]([NH2:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCN(CC)CC
Reactant: Nc1cccc2c(N)cccc12
Product: Nc1ccc2ccccc2c1N
Yield: 76 %

Procedure:
1″,5″-[Bis-(4′-O-demethyl-4β-N-4-desoxypodophyllotoxin)] naphthalene diamine (4b) was prepared according to the method described earlier, employing 1,5-diamino naphthalene (80 mg, 0.5 mmol), Bu4N30I−(185 mg, 0.5 mmol), Et3N (150 mg, 1.5 mmol) and 4′-O-demethyl-4β-bromo-4-desoxy podophyllotoxin (462 mg, 1.0 mmol) to give the product in 76% yield. Spectral data: 1H NMR (CDCl3); 7.22-7.28 (d, 2H), 7.10-7.19 (t, 2H), 6.73 (S, 2H), 6.58 (S, 2H), 6.50 6.55 (d, 2H), 6.33 (S, 4H), 5.98 (ABq, 4H), 5.34 (S, 2H), 4.87 (br, 2H), 4.63-4.70 (d, 2H), 4.52-4.59 (d, 2H), 4.36-4.48 (t, 2H), 3.85-3.95 (d, 2H), 3.82 (3, 6H), 3.20-3.31(dd, 2H), 2.98-3.16 (m, 2H); FAB MS: m/z 922 (M+); mp. 238-240° C.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:30][Mg]Br.Cl>O1CCCC1.CCOCC>[CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]([OH:21])[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[Mg]Br
Reactant: CCCCCCCCCCCCCCCCOCC(C=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(OCc1ccccc1)C(C)O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10 g of 3-(hexadecyloxy)-2-(phenylmethoxy)-propanal in 120 ml of dry tetrahydrofuran, under argon, at 5° C., was added dropwise 16.4 ml of 3M methyl magnesium bromide in ether at a rate to maintain the temperature below 8° C. The mixture was stirred at 5° C. for 15 minutes, then at room temperature for 3 hours, recooled to 5° C. and 50 ml of 1N hydrochloric acid was added dropwise at a rate to maintain the temperature below 10° C. The organic phase was separated and the aqueous phase extracted with ether. The ether extract was combined with the organic phase, washed with saturated aqueous sodium bicarbonate, then saturated brine, dried and taken to dryness. The residue was dissolved in petroleum ether, washed with saline, dried and taken to dryness. The residue was purified by HPLC using ether:hexane (1:5), giving 6.16 g of the desired compound as a pale yellow oil.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:8][N:9]2[CH2:28][CH2:27][C@:16]34[C:17]5[C:18]6[O:26][CH:15]3[C:14](=[O:29])[CH2:13][CH2:12][C@@:11]4([F:30])[C@H:10]2[CH2:23][C:22]=5[CH:21]=[CH:20][C:19]=6[O:24]C)[CH2:7][CH2:6]1.[OH-].[NH4+]>C(Cl)(Cl)Cl>[CH:5]1([CH2:8][N:9]2[CH2:28][CH2:27][C@:16]34[C:17]5[C:18]6[O:26][CH:15]3[C:14](=[O:29])[CH2:13][CH2:12][C@@:11]4([F:30])[C@H:10]2[CH2:23][C:22]=5[CH:21]=[CH:20][C:19]=6[OH:24])[CH2:6][CH2:7]1
Reactant: COc1ccc2c3c1OC1C(=O)CC[C@@]4(F)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1CC[C@@]2(F)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 0 °C

Procedure:
Boron tribromide (2.5 ml) was dissolved in chloroform (75 ml), and chilled to 20°-25°. A solution of 17-(cyclopropylmethyl)-4,5-epoxy-14-fluoro-3-methoxymorphinan-6-one (1.25 g in 25 ml chloroform) was added and the mixture stirred at that temperature for one-half hour. The reaction mixture was then dumped with good stirring onto 80 g of ice containing 5 ml of concentrated ammonium hydroxide at approximately pH 9.2. The chloroform solution was vigorously shaken, washed with water, then extracted with 5% sodium hydroxide solution. The alkali extract was then separated, acidified, and the liberated phenolic compound taken up in chloroform, washed, and dried over molecular sieve. The dried solvent extract was evaporated, and the crude product column chromatographed using silica gel and, as eluant, a solvent mixture comprising 95% chloroform and 5% ethanol. The purified product was crystallized from ethanol, m.p. 188°-190°.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:13])[N:7]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2ccccc2C(=O)N1SC(Cl)(Cl)C(Cl)Cl
Temperature: 0 °C
Yield: 15.9 %

Procedure:
A 250-ml flask equipped with condenser, stirrer and thermometer and immersed in an ice bath was charged with 150 ml of dichloromethane, 8.3 g (0.047 mol) of 2,2-dimethyl-1,3-benzoxazin-4-one and 10.9 g (0.047 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. Then 4.75 g (0.047 mol) of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over a period of 15 minutes. The resulting solution was stirred at 0° C. for 45 more minutes. The crude reaction mixture was washed three times with equal quantities of water. The organic phase was dried and then stripped of solvent. The resulting residue was washed with 200 ml of hexane and filtered. The dried filter cake, 5.1 g, was unreacted 2,2-dimethyl-1,3-benzoxazin-4-one. The filtrate was stripped of hexane and the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane to give 2.8 g of 2,2-dimethyl-3-(1',1',2',2'-tetrachloroethylthio)-1,3-benzoxazin-4-one. Analysis, calculated for C12H11Cl4NO2S: %C, 37.81; %S, 8.55. Found: %Cl, 40.0; %S, 8.8. NMR spectra confirmed the assigned structure. The infrared spectra had strong adsorption at 1785, 1600, 1460, 1300, 1240 and 740 cm-1. These spectra also had many distinct, medium-strength adsorption bands in the 800-1700 cm-1 region.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])=O)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](=[S:30])[NH2:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:30][C:28]([C:27]([CH3:32])([CH3:31])[CH3:26])=[N:29][C:9]=2[C:11]2[C:12]([F:25])=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=S
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Yield: 17 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (10 g, 27.2 mmol) NBS (5.08 g, 28.6 mmol) and 2,2-dimethylpropanethioamide (3.51 g, 29.9 mmol) the title compound of Step A was obtained (2.15 g, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br. s., 1H), 8.67 (d, J=5.3 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 5.89-6.01 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.4 Hz, 1H), 4.60 (d, J=5.3 Hz, 2H), 1.45 (s, 9H); MS (ESI): 464 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([O:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCOc1cc2c(cc1O)c1cc(OCCCCC)c(OCCCCC)cc1c1cc(OCCCCC)c(OCCCCC)cc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCOc1cc2c3cc(OCCCCC)c(OCCCCC)cc3c3cc(OC(=O)C(C)(C)C)c(OCCCCC)cc3c2cc1OCCCCC
Temperature: 80 °C

Procedure:
181 mg (1.5 mmol) pivaloyl chloride was added to a solution of 673 mg (1 mmol) 2-hydroxy-3,6,7,10,11-pentapentyloxytriphenylene (see Henderson et al., Liquid Crystals 18 (1995) 191) in 1 mL pyridine. The mixture was heated for one hour at 80° C., diluted with diethyl ether and extracted repeatedly with dilute HCl and sodium carbonate solution. Purification was performed by crystallization from ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>CO>[CH3:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CO
Product: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
(a-1) To a stirred and cooled solution of 50 parts of 1-(4-chloro-3-nitrophenyl)ethanone in 240 parts of methanol was added a solution of 40 parts of methanamine in 160 parts of methanol. The reaction mixture was stirred for 12 hours at 60° C. The reaction mixture was evaporated to dry, yielding 50 parts (100%) of 1-[4-(methylamino)-3-nitrophenyl]ethanone as a residue (int. 87).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(F)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-fluorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]#[N:17])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22]>>[C:16]([CH2:15][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:18][CH3:19])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=1)#[N:17]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC#N
Product: COc1cc(F)ccc1-c1ccncc1N(CC#N)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 2-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-ylamino)acetonitrile and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (51%). MS (ESI): m/z=508.096 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccccn2)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (20 ml) was added to 2-fluoro-4-(pyridine-2-yl)benzoic acid (1.91 g, 8.66 mmol) and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to yield 2-fluoro-4-(pyridin-2-yl)benzoyl chloride.