Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2].IC.[CH3:25]C([O-])(C)C.[K+]>C1COCC1>[C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH3:25])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.065 g, 0.209 mmol) in THF (1 mL) was added iodomethane (0.59 g, 4.18 mmol), followed by dropwise addition of t-BuOK (1M in THF, 0.63 mL, 6.3 mmol). After 10 min, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 325 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:40]2[CH2:43][CH:42]([CH:44]([C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[C:45](O)=[O:46])[CH2:41]2)=[CH:35][CH:34]=1>ClCCl.C(N(CC)CC)C>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH:39]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[N:40]2[CH2:43][CH:42]([CH:44]([C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[C:45]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[O:46])[CH2:41]2)=[CH:57][CH:58]=1
Reactant: O=C(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CN(C)CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCCNC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
(RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethyl-aminopropyl)acetamide may be prepared in the following manner: 0.015 cm3 of N,N-dimethylpropane-1,3-diamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20° C. The solution obtained is stirred at a temperature in the region of 20° C. for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4 cm3 of silica (0.060-0.200 mm) conditioned with dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-methanol (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 33 mg [lacuna] (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethylamino-propyl)acetamide are thus obtained in the form of white crystals [1H NMR spectrum (300 MHz, CDCl3, with addition of a few drops of CD3COOD d4, δ in ppm): 1.91 (mt: 2H); 2.71 (s: 6H); 2.95 (mt: 2H); from 3.15 to 3.40 (mt 2H); from 3.40 to 3.60 (mt: 1H); from 3.60 to 3.80 (mt: 2H); 4.00 (mt: 2H); 4.28 (d, J=10.5 Hz: 1H); 5.22 (s 1H); 6.68 (tt, J=9 and 2.5 Hz: 1H); 6.90 (mt: 2H); 7.33 (mt: 4H); 7.46 (d, J=8 Hz: 4H)].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([F:12])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[N:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N+]=[N-].O>CO.C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:17]([C:16]1[NH:13][C:9]2[C:6]([CH:7]=1)=[C:5]([F:12])[C:4]([Cl:3])=[CH:11][CH:10]=2)=[O:18]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2c(F)c(Cl)ccc2[nH]1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
Ethanol (100 mL) was added to sodium hydride (60% sodium hydride content, 4.7 g) at 0° C. under argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was added to the reaction mixture, and after the thus-obtained mixture was stirred for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The organic layer was sequentially washed with 1N aqueous sodium hydroxide, water, and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), to thereby give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily compound. Methanol (20 mL) was added to sodium hydride (60% sodium hydride content, 1.6 g) under argon atmosphere at 0° C., and the thus-obtained mixture was stirred for 10 minutes. After the reaction mixture was cooled to −20° C., a solution of the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within 20 minutes. After the reaction mixture was heated to 0° C., the mixture was stirred for 2.5 hours, and water (40 mL) was added thereto. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl acetate. The extract was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (toluene:hexane=3:17), to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g). This compound was dissolved in xylene (50 mL), and the solution was stirred at 130-140° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride). The thus-obtained compound was crystallized from diethyl ether-hexane, to thereby give the title compound (440 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl.[Cl:18]CCC[N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.CN(C)[CH2:31][CH2:32][CH2:33]Cl>>[ClH:18].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH2:31][CH2:32][CH2:33][CH:26]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:27]2)[CH2:13][CH2:12]1
Reactant: CN(C)CCCCl
Reactant: ClCCCN1CCCCC1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: Cl
Product: c1ccc2cc(C3CCN(CCCC4CCCNC4)CC3)ccc2c1

Procedure:
Using 4-(2-naphthyl)piperidine (167 mg, 0.67 mmol) and 1-(3-chloropropyl)piperidine hydrochloride (198 mg, 1.0 mmol) instead of 4-(3-indolyl)piperidine and 3-dimethylaminopropyl chloride hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 4. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; hexane:chloroform=1:1) to afford a free form (187 mg) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from ethanol to afford the title compound (177 mg, yield: 64%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:26]#[N:27]>CO>[C:26]([C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:27]
Reactant: N#C[Cu]
Reactant: COc1ccc2nc3cc4ccccc4cc3c(Cl)c2c1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COc1ccc2nc3cc4ccccc4cc3c(C#N)c2c1
Temperature: 170 °C
Reaction time: 4.5 h
Yield: 176 %

Procedure:
A mixture of 12-chloro-2-methoxy-benz[b]acridine (562 mg, 1.905 mmol), potassium cyanide (136 mg, 2.096 mmol) and copper(I) cyanide (86 mg, 0.953 mmol) in methanol. (3.7 ml) was stirred at 170° C. in a sealed-tube for 4.5 hours. The resulting mixture was filtrated, and the solid was washed with chloroform/methanol (2:1, 10 ml). The combined filtrate was evaporated under reduced pressure to give a residue, which was flash-chromatographed on a silica column packed with chloroform and eluted with 1% methanol/chloroform to yield 12-cyano-2-methoxy-benz[b]acridine (477 mg, 88%). Rf 0.6 (silica gel, 1% methanol/chloroform). MS (CI, CH4): m/z 285 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:66]=[CH:65][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:64])[CH2:25][N:26]3[CH2:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][C:36](=[O:62])[N:37]4[CH2:42][CH2:41][N:40]([C:43]([NH:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([CH2:53][NH:54]C(OC(C)(C)C)=O)=[CH:49][CH:48]=5)=[O:44])[CH2:39][CH2:38]4)[CH2:29][CH2:28][C:27]3=[O:63])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:74]>ClCCl.O1CCOCC1>[ClH:74].[ClH:74].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:64])[CH2:25][N:26]3[CH2:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][C:36](=[O:62])[N:37]4[CH2:42][CH2:41][N:40]([C:43]([NH:45][CH2:46][C:47]5[CH:48]=[CH:49][C:50]([CH2:53][NH2:54])=[CH:51][CH:52]=5)=[O:44])[CH2:39][CH2:38]4)[CH2:29][CH2:28][C:27]3=[O:63])[CH2:20][CH2:19]2)=[O:17])=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCN(C(=O)CN3CCC(=O)N(CC(=O)N4CCN(C(=O)NCc5ccc(CNC(=O)OC(C)(C)C)cc5)CC4)CCC3=O)CC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(CNC(=O)N2CCN(C(=O)CN3CCC(=O)N(CC(=O)N4CCN(C(=O)NCc5ccc(CN)cc5)CC4)CCC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 g of 1,5-bis-{2-[4-(4-tert-butyloxycarbonylaminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione (starting material A1) is suspended in 2 ml of dichloromethane and then admixed with 2 ml of trifluoroacetic acid. The mixture is stirred at RT overnight, and 2 ml of a solution of HCl in dioxane are then added. The mixture is concentrated to dryness using a rotary evaporator. The residue is twice triturated with ether and the solvent decanted off. The residue is then dried under high vacuum. This gives 0.17 g of the title compound of m.p. from 90° C. (decomposition). The mass spectrum shows the molecular peak MH+ at 719 Da.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[O:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20]CCCC)[CH2:15][CH2:14]1)[N+:10]([O-:12])=[O:11].O(C1CCNCC1)[N+]([O-])=O.C(Br)CCCCC>C(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([O:9][N+:10]([O-:12])=[O:11])[CH2:14][CH2:15]1)[CH3:20]
Reactant: CCCCCCN1CCC(O[N+](=O)[O-])CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=[N+]([O-])OC1CCNCC1
Solvent: CCO
Solvent: CCCCCCBr
Product: CCN1CCC(O[N+](=O)[O-])CC1
Yield: 50 %

Procedure:
4-nitroxy-1-hexylpiperidine fumarate from 4-nitroxypiperidine and n-hexyl bromide; yield 50% of theory; solvent: ethanol; m.p. 102°-103° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][O:15][CH:16]1[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[N:20]([C:28](=[O:47])[C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:31][C:30]=2[O:45][CH3:46])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC>[NH:12]([CH2:13][CH2:14][O:15][CH:16]1[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[N:20]([C:28](=[O:47])[C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:31][C:30]=2[O:45][CH3:46])[CH2:19][CH2:18][CH2:17]1)[C:2]([NH2:3])=[O:1]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNC(N)=O)c2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
0.12 g of sodium cyanate and 0.22 ml of trifluoro-acetic acid were added to a solution of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 15 ml of dry dimethylformamide. The mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was mixed with slight amounts of a saturated aqueous sodium hydrogen-carbonate solution and hexane, followed by extraction with ethyl acetate. The organic layer was water-washed, then dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The residue was recrystallized from acetone-n-hexane to obtain 0.41 g (76%) of 5-(2-ureidoethoxy)-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].CI>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH3:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 804.5 %

Procedure:
With 82 g (0.335 mole) of 2-nitro-4-phenylmethoxy-phenol, 46 g (0.035 mole) of K2CO3, 83 ml (1.34 moles) of methyl iodide and 2 g of TBAB in 400 ml of acetone were refluxed for 12 hours. The cooled solution was filtered and evaporated. The residue was taken up with methylene chloride, washed with water then dried on sodium sulfate. Evaporation of the solvent gave 73 g (Yield=85%) of 2-nitro-4-phenylmethoxy-anisole.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[N:4][N:3]=1.C([Li])CCC.[C:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:29]2([OH:32])[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:27][CH2:28]2)=[N:4][N:3]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Cc1nncn1-c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(C2(O)CCN(CCc3ccccc3)CC2)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.6 g of 3-methyl-4-phenyl-4H-1,2,4-triazole (10 mmol) in 15 ml of THF at -78° C. is added 7.0 ml of n-butyllithium (1.6N in hexane). The mixture is stirred for 50 minutes before a solution of 2.44 g of N-(2-phenylethyl)-4-piperidinone in 12 ml of THF is charged into the flask. After stirring for 30 minutes at -78° C. and then 1 hour at -20° C. the mixture is poured into cold water and is extracted three times with chloroform. The combined chloroform extracts are washed twice with water, brine, dried over sodium sulfate and concentrated in vacuo to yield an amber oil.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.CN(CCN(C)C)C.[CH:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1.O>[N:17]1([CH:16]([C:15]2[CH:14]=[C:13]([CH3:12])[CH:24]=[CH:23][CH:22]=2)[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)(C)C=O
Reactant: Cc1cccc(Cn2ccnc2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cccc(C(C(O)C(C)(C)C)n2ccnc2)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
39 ml (60 mmol) of a 1.55 molar n-butyllithium/hexane solution were added dropwise to a solution of 5.17 g (30 mmol) of N-(3-methylbenzyl)-imidazole and 3.49 g (30 mmol) of TMEDA in 60 ml of absolute THF at -70° C. The mixture was stirred for 30 minutes at about -70° C., after which a solution of 3.80 g (33 mmol) of 75% strength pivalaldehyde in 30 ml of absolute THF was added dropwise at about -70° C. in the course of 20 minutes, stirring was continued for 20 minutes at about -70° C. and the mixture was allowed to warm up to room temperature in the course of 2 hours. Thereafter, water was added, while cooling, and the resulting mixture was extracted with ether. The residue (9.3 g) from the ether extract was crystallized from a diisopropyl ether/hexane mixture. This gave 2.2 g of crystals, which consisted of about 90% of a by-product, 1-(3-methylbenzyl)-2-(1-hydroxy-2,2-dimethylprop-1-yl)-imidazole. The residue from the mother liquor was recrystallized from a diisopropyl ether/acetonitrile solution, and the crystalline product isolated in this procedure was then recrystallized twice from acetonitrile. 0.64 g (=8.3% of theory) of pure 1-(1-imidazolyl)-1-(3-tolyl)-3,3-dimethylbutan-2-ol of melting point 126° C. was obtained in this manner.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)#[N:2].CO.[NH3:13]>[Ni].[H][H]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH2:13])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)CCCCC#N
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCCCCCC(N)=O
Temperature: 80 °C
Yield: 97 %

Procedure:
25 parts of methyl 5-cyanovalerate in 40 parts of methanol are heated to 120° C in a vibratory autoclave together with 24 parts of liquid ammonia and maintained at said temperature for 6 hours. After cooling and venting the autoclave, addition is made of 2.25 parts of a nickel catalyst (77% by weight of nickel) as prepared in Example 1, suspended in 24 parts of methanol. Ammonia and methanol lost during venting are replenished. The pressure is raised to a total pressure of 100 bars by pumping in hydrogen at room temperature. After heating to 80° C, the total pressure is 150 bars. Hydrogenation is continued with replenishment of the hydrogen until no further hydrogen is absorbed. After cooling and venting the autoclave, the reaction mixture is filtered to isolate the catalyst and the filtrate is evaporated to dryness. There are thus obtained 22.4 parts of 6-aminocaproamide (97% of theory), m.p. 49° to 50° C. The IR spectrum of this product and that of authentic 6-aminocaproamide are identical.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:20])=[O:19]
Reactant: OCCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccccn1

Procedure:
A solution of 2-pyridin-2-yl-ethanol (Aldrich, 0.11 mL, 0.99 mmol), triethylamine (0.42 mL, 3.0 mmol), and methanesulfonyl chloride (0.12 mL, 1.5 mmol) in 5 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:19]O>>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:19])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of 8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (16 g, 0.084 mol) in MeOH was added thionylchloride (23 g, 0.2 mol). The mixture was then stirred at rt for 12 h. The solvent was removed under vacuum and the residue was taken up in EtOAc (200 ml). The organic layer was washed with a 10% aqueous solution of NaHCO3, dried over MgSO4 and evaporated to give 16 g (94%) of the titled compound as a liquid. TLC: Chloroform/MeOH (9/1), Rf=0.9.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[O:1][C:2](=[O:3])[CH:4]=[CH:5]2)([O-:14])=[O:13]
Reactant: O=c1ccc2ccccc2o1
Reactant: O=[N+]([O-])O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2o1
Yield: 85 %

Procedure:
In greater detail, coumarin (10 g, 68 mmol) was nitrated as described in the literature with an excess of fuming nitric acid overnight at room temperature to give 6-nitrocoumarin as the only major product. The 6-nitrocoumarin exhibited the following characteristics: Yield 85%. 1H NMR (DMSO-d6): 8.74 (d, J=3 Hz, 1H), 8.42 (dd, J=3, 9 Hz, 1H), 8.24 (d, J=10 Hz, 1H), 7.63 (d, J=9 Hz, 1H), 6.70 (d, J=10 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.O>C(OCC)(=O)C>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
The mixture of 50.7 g (0.35 mol) 1,2-diamino-4,5-difluorobenzene, 55.1 g (0.35 mol) 4-chlorobenzoic acid and 507 g polyphosphoric acid was heated to 160° C. and stirred at this temperature for 90 min. After cooling to 55° C., 1000 mL water and 500 mL ethyl acetate were added. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9). The suspension was filtered over dicalite and the filter cake was washed with 1.5 L ethyl acetate. The phases were separated and the aqueous phase was washed with 0.5 L ethyl acetate. The organic phases were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (v/v, 4:1 to 1:1) as eluant. The fractions containing the product in pure form were pooled and evaporated. The remaining fractions were dissolved in ethyl acetate, washed twice with 1M aqueous sodium hydroxide solution and brine, the combined aqueous layers extracted once with ethyl acetate and the combined organic layers dried over magnesium sulfate and filtered. Chromatography over silica gel afforded a second batch of compound. Total yield: 75 g (80%) light yellow solid. MS (ES+): 265 (M+H).
Reaction SMILES: CC([O:4][C@@H:5]1[C@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:8]([O:19][C@:20]2([CH2:35][OH:36])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@@H:21]2[O:31][C:32]([CH3:34])=[O:33])[O:7][C@@H:6]1[CH2:37]O)=O.[C:39]([OH:42])(=[O:41])[CH3:40]>C1(C)C=CC=CC=1>[CH3:40][C:39]([O:42][CH2:37][C@H:6]1[O:7][C@H:8]([O:19][C@@:20]2([CH2:35][OH:36])[O:24][C@@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@H:21]2[O:31][C:32]([CH3:34])=[O:33])[C@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:5]1[OH:4])=[O:41]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CO)O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@H](O[C@@]2(CO)O[C@@H](CO)[C@@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O
Temperature: 25 °C
Yield: 83.3 %

Procedure:
2,3,4,3',4'-Penta-O-acetylsucrose (2 g; purity 83.63%) and glacial acetic acid (0.2 liter) were added to toluene (10.0 liter) and the mixture was heated to reflux and maintained at reflux for 6 hours or until the acetyl migration was completed. The solution was cooled to ambient temperature and the precipitate filtered off, washed with fresh toluene and dried in a vacuum oven at 40° C. to give 2,3,6,3',4'-penta-O-acetylsucrose (15.90 g; purity 87.65%) in an overall yield of 83.3%