Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]([CH3:13])([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:13][C:5]([OH:12])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:4]#[CH:3]
Reactant: CCCCCCC(C)(O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(C)(O)CCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-trimethylsilyl-3-methyl-1-nonyn-3-ol (1.94 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][CH:2]=1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[CH:11][CH:10]=1>N1CCCCC1.C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[NH:15][CH:6]([C:4]3[O:3][CH:2]=[CH:1][CH:5]=3)[O:7][N:14]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: NC(=NO)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Clc1ccc(C2=NOC(c3ccco3)N2)cc1
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of 2-furfural (0.69 mL, 804 mg, 8.4 mmol), 4-chloro-N′-hydroxybenzimidamide (1.02 g, 6.0 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g). The mixture was cooled to room temperature and the solvent was removed in vacuo. After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid upon standing (85 mg) with a yield of 6%. LC-MS [M+H] 249 (C12H9ClN2O2+H, expected 249.04)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38]
Reactant: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 3-[[2-chloro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (128 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (172 mg, 0.53 mmol, 1.5 eq). The reaction was stirred at room temperature for 30 min then ethylbromoacetate (70.5 mg, 0.42 mmol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for further 3 h then water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and the residue obtained purified by chromatography (petroleum ether:EtOAc, 100:1 to 20:1) to give the title compound as a colourless oil (120 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@@H:14]1Br)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2].[Cl-].[Zn+2].[Cl-]>[C:9]([O:12][C@@H:13]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:14]1[O:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: Cc1ncccc1O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
6 g (73.7 mmol) of zinc oxide, 2.6 g (19 mmol) of zinc chloride and 4 g of 4 Å molecular sieve are mixed. This mixture is desiccated perfectly and 2 g (18.3 mmol) of 2-methyl-3-pyridinol and 6.6 g (18.6 mmol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide in 40 ml of toluene and 40 ml of acetonitrile are then added. The mixture is stirred at 60° C. for 18 hours and then filtered. The filtrate is concentrated under reduced pressure and the evaporation residue is purified by chromatography on silica gel using an ethyl acetate/hexane mixture (7/3 then 100% ethyl acetate; v/v) as the eluent to give the expected product in the form of a beige solid (yield=7%).
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:12]([CH:14]=[CH2:15])=[O:13]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]#[C:6][CH:12]([OH:13])[CH:14]=[CH2:15]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Product: C=CC(O)C#CC(C)(C)C

Procedure:
Reacting t-butylacetylene at −40° C. or less with butyllithium, cooling the reaction mixture at −40° C. or less with acrolein further aging the reaction mixture at −50° C. for 30 minutes to give 6,6-dimethylhept-1-en-4-yn-3-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[NH4+]>C(#N)C>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1cc(O)c(C=O)cc1Cl
Temperature: 70 °C
Yield: 21.7 %

Procedure:
2-Hydroxy-4-methoxy-benzaldehyde (0.974 g, 6.40 mmol) was dissolved in 10 mL of acetonitrile and treated with N-chlorosuccinimide (0.983 g, 1.15 eq.) and ammonium nitrate (0.102 g, 0.20 eq.), and the mixture was warmed to 70° C. for roughly 5 h. Evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=85/15), and direct crystallization from heptane/AcOEt, produced then 0.259 g of the title compound as white crystals.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:12][CH2:13][CH3:14]
Reactant: CCCI
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared by reaction of isovanillin with propyl iodide in DMF with K2CO3 as base as described in M. J. Ashton, D. C. Cook, G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J. Ratcliffe, J. E. Souness, S. Thurairatnam, N. Vicker J. Med. Chem. 1994, 37, 1696-1703.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1>>[CH3:13][C:14]1[N:18]2[CH2:2][CH2:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:17]2=[CH:16][N:15]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccccc1

Procedure:
Combine 270 g (1.48 mol) of 4-chlorobutyrophenone with 600 g (7.3 mol) of 2-methylimidazole and heat to 175° C. for 24 hr. Crystallization from ether provides the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]2[C:18]=1[F:31]>>[F:31][C:18]1[C:19]2[N:20]([N:23]=[CH:24][C:25]=2[C:26]([OH:28])=[O:27])[CH:21]=[CH:22][C:17]=1[N:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:7]1[CH:8]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=1[O:14][CH3:15]
Reactant: CCOC(=O)c1cnn2ccc(Br)c(F)c12
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Agent: Cl
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1F

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(5-Fluoro-2-methoxyphenyl)pyrrolidine hydrochloride (step-1) and Ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (step-4 of example-248) to afford the product as white solid. MS (ESI): m/z 374.12 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[N:21](COCC[Si](C)(C)C)[C:22]([C:25]2[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:38][C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5C(OC(C)(C)C)=O)=[N:40][CH:41]=4)=[CH:33][CH:32]=3)=[N:29][CH:30]=2)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:38][C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][NH:43]5)=[N:40][CH:41]=4)=[CH:33][CH:32]=3)=[N:29][CH:30]=2)=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4COCC[Si](C)(C)C)cn3)cc2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2cnc([C@@H]3CCCN3)[nH]2)ccc1-c1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Yield: 36.3 %

Procedure:
TFA (8 mL) was added in one portion to a stirred solution of (S)-2-[5-(2-{4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 1.98 mmol) in dry CH2Cl2 (30 mL) at room temperature. The flask was sealed and the mixture was stirred at room temperature for 16 h before the solvent(s) were removed in vacuo. The residue was taken up in methanol, filtered through a PVDF syringe filter (13 mm×0.45 μm), distributed to 8 pHPLC vials and chromatographed by HPLC (gradient elution from 10% B to 100% B over 13 min on a Phenomenex C18 column, 30×100 mm, 10 μm, where A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA). After concentration of the selected test tubes by speed vacuum evaporation, the product was dissolved in methanol and neutralized by passing the solution through an UCT CHQAX 110M75 anion exchange cartridge. There was isolated the title compound as a yellow mustard-colored solid (306.7 mg, 36% yield) upon concentration of the eluant.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Reactant: c1cn[nH]c1
Product: Fc1ccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of phenylmethyl 2-(3-hydroxypropyl)-1-piperidinecarboxylate (2.14 g, 7.72 mmol) in anhydrous dichloromethane (34 ml) was added carbon tetrabromide (5.12 g, 15.43 mmol)). The resulting solution was cooled in ice/water. A solution of triphenylphosphine (4.05 g, 15.43 mmol) in 10 ml dry DCM was added dropwise over 30 mins., producing a deep amber/brown solution. After complete addition the reaction was allowed to warm slowly to ambient temperature and stirring continued overnight. The reaction mixture was filtered to remove the precipitate, washed with ether and the filtrate evaporated to approx 10 ml. This was then loaded onto a 100 g silica cartridge and purified by chromatography using a gradient of Flashmaster 0-25% ethylacetate in cylcohexane over 40 mins. on a Flashmaster collecting all the eluent. The product peak was identified by TLC and the fractions combined and evaporated in vacuo to give the title compound as a clear oil (2.13 g).
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44](=[O:59])[NH:45][C@H:46]([C:54]3[S:55][CH:56]=[CH:57][N:58]=3)[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44](=[O:59])[NH:45][C@H:46]([C:54]1[S:55][CH:56]=[CH:57][N:58]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:69])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 75.3 %

Procedure:
According to general procedure A (below), from #53 (701 mg, 0.726 mmol) in dichloromethane (10 mL, 0.07 M) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane). The residue was diluted with diethyl ether and heptane and was concentrated in vacuo to afford #54 (406 mg, 75%) as a white solid. LC-MS: m/z 743.6 [M+H]+, retention time=0.70 minutes; HPLC (Protocol A): m/z 743.4 [M+H]+, retention time=6.903 minutes, (purity >97%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.5 Hz) and 8.86 (br d, J=8.7 Hz), total 1H], [8.04 (br d, J=9.3 Hz) and 8.08 (br d, J=9.3 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.2 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.2 Hz), total 1H], 7.13-7.31 (m, 5H), [5.39 (ddd, J=11, 8.5, 4 Hz) and 5.53 (ddd, J=12, 9, 4 Hz), total 1H], [4.49 (dd, J=9, 8 Hz) and 4.60 (dd, J=9, 7 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), 1.21 (s, 3H), 1.13 and 1.13 (2 s, total 3H), [1.05 (d, J=6.7 Hz) and 1.10 (d, J=6.7 Hz), total 3H], 0.73-0.80 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH2:14](O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[C:2]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)[O:1][CH2:14][CH2:15]1
Reactant: OCCO
Reactant: CCOC(=O)N1CCCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC2(CC1)OCCO2
Yield: 106.2 %

Procedure:
A mixture of ethyl hexahydro-4-oxoazepine-1-carboxylate (0.585 mol), 1,2-ethane-diol (0.585 mol) and p-toluenesulfonic acid (0.0058 mol) in toluene (800 ml) was stirred and refluxed overnight, using a water separator (10.5 ml was separated). The solvent was evaporated, yielding 142.5 g of ethyl 1,4-dioxa-8-azaspiro[4.6]undecane-8-carboxylate (intermediate 4).
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:12]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[OH:4])[CH2:14][CH2:13]1
Reactant: CC(=O)Oc1c(C)cccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc(C2CC2)c1O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 67.6 %

Procedure:
A 500 ml three-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer and a drying tube. A solution of 2-cyclopropyl-6-methylphenyl acetate (18.3 g, 96.2 mmol) in methanol (100 ml) was added thereto. Potassium carbonate (26.5 g, 192 mmol) was added thereto at once and the mixture was stirred at room temperature for 75 minutes. After water (300 ml) was added to the reaction mixture, the resulting mixture was concentrated by an evaporator to remove most of methanol. The obtained mixture was cooled to 0° C. and 4M hydrochloric acid (100 ml) was added thereto such that the temperature of the mixture did not exceed 25° C. This was extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture (3×200 ml). The organic layer was combined and successively washed with water (2×200 ml) and a saturated aqueous NaCl solution (50 ml), followed by drying with anhydrous sodium sulfate (90 g). After the solid was removed by filtration and the filtrate was concentrated to obtain 13.8 g of a crude product of 2-cyclopropyl-6-methylphenol as a brown oil. The crude product was distilled (7.6-7.8 mmHg, 94-98° C.) to obtain 9.64 g of 2-cyclopropyl-6-methylphenol as a light purple oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11].[H-].[Na+].Br[CH2:19][O:20][CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11]
Reactant: CON(C)C(=O)Cc1ccc(O)cc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(CC(=O)N(C)OC)c(Br)c1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
A solution of 2-(2-bromo-4-hydroxyphenyl)-N-methoxy-N-methylacetamide (1.37 g) in THF (5 mL) was slowly added to a suspension of sodium hydride (0.22 g) in THF (30 mL) at 0° C. After stirring for 10 min, bromo(methoxy)methane (1.25 g) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 hr. The mixture was poured into water and extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (1.34 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(CCc4cccc(N(S(C)(=O)=O)S(C)(=O)=O)c4)CC3)cccc2n1
Reaction time: 18 h

Procedure:
To a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (370 mg) and triethylamine (178 μL) in DCM (3 mL) was added methanesulfonyl chloride (33 L). The mixture was stirred for 18 h, then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic layer was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH, (20:0)→(20:1)] to give the title compound (342 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 67.5 °C
Reaction time: 23 h
Yield: 77.3 %

Procedure:
Into a solution of methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (3/1.5 ml) was added at room temperature an aqueous solution (0.7 ml) of potassium carbonate (140 mg), and the resulting mixture was stirred at 65-70° C. for 23 hours. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture until the pH was adjusted to 5, and the precipitated crystals were collected by filtration. The crystals were washed with water, 2-propanol and diisopropyl ether to obtain 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (149 mg) as light yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-methylnitrobenzene (15.5 g), imidazole (6.8 g), and sodium carbonate (11.1 g) was heated at 100° for 24 hours in dimethylformamide (DMF). The mixture was then concentrated in vacuo, the residue was acidified to pH1 with 4M hydrochloric acid, and the resulting solution was extracted with chloroform (2×25 cm3). The aqueous phase was basified to pH10 with 2.5M sodium hydroxide solution and the mixture was extracted with chloroform (3×100 cm3). The dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallised from ethyl acetate to afford 1-(3-methyl-4-nitrophenyl)imidazole, m.p. 112°-115°, (10.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][OH:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:15])([O-:3])=[O:2].NC1C=C([N+]([O-])=[O:24])C(C)=C([N+]([O-])=O)C=1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:24])=[O:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:15])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cc(N)cc1[N+](=O)[O-]
Reactant: Cc1c([N+](=O)[O-])cc(NO)cc1[N+](=O)[O-]
Product: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
An alternate method of pentanitroaniline synthesis, based on a recent patent (Reference 6), was examined (FIG. 4). 2,4,6-trinitrotoluene (TNT) (10) is dissolved in p-dioxane and H2S gas is bubbled through the solution holding the temperature below 50° C. The sulfur which precipitates is filtered off and the filtrate is poured over ice mixed with water to produce a mixture of the desired intermediate 4-amino-2,6-dinitrotoluene (11) and the partially reduced product 2,6-dinitro-4-hydroxylaminotoluene (12); the ratio of 11:12 usually is 3:2, but varies from 1:2 to 2:1. The crude mixture of 11 and 12 is suspended in hydrochloric acid and treated with potassium iodide. The hydrochloric acid and potassium iodide form hydroiodic acid (HI) which serves as the reducing agent to convert the hydroxylamine 12 into the amine 11. Cooling, filtration, and recrystallization provide the desired 11 in 45% overall yield from TNT. The amine 11 is nitrated using concentrated sulfuric acid/90% nitric acid with heating to 80° C. (Under these nitration conditions, the methyl group on the amine is oxidized, carbon dioxide is liberated, and subsequent nitration occurs at this position on the aromatic ring.) The nitrated mixture is allowed to cool to 60° C. and then extracted with dichloroethane. The extract is dried and concentrated to produce pentanitroaniline (9) in 22% yield (10% overall yield from TNT).