Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH:5]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1)[OH:6].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C1C=CN=CC=1.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH:5]([O:6][C:32](=[O:34])[CH3:33])[C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ncc(C(O)C(Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1ncc(C(OC(C)=O)C(Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 2 h
Yield: 110.2 %

Procedure:
A solution of methyl-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-[(4-pyridyl)methyl]propanoate (3.32 g, 7.5 mmol) dichloromethane (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with dichloromethane and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol methyl-acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH:19]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:25]([C:26](=[O:36])[CH2:27]P(=O)(OCC)OCC)=[CH:24][C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2>C(Cl)Cl.[Cl-].[Li+].C1COCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:27]/[C:26]([C:25]1[S:21][C:22]2[CH:40]=[CH:39][CH:38]=[CH:37][C:23]=2[CH:24]=1)=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CC(=O)c1cc2ccccc2s1)OCC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, is charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (99.2 g, 0.362 mol) in DCM and lithium chloride (1 molar equivalent) dissolved in THF. Diethyl 2-(benzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) is added neat and rinsed with DCM. Some lithium chloride precipitates from solution when the THF and DCM solutions are mixed. The mixture is stirred under nitrogen and cooled to −20° C. After adding the phosphonate and subsequent stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) is added neat via addition funnel and the temperature is held at −5° C. and stirred at this temperature for 19 hours. The temperature is adjusted to 0° C. and treated with 5% aqueous citric acid and the layers are separated. The organic layer is dried over magnesium sulfate and filtered. The crude product is purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 4a.
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:48](Cl)([CH3:51])(=[O:50])=[O:49].[OH-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][O:35][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:31][CH:32]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) (1.2 g; 2.35 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and 1.5 mL of diisopropylethyl amine was added. A second solution containing 0.75 mL mesyl chloride in 3 mL CH2Cl2 was added dropwise to the stirring reaction solution under N2 and the reaction allowed to warm to rt for 1 hr. 0.1N Sodium hydroxide was then added carefully to the reaction, and the layers separated. The CH2Cl2 layer was washed with brine and dried over solid sodium sulfate, then filtered and evaporated to a light red-brown oil (1.5 g). The crude methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) was used directly in subsequent reactions.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:21][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(O)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Part A. Pyridine (0.66 mL, 8.21 mmol) was added slowly to an ice cooled solution of 4-nitrophenyl butanol (1.0 gm,5.13 mmol) and dibromotriphenylphosphorane (2.8 gm, 6.66 mmol) in 20 mL acetonitrile under a nitrogen atmosphere. The reaction solution was stirred for 1/2 hr and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated invacuo to give a residue. The residue was filtered through a short plug of silica gel and then the product was purifed by flash chromatography on silica gel eluting methylene chloride:hexane (v:v, 50:50), to give 1-bromo-4-(4-nitrophenyl)butane as an oil 1.3 gm (98%) MS 275(M+NH4)+ 1 H NMR (CDCl3): 8.2(d, 2H), 7.4(d, 2H), 3.4(t, 2H), 2.8(t, 2H), 1.8-2.0(m, 4H).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C(O)CCC>CO>[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[N:23]=[C:22]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1nccc(N2CCc3ccccc32)n1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 219 mg, 0.77 mmol) in methanol (2 ml) was added to a solution of 2-chloro-4-(indolin-1-yl)pyrimidine (Method 3, 200 mg, 0.86 mmol) in ii-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica (1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (201 mg, 61%). NMR: 2.19 (s, 6H), 2.21-2.3 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.25 (m, 2H), 3.8-4.1 (m, 5H), 5.75 (m, 1H), 6.2 (m, 2H), 6.8-6.9 (m, 3H), 7.0-7.1 (m, 1H), 7.15-7.25 (m, 1H), 7.5-7.6 (m, 2H), 8.05-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.95 (s, 1H); MS (MH+): 406.5.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30]Br)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 63 %

Procedure:
To a solution of 5-iodosalicylaldehyde (2 g, 8.2 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (1.15 g, 8.2 mmol), and 4-bromomethyl-piperidine -1-carboxylic acid tert-butyl ester (2.3 g, 8.2 mmol, Pharmacore). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 4-(2-formyl-4-iodo-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (Yield 2.3 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11](=[O:44])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:16][CH:15]=[C:14]([O:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:13]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:26][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:27][CH2:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)=[CH:15][CH:16]=3)[C:11](=[O:44])[C:10]=2[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-(2-(3-fluoro-4-methoxyphenyl)-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (96 mg, 0.2 mmol) obtained in Step 1 in CH2Cl2 was added trifluoroacetic acid (20 eq, 2.4 mmol). After being stirred for 1 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[CH2:19][OH:20])[C:3]=1[O:23][CH2:24][CH3:25].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH2:24][CH3:25]
Reactant: CCOc1c(C(C)=C(F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E>3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)- 2-fluoro-but-2-en-1-ol (Compound A-136, 908 mg, 2.2 mmol), tetrapropylammonium perruthenate (20 mg, 0.057 mmol) and 4-methylmorpholine N-oxide (516 mg, 4.4 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:50])([CH3:49])[CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:32]CCCCOC3C=CC(C4NN=NN=4)=CC=3)=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:22]=[N:21]1>>[CH3:49][C:18]([CH3:17])([CH3:50])[CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[NH:22][NH:21]1
Reactant: CCCc1c(OCCCCOc2ccc(-c3nnn[nH]3)cc2)ccc2c1nnn2CC(C)(C)C
Reactant: COC(=O)c1ccc(OCCCCBr)cc1
Product: CCCc1c(OCCCCOc2ccc(C(=O)O)cc2)ccc2c1NNN2CC(C)(C)C

Procedure:
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and the mixture of N-alkylated benzotriazoles from example 6. 1H NMR (500 MHz, DMSO) δ 12.58 (bs, 1H), 7.89 (d, 2H), 7.66 (d, 1H), 7.37 (d, 1H), 7.25 (d, 1H), 7.01 (d, 2H), 4.44 (s, 2H), 4.14 (m, 4H), 3.01 (t, 2H), 1.93 (m, 4H), 1.71 (m, 2H), 0.96 (s, 9H), 0.91 (t, 3H). MS (ESI): 440 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:4]=1.[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[C:26]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:4]=3)=[C:25]([OH:30])[CH2:24]2)[CH:20]=1
Reactant: ClCc1nc(-c2ccccn2)no1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(-c4ccccn4)no3)C(=O)O2)cc1Cl
Yield: 9 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]pyridine (from Step 1, below) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 9%.
Reaction SMILES: C(Cl)(=O)CCCCC([Cl:8])=O.OCCCCCCCCCCCCCCC[C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]CCCCCCCCCO)C)=[O:28]>C(Cl)(Cl)Cl>[Cl:8][C:27]([O:29][CH2:30][O:32][C:33](=[O:50])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:28]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Solvent: ClC(Cl)Cl
Product: O=C(Cl)OCOC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 415.4 %

Procedure:
In a three-necked round bottomed flask equipped with a reflux condenser, a glass gas inlet tube and a pressure equalizing dropping funnel was placed freshly distilled adipoyl chloride (2.60 ml, 17.50 mmol) dissolved in absolute chloroform (15 ml). The temperature was raised to ca. 50° C. and under a gentle stream of nitrogen through the solution, a solution of ethylidene bis(16-hydroxyhexadecanoate) (1.0 g, 1.75 mmol) in absolute chloroform (30 ml) was added dropwise and left at this temperature a further 3 hours after addition. The mixture was then cooled to room temperature and quickly transferred into a 50 ml round bottomed flask equipped for distillation under reduced pressure. Chloroform was first distilled off at normal pressure, then oil-pump vacuum was established and excess adipoyl chloride distilled off at ca. 75° C., 5 mbar pressure, leaving the residual title compound (1.56 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C(N)CCC>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC[N+](=O)[O-]
Reactant: CSc1ccc(C=O)cc1
Solvent: CCCCN
Solvent: CCO
Product: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Reaction time: 21 h
Yield: 44.5 %

Procedure:
The intermediate 1-[4-(methylthio)phenyl]-2-nitro-1-propene was prepared as follows: [U.S. Pat. No. 3,117,160, Example V]; a mixture containing 15.2 g of 4-(methylthio)benzaldehyde, 7.5 g of nitroethane, 0.73 g of n-butylamine and 40 ml of absolute ethanol was refluxed with stirring for 21 hours and the solvent then removed by distilling in vacuo. The residue was recrystallized from absolute ethanol (total volume of 60 ml) washed with a small quantity of cold ethanol and dried in vacuo at room temperature to produce 9.3 g of 1-[4-(methylthio)phenyl]-2-nitro-1-propene, m.p. 74°-76° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([CH:18]([CH3:21])[C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
Benzoyl chloride (27.09 g., 0.19 mole.) was added, with cooling, during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (28.35 g., 0.175 mole.) in dry pyridine (200 ml.) at 0°-3°C. After addition was complete, the mixture was heated at 100°C. for 1 hour. It was then evaporated under reduced pressure to yield crude 2-(3-benzamido-4-hydroxyphenyl) propionitrile as an oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:35])[CH2:18][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:16]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:15]=2[O:14]1>ClCCl>[C:33]([C:30]1[CH:31]=[CH:32][C:15]2[O:14][C:13]([CH3:35])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]=3[O-:9])[C:16]=2[CH:29]=1)#[N:34]
Reactant: CC1(C)CC(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 2 h
Yield: 69.7 %

Procedure:
203 mg of m-chloroperbenzoic acid were added at room temperature to a solution of 314 mg of 3,4-dihydro-2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane. After stirring for 2 hours the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was recrystallized from diethyl ether to give 230 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-quinoline-1-oxide of melting point 183°-185° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:19])[CH2:15][CH2:16][CH:17]=[O:18].[C:22]([O:25][CH2:26][C:27]([CH2:29][Si](C)(C)C)=[CH2:28])(=[O:24])[CH3:23].ClCCl>C(N(CC)CC)C>[C:22]([O:25][CH2:26][C:27]([CH2:29][CH:17]([OH:18])[CH2:16][CH2:15][C@H:14]([C@@H:8]1[C@:9]2([CH3:13])[CH:5]([CH:4]([O:3][Si:2]([CH3:1])([CH3:20])[CH3:21])[CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:7]1)[CH3:19])=[CH2:28])(=[O:24])[CH3:23]
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: C[C@H](CCC=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(COC(C)=O)CC(O)CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 57 %

Procedure:
A 1.72 g amount of the compound (4-7), (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-pentanal and 1.10 g of 2-(trimethylsilyl-methyl)-2-propenyl acetate were taken in a 200 ml eggplant-shaped flask, then 30 ml of dichloromethane was added and the solution stirred at −78° C. To this was added 0.86 ml of BF•Et2O, then the solution stirred at −78° C. for 1 hour. Further, 3 ml of triethylamine was added to stop the reaction, then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (IR-60, 150 g, hexane/ethyl acetate=50/1 to 9/1) to obtain the desired product (4-8), (7R)-2-acetoxymethyl-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octen-4-ol in an amount of 1.32 g (yield 57%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O.Cl>[NH:12]([C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Yield: 77 %

Procedure:
6-Chloronicotinic acid (8.0g) was added to 85% hydrazine hydrate (35 ml). The reaction mixture was placed in a 100° C. oil bath for 4 hours. The homogeneous reaction mixture was concentrated to dryness to give a white solid. The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed. The precipitate was isolated by filtration and the solid was washed with 95% ethanol and ether to give 6.0 g of a pale brown solid; yield 77% m.p. 292°-293° C.;
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[CH3:9][C@H:10]1[CH:14]=[CH:13][C@@H:12]([CH3:15])[N:11]1[CH2:16][C:17](OC)=[O:18].Cl>C(O)(C)C.CO>[NH2:4][C:3]([NH2:5])=[N:2][C:17](=[O:18])[CH2:16][N:11]1[C@H:12]([CH3:15])[CH:13]=[CH:14][C@@H:10]1[CH3:9]
Reactant: N=C(N)N
Reactant: COC(=O)CN1[C@H](C)C=C[C@@H]1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: C[C@@H]1C=C[C@H](C)N1CC(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of guanidine hydrochloride (0.6 g.) sodium methoxide (from 0.138 g. of sodium), and methanol (5 cm3) was stirred at room temperature for 1 hour. Methyl cis-(2,5-dimethyl-2,5-dihydropyrrol-1-yl)acetate was then added (0.6 g.) and the mixture stirred overnight (16 h.). The solution was then evaporated and the residue partitioned between water (1.5 cm3) and ether (3 cm3). After stirring at 0° C. for about 3 hours a white precipitate separated. The precipitate was collected and washed with water and ether to give 0.24 g. of title base. The base was dissolved in isopropyl alcohol (3 cm3) and acidified with ethanolic hydrogen chloride. On cooling in ice the title compound hydrochloride was collected and washed with isopropyl alcohol. The product was then dissolved in hot ethanol (3 cm3) diluted with ethyl acetate (2 cm3) and cooled to give pure title compound as the hydrochloride (0.15 g.), m.p. 207°-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To a solution of (3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic Acid ethyl ester (119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405 mmol). The reaction was stirred at room temperature for 2.5 h and 1N HCl was added. The product was extracted into CH2Cl2 (3×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by medium pressure chromatography (3:1 hexanes:EtOAc) to provide the title compound (101.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.36 (m, 8H), 4.274.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74 (s, 3H), 2.33 (s, 3H); MS 376 (M+1).