Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
(S)-tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (8.85 g, 24 mmol) was dissolved in DMF (100 ml), and then NaN3 (6.24 g, 96 mmol) and NaI (0.36 g, 2.40 mmol) were added, followed by stirring at 70° C. for 4 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:10), to give (S)-tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 92%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[N-:12]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.CCOC(C)=O>[Cl:11][C:4]1[C:5]([C:6]#[N:7])=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][NH2:12]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(CBr)c1Cl
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(bromomethyl)-2-chlorobenzonitrile (0.87 mmol) in 9 mL DMF was added NaN3 (1.3 mmol) and the resulting brown solution was stirred at RT for 20 min. The reaction mixture was diluted with EtOAc, washed twice with water and brine, dried over MgSO4 and concentrated in vacuo. The crude azide was redissolved in 4.3 mL THF and 0.1 mL water. Triphenylphosphine (1.04 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was acidified with 0.1N HCl solution until pH 3 and it was extracted 3 times with Et2O. The ageous phase was basified with 1M NaOH solution and extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellowish oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].[CH3:13][O:14][CH2:15][CH2:16][OH:17].[H-].[Na+].Cl>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:17][CH2:16][CH2:15][O:14][CH3:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: COCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(C(=O)O)cc1C#N
Temperature: 70 °C
Yield: 93.2 %

Procedure:
3-Cyano-4-fluorobenzoic acid (500 mg, 3.03 mmol), 2-methoxyethanol (461 mg, 6.06 mmol), and 60% w/w NaH (363 mg, 9.08 mmol) were combined in acetonitrile (15 mL) and the reaction mixture was heated at 70° C. overnight. The reaction mixture was made acidic by the addition of 1N HCl and was extracted with ethyl acetate. The organics were dried over sodium sulfate, evaporated and purified by column chromatography (0-10% methanol in dichloromethane) to yield 3-cyano-4-(2-methoxyethoxy)benzoic acid (625 mg, 93%). 1H NMR (400 MHz, CD3CN) δ 9.60 (s, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 4.34 (dd, J=5.2, 3.7 Hz, 2H), 3.79 (dd, J=5.2, 3.6 Hz, 2H), 3.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][C:7]=1[Cl:8].N[C:34](N)=[O:35].O>ClC(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][CH2:18]3)[C:34](=[O:35])[NH:32][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: NC(N)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 4 parts of 4,5-dichloro-N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,2-benzenediamine and 1.5 parts of urea is stirred for 3 hours in an oil-bath at 190° C. After cooling, water and trichloromethane are added. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 5,6-dichloro-1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.3° C.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C1(C(S)C2C=CC(CCl)=CC=2)C=CC=CC=1.[OH:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[NH:47][C:46](=[O:51])[CH2:45][CH2:44]2>CS(C)=O>[C:11]1([S:17][CH2:9][C:1]2[CH:6]=[CH:5][C:4]([CH2:7][O:40][C:41]3[CH:42]=[C:43]4[C:48](=[CH:49][CH:50]=3)[NH:47][C:46](=[O:51])[CH2:45][CH2:44]4)=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: SC(c1ccccc1)c1ccc(CCl)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCc2cc(OCc3ccc(CSc4ccccc4)cc3)ccc2N1

Procedure:
p-Xylylene dichloride was reacted with thiophenol in a mol ratio of 1:1 in the presence of excess potassium carbonate in dimethylsulfoxide. The obtained 4-(phenyl-mercapto-methyl)-benzyl chloride (identification: thin-layer chromatogram) was further reacted with 6-hydroxy-3, 4-dihydro-carbostyril analogous to Example 140 without isolation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)=[CH:4][CH:3]=1.CN(C(O[N:37]1N=N[C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NCCCCN[C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:28])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCNC(=O)OC(C)(C)C)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0 g, 2.5 mmol), HATU (1.9 g, 5 mmol) and DIPEA (0.88 ml, 5 mmol) was stirred for 80 minutes at room temperature, to this was added 1,1-dimethylethyl (4-aminobutyl)carbamate (1.05 ml, 5.0 mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2 h before it was concentrated. The residue was taken up in dichloromethane and washed with 1N HCl. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/methanol 95/5 to give the title compound as a yellow solid (1.2 g). LC/MS (Method D): rt=3.04 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(O)c1ccc(Br)cn1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)cn1
Yield: 94.4 %

Procedure:
A solution of 1-(5-bromopyridin-2-yl)ethanol (1.0 g, 4.95 mmol), phenol (835 mg, 8.87 mmol), and triphenylphosphine (1.8 g, 6.86 mmol) was stirred in dry tetrahydrofuran (70 mL) at 0° C. under nitrogen atmosphere. To this mixture was added dropwise diisopropyl diazene-1,2-dicarboxylate (1.4 g, 6.92 mmol) over 5 minutes, and the reaction was monitored by thin layer chromatography. After complete disappearance of starting material, the solvent was removed under reduced pressure and the resultant oil was purified by flash column chromatography (hexane/ethyl acetate, 1/1) to give 5-bromo-2-(1-phenoxyethyl)pyridine (1.3 g, 94.4%) as a white solid. LRMS (M+H+) m/z: calcd 278.01. found 278 1H NMR (300 MHz, DMSO) δ 8.60 (d, J=2.1 Hz, 1H), 7.93 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.18 (m, 2H), 6.86 (m, 3H), 5.39 (m, 1H), 1.63 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:9]3([O:34][C@H:10]3[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:35][CH2:36][CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@:9]([OH:34])([C@H:10]([NH:35][CH2:36][CH2:37][C:38]3[N:42]=[CH:41][NH:40][CH:39]=3)[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Reactant: NCCc1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
5,6α-epoxicholestan-3β-yl butyrate (10.4 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl butyrate as a white solid (7.8 g, 57%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O=[C:25]([CH2:29][CH2:30][CH3:31])[CH2:26][C:27]#[N:28].CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH2:29][CH2:30][CH3:31])[C:26]([C:27]#[N:28])=[C:16]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCC(=O)CC#N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Yield: 55.7 %

Procedure:
A solution of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)(phenyl)methanone (2.0 g, 6.1 mmol), 3-oxohexanenitrile (0.81 g, 7.3 mmol) and methanesulfonic acid (0.59 g, 6.1 mmol) in toluene (50 ml) was stirred at 110° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from disopropyl ether to give 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, yield 56%) as pale-yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Br.C(O)(=O)C.CS(C)=O>C(O)(=O)C>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C1CCC(C(=O)O)=NN1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
To a solution of 6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylic acid (20 g) in acetic acid (50 mL) is added 25% hydrobromic acid/acetic acid (200 mL) and thereto is added dropwise dimethylsulfoxide (22.0 g) at room temperature. The mixture is stirred at room temperature for 3 days. The resultant precipitates are collected by filtration, washed successively with acetic acid and water and dried at 40° C. overnight to give 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (10.55 g, yield; 54%) as colorless crystals. MS (ESI) m/z: 139 [M−H]−
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:30])[C:14]([CH2:26][CH2:27][C:28]#N)=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:31].[Na+].[OH2:33]>>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:30])[C:14]([CH2:26][CH2:27][C:28]([OH:33])=[O:31])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: O
Reactant: CCCCCCCCN1CCc2c(C)c(CCC#N)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Product: CCCCCCCCN1CCc2c(C)c(CCC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21

Procedure:
N-(1-Octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (1.14 g) was dissolved in ETOH (26 ml), and a solution of NaOH (1.1 g) in water (7.5 ml) was added, which was followed by refluxing for 14 hr under a nitrogen atmosphere. EtOH was evaporated under reduced pressure. The obtained residue was dissolved in warm water (30 ml) and washed with AcOEt (30 ml). The aqueous layer was neutralized with 2N HCl and extracted with CHCl3 (50 ml). CHCl3 layer was evaporated under reduced pressure to give 830 mg of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[S:2]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate 40 (1.002 g, 3.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added pyridine (0.46 mL, 6 mmol) and morpholine (0.395 mL, 5 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 0% to 20% EtOAc in CH2Cl2) gave methyl 4-methoxy-3-(morpholinosulfonyl)benzoate 41 (0.970 g, 81% yield) as a white solid. Mass spectrum: calculated for C13H17NO6S 315.1. found 316.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]2[CH:32]=[CH:33][S:34][C:30]=2[CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]5[CH:32]=[CH:33][S:34][C:30]=5[CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nccc2sccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nccc5sccc45)cc3CC[C@@H]12
Yield: 24.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chlorothieno[3,2-c]pyridine (78 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 37 mg (25%) of the title compound as a white solid. mp 196°-197°. FDMS: m/e=394. α[D]589 =+75.17 (c=0.57, chloroform).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl>CCOCC>[CH:1]1([NH:6][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentyl amine (50.0 g, 587 mmols) was dissolved in anhydrous ether (500 ml) and triethylamine (69.3 g, 685 mols) was added. The resulting solution was cooled in an ice bath and then tert-butyl bromoacetate (95.4 g, 489 mmols) in ether (150 ml) was added slowly over approximately three hours. The reaction mixture was allowed to stir overnight at room temperature. The reaction was acidified to pH 1 with aqueous hydrochloric acid and the layers were separated. The aqueous layer was washed with ethyl acetate and then basified to pH 10 with aqueous ammonium hydroxide. The product was extracted several times into methylene chloride and the combined organic extract was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and evaporated to yield the desired product as a slightly yellow oil (56.9 g, 58.4%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[O:12]=[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][NH:16][C:15]([CH:27](O)OC)=[CH:14]1.[CH2:31]([O:33][C:34](=[O:55])[CH:35]=[P:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:32]>>[O:12]=[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][NH:16][C:15](/[CH:27]=[CH:35]/[C:34]([O:33][CH2:31][CH3:32])=[O:55])=[CH:14]1.[C:49]1([P:36](=[O:8])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)/C=C/c1cc(=O)c(OCc2ccccc2)c[nH]1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
p-Toluenesulfonic acid (0.5 g), 6.26 g of 1,4-dihydro-4-oxo-2-[(hydroxy)(methoxy)methyl]-5-(phenylmethoxy)pyridine and 8.35 g of (triphenylphosphoranylidene)acetic acid ethyl ester were stirred for three hours at 70° C. A clear dark solution was formed. Evaporation of the solvent in vacuo yielded an oily residue of the title compound and triphenylphosphine oxide. This was dissolved in 30 ml of isopropanol. After standing overnight in a refrigerator, the resulting crystals were filtered off, washed with ether and recrystallized from isopropanol (yield: 5.72 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CS(C)=O.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[N:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])=[CH:14][CH:13]=1
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Reactant: N#Cc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C#N)cc2)nc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (120 mg, 0.5 mmol) in DMSO (1 mL) was added cesium carbonate (196 mg, 0.6 mmol) and 2-fluoronicotinonitrile (61 mg, 0.5 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 5% of MeOH in CH2Cl2, followed by trituration with ether, to provide 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinonitrile as off-white solid. MS (ESI, pos. ion) m/z: 342.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].Cl>ClCCl>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Yield: 59.9 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane (58 mL), triethylamine (2.6 mL, 18.5 mmol) and methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added at 0° C., and the mixture was stirred under reflux for 18 hr. To the mixture was added 4 mol/L hydrochloric acid (90 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%). [step 2] N-(3-Chloro-2-nitrophenyl)-2-methoxyacetamide (900 mg, 3.68 mmol) obtained in step 1 was dissolved in ethanol (7.4 mL), tin chloride dihydrate (4.0 g, 17.7 mmol) was added and the mixture was stirred at 100° C. for 4 hr. The mixture was adjusted to pH 10 with 4 mol/L aqueous sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (710 mg, 98%).
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:27]=1)=O>ClCCl>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[C:28]1[CH:27]=[C:26]([CH:24]=[CH:8][C:9](=[O:11])[CH3:10])[O:30][N:29]=1
Reactant: O=Cc1cc(C2CCCCO2)no1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)C=Cc1cc(C2CCCCO2)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
47 g of 1-triphenylphosphoranylidene-2-propanone were dissolved in 50 ml of dichloromethane, and 27 g of 5-formyl-3-tetrahydropyran-2-ylisoxazole were added. The reaction mixture was stirred for 1 day at room temperature and then evaporated down, the residue being stirred in methyl tert-butyl ether. After the triphenylphosphine oxide had been separated off, 43 g of a yellow oil remained.