Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[N:35]=[C:36]([CH2:39][NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])[S:37][CH:38]=1.[C:46](=[O:49])([O-])[O-:47].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:43][C:42]([F:45])([F:44])[C:46]([OH:47])=[O:49].[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[N:35]=[C:36]([CH2:39][NH:40][CH2:41][C:42]([F:44])([F:45])[F:43])[S:37][CH:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)CNCc1nc(Br)cs1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNCC(F)(F)F)n4)cc23)CC1
Product: O=C(O)C(F)(F)F
Yield: 70.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2 mL) and water (0.7 mL) was added N-[(4-bromo-1,3-thiazol-2-yl)methyl]-2,2,2-trifluoroethanamine (30 mg, 0.11 mmol) and potassium carbonate (83 mg, 0.6 mmol). The resulting mixture was degassed for 5 min before the addition of tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol). The mixture was reacted in a CEM microwave tube at 160° C. for 20 min. Organic layers were separated and concentrated. The resulting residue was purified by Gilson Preparatory HPLC to give 25 mg of the title compound (47.2%).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:49].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:51]([O:50][C:48]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C:2]2=[O:7])[CH:10]=1)(=[O:25])=[O:26])=[O:49])[CH2:52][CH2:53][CH3:54]
Reactant: CC(C)Cc1cc(-c2cccc(CN3C(=O)CCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(CN2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-(3-pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (95.0 mg, 0.205 mmol; see step (f)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (91.3 mg, 0.616 mmol) and butyl chloroformate (261.1 μL, 2.05 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by LCMS (Liquid Chromatography Mass Spectrum; 25-100% CH3CN in water) to give the title compound in 76% yield, over two steps, (79.1 mg, 0.156 mmol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1)[CH:2]=[CH2:3]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: C=CCOc1ccccc1OCC1CO1
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 10.3 g of 1-(o-allyloxy-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from isopropanol to yield the 1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 122°-125°C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:14][S:15]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A solution of (S)-tetrahydrofuran-3-ol (1.0 g, 11 mmol) and triethylamine (9.4 mL, 86 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (S)-tetrahydrofuran-3-yl methanesulfonate (1.52 g, brown oil, 83% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10](F)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2].[O:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2]
Reactant: N#Cc1cnc2cc(F)cc(F)c2c1O
Reactant: OC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(F)cc(OC3CCOCC3)c2c1O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (2.06 g), tetrahydro-2H-pyran-4-ol (1.02 g) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 30.0 ml) in anhydrous tetrahydrofuran (100 ml) was stirred and heated under nitrogen at 60° C. for 1.5 hours. Acetic acid was added until pH6 was reached and then the solution was evaporated to dryness. The residue was dissolved in aqueous sodium hydroxide solution (2.0M) and the resulting solution was filtered through a GF/A glass fibre pad. The filtrate was acidified to pH5 with acetic acid and the resulting oily precipitate allowed to stand 3 days when it had become solid. The solid was collected and washed with water then air-dried. (1.8 g, 62%); NMR spectrum: (DMSOd6) 1.67 (m, 2H), 1.92 (m, 2H), 3.50 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 8.52 (s, 1H); Mass spectrum: M+H+ 289.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:49][O:48][C:44](=[O:47])/[CH:45]=[CH:46]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:22][C:21]2=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of 6-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (1.04 g, 2.62 mmol), Pd(OAc)2 (59 mg, 0.262 mmol), PPh3 (137 mg, 0.52 mmol), TEA (0.73 ml, 5.2 mmol), methyl acrylate (0.47 ml, 5.2 mmol) in dry DMF (10 ml) was heated at 100° C. for 8 h. The mixture was cooled down to RT, filtered on a celite pad and washed with AcOEt (100 ml). The filtrate was washed with NH4Cl and saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 70:30) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (594 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][O-].[Na+]>>[CH3:20][O:8][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: C[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(C)n1

Procedure:
Successive treatment of 6-methyl-2-pyridone with a mixture of phosphoryl choride and phosphorus pentachloride, and sodium methoxide gives 6-methoxy-2-methylpyridine which may be converted into 2-bromomethyl-6-methoxypyridine with N-bromosuccinimide. Substitution of 2-bromomethyl-6-methoxypyridine for 2-chloromethyl-3-methoxypyridine in the general procedure of Example 1(iii)-(v) leads to the preparation of N-cyano-N'-methyl-N"-[2-((6-methoxy-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[S:12])=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[S:12])=[N:8][CH:9]=1
Reactant: COC(=S)Cc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=S)Cc1ccc(N)cn1
Yield: 55.5 %

Procedure:
A mixture of methyl 5-nitro-(pyrid-2-yl)-thioacetate (6.3 g, Reference Example 2) iron powder (12 g), ammonium chloride (1 g), ethanol (150 ml) and water (150 ml) was heated at reflux for 2 hours. The reaction mixture was cooled and then filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue was subjected to flash chromatography on silica gel eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound as a yellow oil (3.0 g).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].S([O-])([O-])(=O)=S.[Na+].[Na+].I[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:7][CH:3]([CH2:4][CH2:5][CH3:6])[C:2]#[C:1][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]
Reactant: Fc1ccc(I)c(F)c1F
Reactant: C#CC(O)CCC
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(O)C#Cc1ccc(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 4-iodo-1,2,3-trifluorobenzene was dissolved into DMF, into which triethylamine, copper iodide (I), and tetrakistriphenylphosphine palladium (0) were added and heated to 55° C. Then, the DMF solution containing 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography (silica gel, toluene/hexane) to obtain 1-(3-hydroxy-1-hexynyl)-2,3,4-trifluorobenzene.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][C:3]=12.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:3]2[CH:15]=[CH:14][NH:13][C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Product: CCOC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
A mixture of ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.5 g, 3.9 mmol) and cyclohexylamine (2.34 g, 23.6 mmol) was stirred at about 80° C. for about 24 h. The solvent was removed under reduced pressure. The residue was suspended in Et2O and the precipitate was collected by filtration and dried under vacuum. The solid was washed with water and dried under vacuum again to give ethyl-4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.54 g, 48%): LC/MS (Table 2, Method b) Rt=2.56 min.; MS m/z: 288 (M+H)+.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][CH:10]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].O>C(Cl)Cl>[CH3:9][CH:10]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CSc1ccccc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(CSc1ccccc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 60.1 %

Procedure:
1.3 g of N-methylmorpholine was added to a suspension containing 3.0 g of N1 -(1-methyl-2-phenylthioethyl)-L-valinamide hydrochloride suspended in 80 ml of methylene chloride, at -15° C. After 1.9 g of phenyl chloroformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.3 g of the desired product in the form of a white crystal (yield: 54%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH:23]=[CH:24][C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]#[C:25]/[CH:24]=[CH:23]/[CH2:22][N:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CC(=O)c1cccc(CNC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Yield: 61.6 %

Procedure:
The procedure described in Example 13 was repeated, except that 3′-(N-isopropylaminomethyl)acetophenone (1.66 g; 8.7 mmol), sodium carbonate (925 mg; 8.7 mmol), and 1-bromo-6,6-dimethyl-2-hepten-4-yne (1.74 g; 8.7 mmol) were used, to thereby yield 1.67 g of the target compound (yield: 61.8%).
Reaction SMILES: O[CH2:2][CH2:3][Si:4]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]O.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.O>[CH2:27]([N:34]1[CH2:6][CH2:5][Si:4]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C[Si](CCO)(CCO)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si]1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8.5 g of 2-[(2-hydroxy-ethyl)-methyl-phenyl-silanyl]-ethyl alcohol is put in 80 ml of anhydrous dichloromethane under nitrogen. 14.2 ml of triethylamine is added, and then, at 0° C., 6.9 ml of mesyl chloride is added dropwise using a dropping funnel. The mixture is stirred for 2 h at 0° C. and gradually turns orange with appearance of a precipitate. Once conversion is complete, 14.2 ml of triethylamine is added and then 4.7 ml of benzylamine at 0° C. The reaction mixture is brought back to room temperature and then refluxed for 6 h. After hydrolysis with H2O at room temperature, the reaction mixture is extracted with ethyl acetate three times. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The raw product obtained is chromatographed on silica gel, eluting with a gradient of ethyl acetate and heptane containing 3% of triethylamine varying from 0/10 to 3/7. 3.6 g of 1-benzyl-4-methyl-4-phenyl-[1,4]azasilinane is obtained in the form of a clear yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]1[CH:14]([Cl:15])[CH2:13][CH2:12][CH2:11][O:10]1.Cl.O>CCOCC>[Cl:15][CH:14]1[CH2:13][CH2:12][CH2:11][O:10][CH:9]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: ClC1CCCOC1Cl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: ClC1CCCOC1c1ccccc1
Yield: 93 %

Procedure:
Into a dry flask fitted with dropping funnel reflux condenser, drying tube and mechanical stirrer was placed 51 g of magnesium turnings, followed by the addition of 200 ml of dry ether. A small portion of bromobenzene was added to initiate the reaction, followed by the remainder of 330 g (2.1 mole) of bromobenzene in 1 liter of dry ether at a rate sufficient to maintain reflux. The mixture was cooled in an ice-salt bath to which was added dropwise the cold ethereal solution of 2,3-dichlorotetrahydropyran. After completing the addition, the slurry was refluxed for 3 hours, cooled in an ice-water bath and 300 ml of cold 20 percent hydrochloric acid added slowly to the stirred mixture. The addition of 500 ml of water dissolved the precipitated salts, the layers were separated, the aqueous phase extracted with ether (2×200 ml) and the combined ethereal layers washed with brine (200 ml) and dried over anhydrous potassium carbonate. In vacuo removal of solvent left an amber liquid which was distilled through a 20 cm Vigreux column, whereby 256 g was collected at 77°-90°/0.25 mm Hg. The product was redistilled at 153-154/16 mm Hg, the distillate crystallizing to give needles m.p. 39.5°-40.5°. The crude yield was 256 g (93% yield based on dihydropyran).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]1=2.O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:36]=[C:31]1[CH2:32][CH2:33][C:34](=[O:35])[N:30]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:28])[C:7]3[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)ON3C(=O)CCC3=O)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
To a solution of 200 mg (0.52 mmol) of 8 in 40 ml of dichloromethane (distilled over calcium hydride) was added 92 mg (0.8 mmol) of N-hydroxysuccinimide and 152 mg (0.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml of brine, 2×50 ml of saturated sodium bicarbonate followed by 2×50 ml of brine. The resulting solution was dried (Na2SO4) and concentrated to give 245 mg (0.51 mmol, 98%) of 9 as a white solid.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].CSC(SC)=C[N+]([O-])=O.[CH3:23][CH2:24][N:25](CC)[CH2:26]C>C(O)C>[CH3:26][NH:25][C:24]1[CH:23]=[C:13]2[N:8]([C:7]=1[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: CCOC(=O)C[n+]1ccccc1
Reactant: CCN(CC)CC
Agent: CSC(=C[N+](=O)[O-])SC
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1c(NC)cc2ccccn12

Procedure:
A mixture of 1-ethoxycarbonylmethylpyridinium bromide 5 (1 g, 4.1 mmol), 1,1-bismethylthio-2-nitroethene (1.2 g; 8.1 mmol) and Et3N (4.1 g, 40.6 mmol) in ethanol (30 mL) was heated at reflux for 12 h. The solvents and the triethylamine were then evaporated under vacuum. The oil obtained was extracted with water (50 mL) and toluene (3×50 mL). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residue was chromatographed on a column of silica with an elution gradient of 1/1 to 4/1 of ethyl acetate/petroleum ether. This gave 0.5 g of ethyl 2-methylaminoindolizine-3-carboxylate 6 in the form of an oil. 1H NMR (DMSO-d6) δ: 9.11 (br s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.07-7.01 (m, 1H), 6.71-6.66 (m, 1H), 5.88 (br s, 1H), 5.85 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.34 (t, J=7.0 Hz, 1H), 13C NMR (CDCl3) δ: 161.0, 148.9, 138.2, 127.0, 123.4, 115.8, 109.9, 98.6, 84.3, 58.7, 31.0, 14.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Intermediate 9 (0.220 g, 0.772 mmol) was dissolved in acetic acid (1.3 ml) and cooled to 5° C. Sodium nitrite (0.063 g, 0.927 mmol) in 0.35 ml water was added slowly followed by sulphuric acid (0.09 ml). The reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was poured into ice water and pH adjusted to ca. 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a brown solid (0.220 g, 96%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.88 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 6.12 (s, 2H).
Reaction SMILES: [I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=O)[C:3]=1[O:15][CH3:16].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:12]([C:4]1[C:3]([O:15][CH3:16])=[C:2]([I:1])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)#[N:14]
Reactant: COc1c(C(N)=O)cc2c(c1I)CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c(C#N)cc2c(c1I)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a stirred, cooled (0° C.) suspension of 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxamide (2.06 g, 6.22 mmol), triethylamine (2.77 mL, 19.91 mmol), and THF (40 mL) was added trifluoroacetic anhydride (1.23 mL, 8.71 mmol) dropwise via syringe. After addition, the ice bath was removed and the reaction stirred overnight at ambient temperature. The mixture was cooled to 0° C. and excess trifluoroacetic anhydride destroyed with H2O (2 mL). Ethyl acetate (50 mL) was added and the organic layer was washed with H2O (3×25 mL) and brine (25 mL), dried (NaSO4), filtered, concentrated in vacuo and purified by chromatography (100% DCM) to afford a light brown solid (1.96 g, 100%). 1H NMR (CDCl3) δ 7.29 (s, 1H), 4.0 (s, 3H), 2.74 (m, 4H), 1.76 (m, 4H), MS m/z 314 (M+H).