Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)[CH:10]=[CH:9]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:38][C:37]([N:27]1[CH2:26][CH2:25][N:24]([C:16]2[N:15]=[C:14]([O:13][C@@H:11]3[CH2:12][C@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:9]=[CH:10]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:29][CH2:28]1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C1=C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)C[C@@H]1OC1CCCCO1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](OC4CCCCO4)C3)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]-2-(1-piperazinyl)quinazoline (11.07 g) in dry methylene chloride (110 ml) is added triethylamine (7.75 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (4.40 ml) in dry methylene chloride (20 ml). The mixture is stirred under ice-cooling for one hour. The reaction mixture is washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]quinazoline (12.57 g) as oil.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[C:10]#[C:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:11]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1)[CH3:13]
Reactant: CCC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)nn2ccccc12

Procedure:
A solution of 1-aminopyridinium iodide (10 g, 40 mmol) [Aldrich 441503], ethyl 2-pentynoate (5.7 g, 45 mmol) [Aldrich 632112] and potassium carbonate (12.0 g, 90 mmol) were stirred in N,N-dimethylformamide (200 mL) at 20° C. for 16 h. The mixture was poured into water to give a tan suspension. The solid was filtered and washed with water to give the desired to compound (5.0 g, 57%). LCMS for C12H15N2O2 (M+H)+: m/z=219.1. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1H), 8.00 (m, 1H), 7.52 (m, 1H), 7.05 (m, 1H), 4.28 (m, 2H), 3.00 (m, 2H), 1.33 (m, 3H), 1.24 (m, 3H).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>C(Cl)Cl>[Br:24][C:25]([CH3:30])([CH3:29])[C:26]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:8][CH2:9][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:13][CH2:14]2)[CH2:11][CH2:12]3)=[CH:6][CH:5]=1)=[O:27]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To an ice water cooled solution of methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 8; 3.88 g, 15.02 mmol) in DCM (150 mL) was added aluminium chloride (6.01 g, 45.05 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (1.86 mL, 15.02 mmol). The reaction mixture was allowed to stir at ˜0° C. for 30 mins then poured onto ice-water (20 mL). The organic phase was separated and the aqueous phase washed with DCM (2×150 mL), the organic washings combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 120 g Crawford silica cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc to give the product as a white solid (5.18 g, 12.72 mmol, 85%). 1H NMR (CDCl3) δ 1.64-1.69 (6H, m), 1.83-1.88 (6H, m), 2.03 (6H, s), 2.18 (2H, s), 3.66 (3H, s), 7.36 (2H, d), 8.10 (2H, d); Solid Probe MS m/e M+ 407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[NH:12][N:13]=1.O.[NH2:18][NH2:19]>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:18][NH2:19])=[O:16])[NH:12][N:13]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 86.5 %

Procedure:
In methanol (20 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid (1.00 g) was dissolved, and 6 drops of concentrated sulfuric acid was added thereto. The mixture was heated under reflux for 19 hours. After the mixture was allowed to cool, hydrazine monohydrate (0.97 g) was added to the mixture, and the resulting mixture was heated under reflux for 16 hours. The mixture was concentrated under a reduced pressure, and water was added thereto. The precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (912 mg, 87%) as a white powder.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(Cl)(Cl)Cl.CO.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>>[I-:1].[CH3:35][O:34][CH:10]([CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][N+:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1)(=[O:7])=[O:6])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: c1ccc2ncccc2c1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCI)OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCC[n+]1cccc2ccccc21)OC
Product: [I-]

Procedure:
A solution of 88 mg (0.136 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIa6 in 1 ml of quinoline is stirred at 45° C. for 2 days and the product is isolated by extraction with a mixture of chloroform-methanol and the organic layer is washed with 5.7% hydroiodic acid twice and with water once and the solvent is evaporated. The residue is recrystallized from acetone to give 2-methoxy-1-octadecylcarbamoylthio-3-(3-quinoliniopropylsulfonylamino)propane iodide Ia25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Nc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.4 %

Procedure:
Into a 50 mL roundbottom flask, was placed 4-methoxyphenylboronic acid (5.4 g, 35.54 mmol). To this was added 5-bromo-pyrazin-2-ylamine (3 g, 17.24 mmol). Cu(OAc)2 (3.45 g, 19.06 mmol) was added, followed by addition of a solution of DMAP (4.2 g, 34.43 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 12 hours. The reaction progress was monitored by thin layer chromatography (TLC) (ethyl acetate/petroleum ether=1:2). When the reaction was complete, the mixture was filtered, then concentrated under vacuum. The residue was dissolved in ethyl acetate (EtOAc), then washed with water. The organic layer was dried over Na2SO4, then filtered and concentrated. The crude product was purified by silica gel chromatography (SGC) eluting with ethyl acetate/petroleum ether (1:5, v/v) to provide (5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (500 mg, yield 10%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 1-bromomethyl-3-nitrobenzene (the compound of formula (R), 5 mmol, 1.08 g), pyrrolidine (11 mmol, 0.79 g), and 1.0 mL triethylamine (the compound of formula NRR′R″ wherein R═R′═R″=ethyl) in THF (35 mL) was heated at 60° C. for 1 hour. The reaction mixture was allowed to cool to ambient temperature overnight with stirring. Water was then added to the reaction mixture and the product was extracted into diethyl ether. The ether layer was dried over sodium sulfate, filtered, and evaporated to yield 1.03 g (94%) of 1-(3-nitro-benzyl)-pyrrolidine (the compound of formula (S)) which was used in the following reaction without further purification.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][S:13]([C:16]1[CH:17]=C([CH:22]=[CH:23][CH:24]=1)C(O)=O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:16]1[CH:17]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([Cl:9])=[O:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (0.4 mL) and oxalyl chloride (1.90 g) were added to a solution of 3-(methylsulfonyl)benzoic acid (2.00 g) in CHCl3 (including amylene, 40 mL) in a nitrogen gas flow under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to yield a crude product as a yellow solid, which was used in the subsequent reaction.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([O:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOCc1ccccc1
Product: NS(=O)(=O)OCCOCc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(benzyloxy)ethanol except the oil obtained was then further purified by high pressure chromatography as described in earlier examples using methylene chloride as eluting agent. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give title compound in 54% yield as light-yellow, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]#[N:33])[CH:14]=2)=[CH:4][N:3]=1.C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:40][N:39]=[N:38][N:33]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
N-(2-Chloro-5-{4-cyano-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (1.6 g, 3.19 mmol), trimethylsilyl azide (0.734 g, 6.37 mmol) and dibutyl(oxo)stannane (0.079 g, 0.319 mmol) were placed in toluene (30 ml) and the mixture heated at 100° C. for 16 h. The mixture was stirred at this temperature over the weekend. The mixture was cooled to room temperature and the solvent removed in vacuo. The residue was adsorbed onto florisil and chromatographed on silica (100 g cartridge) eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol to give the title compound (1.3 g).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu][C:21]#N.C[Li]>CCOCC.O>[OH:13][CH:8]([C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: N#C[Cu]
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in 10 ml of absolute ether were added dropwise to a cuprate solution which had been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normal methyllithium solution and had been cooled to -78° C. The solution was stirred at -78° C. for 1 h. and then allowed to warm to room temperature. It was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with sodium bicarbonate solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a pale yellow oil.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.[O:29]([CH2:36][CH2:37][CH2:38]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][N:15]([CH2:38][CH2:37][CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: BrCCCOc1ccccc1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(CCCOc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (4.8 g, 16 mmole) and 3-phenoxypropyl bromide (4 g, 18 mmole) in 25 ml DMF containing potassium carbonate (milled, 4.4 g, 32 mmole) was stirred at 80° C. for two hours. After cooling, the mixture was stirred with 300 ml water and was extracted with ethyl acetate-ether. The organic extract was washed with water, saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 9 g of an oil. This oil was purified by HPLC (silica gel, 10% ethyl acetate/dichloromethane) to give 4.7 g (68%) of 7,8-dimethoxy-3-(3-phenoxypropyl)-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine solid, m.p. 95°-100° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:14]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])=[O:15])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31].O>ClCCl>[C:18]([NH:17][S:14]([C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:30]([O:32][CH3:33])=[O:31])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:16])=[O:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1ccc(CCN)cc1S(=O)(=O)NC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 g (4.6 mmol) of methyl 4-(2-aminoethyl)-2-tert-butylaminosulfonylbenzoate and 0.71 ml (5.1 mmol) of triethylamine in 10 ml of dichloromethane was added dropwise to an ice-cooled solution of 1.31 g (13.8 mmol) of methyl chloroformate in 20 ml of dichloromethane. After 2 h at room temperature, water was added, the phases were separated, and the aqueous phase was re-extracted twice with dichloromethane. The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. This gave 1.4 g (81%) of methyl 2-tert-butylaminosulfonyl-4-[2-(methoxycarbonylamino)ethyl]benzoate as a viscous oil.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([O:19][NH:20][C:21]([C:23]1[N:28]=[CH:27][C:26]2[C:29](=[O:32])[O:30][CH2:31][C:25]=2[C:24]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(ONC(C1C(OCC2C=CC=CC=2)=C(CO)C(C(NCC2C=CC(F)=CC=2)=O)=CN=1)=O)C1C=CC=CC=1>>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][C:29]([C:26]3[C:25]([CH2:31][OH:30])=[C:24]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:23]([C:21]([NH:20][O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:22])=[N:28][CH:27]=3)=[O:32])=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: O=C1OCc2c1cnc(C(=O)NOCc1ccccc1)c2OCc1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Product: O=C(NCc1ccc2c(c1)OCO2)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 61.6 %

Procedure:
Piperonylamine (0.035 g, 0.288 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.056 g, 0.144 mmol, 1 eq), compound 1c of example 1, were heated neat at 70° C. for 30 min. The crude product was purified by silica gel (30% ethyl acetate) yielding 0.048 g of N5-(benzo[d][1,3]dioxol-5-ylmethyl)-N2,3-bis(benzyloxy)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (62% yield) as a white solid; MS-ESI m/z 542 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl-].[Na+]>COCCOCCOC.O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(C)nc(N2CCNCC2)c1
Reaction time: 18 h

Procedure:
A solution of 2-chloro-4,6-dimethylpyridine (30 g, 0.212 mol) in diglyme (100 mL) was added over 25-30 min. to a refluxing solution of anhydrous piperazine (147 g, 1.70 mol) in diglyme (150 mL). Heating was continued for 18 h (whereby TLC showed absence of 2-chloro-4,6-dimethylpyridine), then the mixture was cooled to room temperature and diluted with water (3 L). Sodium chloride (50 g) was added and the solution was extracted with ethyl acetate (300 mL×3); the combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo (up to 110° C. & ˜15 mmHg; to remove maximum diglyme) to afford 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (42 g, 103.3%, the G.C. spectrum showed 86.4% product, 10.7% diglyme, and 2.1% dimer.)
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[PH3:5]>C1(C)C=CC=CC=1>[CH2:4]([P:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:3][CH2:2][CH3:1]
Reactant: P
Reactant: C=CCC
Solvent: Cc1ccccc1
Product: CCCCP(CCCC)CCCC
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A 90 liter-autoclave was charged with 9.6 kg (170 mol) butene-1 and 1.75 kg (51 mol) PH3 in the sequential order indicated. Next, the autoclave was heated to 80° C. and the addition of the toluene/ABIN-solution was started. 12 l toluene in which 170 g ABIN (2 mol %, based on PH3) was dissolved was pumped over a period of 2.5 hours into the reactor so that the temperature of the reaction mixture did not exceed 100° C. After a reaction period of 71/2 hours, the whole was allowed to cool and the crude product (18.3 kg) was given into a barrel scavenged with nitrogen.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6](=O)[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH3:2]>CS(O)(=O)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[S:8][CH:7]=1)[CH3:2].[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Agent: CS(=O)(=O)O
Product: CCOC(=O)Cc1csc2cc(OC)ccc12
Product: CCOC(=O)Cc1csc2cccc(OC)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Methoxy-phenylsulfanyl)-3-oxo-butyric acid ethyl ester (10.0 g) is added to pre-cooled methanesulfonic acid (60 mL) at 0˜5° C., then the reaction mixture is allowed to warm to room temperature. After 1 h, the mixture is diluted with ice water and extracted with ethyl acetate. The combined organics are washed with brine, dried over Na2SO4, concentrated. Chromatography on silica gel elited with hexanes and ethyl acetate yields (6-methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (4.8 g) and (4-methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (0.8 g)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DMF (10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1 H NMR (CDCl3) δ6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][S:40]([CH3:43])(=[O:42])=[O:41]>ClCCCl>[C:30]1([C:8]2[CH:7]=[C:6]([CH:3]3[CH2:2][NH:1][C:38](=[N:39][S:40]([CH3:43])(=[O:42])=[O:41])[NH:5][CH2:4]3)[CH:11]=[CH:10][C:9]=2[NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NS(C)(=O)=O)NC2)cc1C1=CCCCC1
Yield: 38.7 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in Example 12, step (d), 250 mg, 0.506 mmol) and N-(bis-methylsulfanyl-methylene)-methanesulfonamide (Australian Journal of Chemistry, 46(6), 873, (1993), 100 mg, 0.506 mmol) in 1,2-dichloroethane (20 mL) was heated at reflux for 4 h. The reaction mixture was concentrated, and the residue was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (117 mg, 39%): Mass spectrum, (ESI, m/z): Calcd. for C28H39N7O4SSi, 598.2 (M+H), found 598.2.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15](Br)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][NH:35][CH3:36]>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([N:35]([CH3:36])[CH3:34])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Br)CS[C@H]12
Product: CN(C)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
p-Nitrobenzyl 7-phenylacetamido-3-bromo-3-cephem-4-carboxylate is reacted with dimethylamine by following the reaction conditions of Example 4 to provide p-nitrobenzyl 7-phenylacetamido-3-dimethylamino-3-cephem-4-carboxylate.