Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][NH:18][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Reactant: CC(C)CCN
Product: CSc1nc(NCC=C(C)C)c2ccnc-2[nH]1

Procedure:
To 400 mg of 4-chloro-2-methylthiopyrrolo[2,3-d] -pyrimidine was added 2 ml of isopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 131 mg (26%), m.p. 155.0° - 155.5°.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(O)C>[C:2]([NH:3][C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1)=[S:16])#[N:1]
Reactant: N#CN
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
The suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (170 mL) was slowly treated with (4-nitrophenyl)isothiocyanate (12.5 mL, 104.5 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (13.6 g), m.p. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][OH:7].[H-].[Na+].Cl[C:16]1[C:25]2[C:20](=[C:21]([OH:26])[CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:27])[CH:17]=1>CN1CCN(C)C1=O>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[C:18]([CH3:27])[CH:17]=[C:16]2[O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(COc2cc(C)nc3c(O)cccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzyl alcohol (1.68 g) in 1,3-dimethyl-2-imidazolidinone (10 ml) was added sodium hydride (60% in oil, 400 mg) portionwise in an ice-water bath under a nitrogen atmosphere. The mixture was stirred for 30 minutes and then 4-chloro-8-hydroxy-2-methylquinoline (770 mg) was added thereto. The reaction mixture was stirred at 150° C. for 3 hours and cooled to ambient temperature followed by partition into ethyl acetate and water. The organic layer was washed with water twice, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether to give a pale yellow powder (812 mg) of 8-hydroxy-4-(3,4-dimethoxybenzyloxy)-2-methylquinoline.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[NH:14][C:15](=[O:24])[CH:16]=[C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:18]=1.[OH-].[Na+].O>CC(C)=O>[NH2:12][C:13]1[N:18]=[C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[C:15]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.08 g (11 mmol) of p-toluenesulfonyl chloride in 20 ml of acetone are added dropwise to a solution of 1.47 g (8 mmol) of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate, 12 ml of 1N sodium hydroxide, 5 ml of water and 50 ml of acetone. The mixture is stirred at room temperature for 18 hours. After filtration of the precipitate, the solvent is evaporated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and water, the organic phase is separated, dried and evaporated under reduced pressure. Crystallization from methylene chloride/methanol yields pure methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate of meltig point 188°-189°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (257 mg) and triphenylphosphine (554 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (253 mg) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Br:14])=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a mixture of 2-azidomethyl-1-bromo-4-nitrobenzene (6.57 g) and THF (50 mL) there was added triphenylphosphine (7.05 g) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours, after which water (10 mL) was added and the mixture was heated to reflux for 15 hours. The solvent in the mixture was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (5.64 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=O)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.[IH:27]>C1C=CC=CC=1.CO>[IH:27].[O:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:3]([N:4]([CH3:6])[CH3:5])[N:2]([CH3:8])[CH3:1])[CH2:21][CH2:20]1
Reactant: CN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Agent: I
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CO
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of tetramethylurea (10.4 g, 10.7 ml) in dry benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.2 g) in dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65°-70° C. gave an oil which was purified by column chromotography on a neutral alumina column (100 g) eluted with hexane to give as an oil. A solution of this base (2.5 g) in methanol (10 ml) was treated with 57% hydroiodic acid (1.3 ml) to give 2-(2-morpholinophenyl)-1,1,3,3-tetramethylguanidine hydroiodide as a pale yellow crystalline solid (m.p. 215°-216° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.[CH3:12][CH:13]([NH2:15])[CH3:14]>>[CH:13]([NH:15][C:8]([CH:3]1[CH2:4][O:5][CH2:6][CH2:7][NH:2]1)=[O:10])([CH3:14])[CH3:12]
Reactant: CC(C)N
Reactant: COC(=O)C1COCCN1
Agent: Cl
Product: CC(C)NC(=O)C1COCCN1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.22 g, 1.2 mmol) and propan-2-amine (2.78 g, 47 mmol) was stirred at 60° C. for 12 hours under N2. The mixture was concentrated in vacuo to give the title compound as brownish sticky oil (0.2 g, 95%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([OH:12])[CH3:11].C(=O)([O-])O.[Na+].Cl[O-].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.CC1(C)N([O])C(C)(C)CCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(O)c1c(F)cc(I)cc1F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1c(F)cc(I)cc1F
Yield: 94.2 %

Procedure:
To a solution of 1-(2,6-difluoro-4-iodo-phenyl)-ethanol (561 mg, 1.98 mmol) in methylene chloride (25 mL) cooled in an ice/water bath were added 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (3 mg, 0.12 mmol), sodium hydrogen carbonate (75 mg, 0.89 mmol) and tetrabutylammonium bromide (19 mg, 0.06 mmol). To this resulting mixture was added a 5% aqueous sodium hypochlorite solution in a dropwise manner until TLC indicated the reaction to be complete. The reaction mixture was diluted with methylene chloride (50 mL) and brine (100 mL) and the organic layer separated. The organic layer was dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo to give 1-(2,6-difluoro-4-iodo-phenyl)-ethanone (526 mg, 94%). HR-MS: calcd for C29H25F2IN4O4 [M+H+] 659.0962. Found 659.0962.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25](=[O:27])(=[O:26])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH:22]=2)=[C:17]([Cl:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:26])(=[O:27])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH2:22]2)=[C:17]([Cl:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)-3-chlorophenyl]propanoate (300 mg, 0.598 mmol) in tetrahydrofuran (6.00 mL) was cooled to 0° C. and treated with lithium tetrahydroborate solution in tetrahydrofuran (2.0 M, 0.329 mL). The reaction was allowed to stir for 0.5 h at rt. After addition of acetic acid (0.5 mL), the solution was diluted with ethyl acetate (100 mL), washed with water (100 mL), separated, dried over sodium sulfate, filtered and was concentrated in vacuo. The crude material was purified by silica gel chromatography (5–30% ethyl acetate/hexanes) to afford the product as a white solid (162 mg, 54%). 1H NMR (400 MHz, CD3OD): δ 7.45–7.42 (m, 2H), 7.31–7.27 (m, 1H), 5.59 (t, J=8.0 Hz, 1H), 4.39–4.36 (m, 1H), 3.70 (s, 3H), 3.38–3.33 (m, 1H), 3.25–3.14 (m, 2H), 2.95–2.92 (m, 1H), 1.67 (s, 9H), 1.37 (s, 9H); LCMS found for C17H24ClN2O5S (M+H)+: m/z=403.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]([CH3:37])[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]([CH3:37])[CH:28]=[C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)cn1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)cn2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 70.2 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.65 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.58 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([NH:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NC2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and cyclohexylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 287°-288° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH2:18][OH:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2>[O-2].[Mn+4].[O-2].ClCCl>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH:18]=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.3 %

Procedure:
A 250-mL round-bottomed flask was charged with [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methanol (1.84 g, 5.1 mmol), manganese (IV) oxide (1.14 g, 13.1 mmol) and dichloromethane (60 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered, concentrated in vacuo, and the residue chromatographed (hexane:ethyl acetate=10:1), affording the title compound (1.6 g, 87% yield). 1H NMR (CDCl3) δ10.3 (s, 1H), 8.9 (s, 1H), 8.8 (s, 1H), 8.3 (d,1H), 7.7 (t, 1H), 7.5-7.4 (m, 3H), 7.2 (s, 1H), 6.6 (s, 1H), 5.7 (s, 2H), MS (Cl); 355, 357, 359.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(OCC)(=O)C.CN(C)C=O.O>[N:33]([CH:9]([C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:10])=[N+:34]=[N-:35]
Reactant: CC(O)C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3-bromophenyl)4-(4-chlorophenyl)-3-methyl-2-butanol (fasting eluting diastereomer, 0.90 g, 2.5 mmol) in ethyl acetate (80 mL) at 0° C. was added triethyl amine (dried over activated molecular sieves, 0.42 mL. 3.1 mmol) and methanesulfonyl chloride (0.22 mL, 2.8 mmol). After stirring at 0° C. for 2 h, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (10 mL). After stirring at room temperature for 0.5 h, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to give the crude sulfonate, which was used without further purification. Thus, a mixture of the sulfonate and sodium azide (0.83 g, 0.13 mol) in dimethylformamide (5 mL) was heated at 120° C. for 4 h. The reaction mixture was cooled to room temperature and was poured into water (40 mL), and the product was extracted with ether (2×20 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound (Diastereomer α). 1H NMR (400 MHz, CD3OD): δ 7.43-7.20 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.10 (q, 1H), 3.10 (d, 1H), 3.00 (d, 1H), 1.10 (s, 3H), 1.02 (d, 3H).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].S(Cl)([Cl:14])(=O)=O>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([Cl:14])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=S(=O)(Cl)Cl
Product: COc1ccc(Cl)cc1OC
Reaction time: 1 h

Procedure:
Into a triple-necked flask of a liter, provided with a magnetic stirring system, with a thermometer, with a calcium chloride trap and with a dropping funnel, were introduced into the cold at about 0° C. and successively 138 g (1 mole) of veratrol then drop by drop 135 g (1 mole) of sulfuryl chloride. When the addition was terminated, the reaction medium was brought to room temperature, then after standing one hour was distilled under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:12][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
14.74 g (74.6 mmol) of 7-chloro-6-fluoro-2H-isoquinolin-1-one (7) were dissolved in 150 ml of toluene. After addition of 30.86 g (111.9 mmol) of silver carbonate and 15.31 g (89.5 mmol) of benzyl bromide, the mixture was stirred at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with water, dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 11.63 g of the title compound. Rt=2.51 min (Method B). Detected mass: 288.1/290.1 (M+H+).
Reaction SMILES: N[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[I:18]I.N([O-])=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O.O>[I:18][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ncccc2N)cc1
Reactant: II
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ncccc2I)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-2-[4-(methylsulfonyl)phenyl]pyridine (1.0 eq.) in AcOH:CH2Cl2 (1:1, 0.13 M) at −20° C. was added I2 (1.5 eq), KI (1.5 eq) then NaNO2(1.5 eq). The mixture was stirred at 20° C. for 2 h then diluted with EtOAc and water. The organic extracts were washed with aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 40:60) afforded the title compound as a white solid.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][CH:4]([C:2]#[N:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCc1ccccc1Cl
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Into a 3-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser, addition funnel and nitrogen inlet is placed a solution of 35.64 g (1.55 moles) of sodium metal in 1050 mm of absolute 2B ethanol. The solution is stirred under nitrogen and cooled to 0° C. in an ice bath and 763.56 g (6.75 moles) of ethyl cyanoacetate is added dropwise over a period of 15 minutes. To this white suspension is added 241.56 g (1.5 moles) to o-chlorobenzyl chloride dropwise over 1 hour. After the addition is complete, the ice bath is removed and the mixture is slowly heated under nitrogen to reflux and held there for 3 hours. The resulting pink-colored mixture is allowed to cool under nitrogen overnight at room temperature. About 1 liter of ethanol is distilled from the reaction mixture and 1.5 liters of water are added. The organic layer is taken up in three 400-ml portions of methylene chloride, and the solutions are combined and washed once with 150 ml of water. The methylene chloride solution is dried over anhydrous magnesium sulfate, filtered and evaporated on a rotary evaporator. The residual liquid is distilled under reduced pressure through an insulated 12-inch Vigreux column. A forerun of ethyl cyanoacetate (boiling point 55° C.-60° C./0.3 mm Hg) comes over first followed by pure ethyl 2-(o-chlorobenzyl)cyanoacetate. The infrared, 'H and 13C nuclear magnetic resonance are used to establish the structure. The yield is 68 percent of product having a boiling point of 130° C.-135° C./0.3 mm Hg.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH:30]=1.[CH2:31](Br)[C:32]#[CH:33]>C(O)CCC>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:32]#[CH:31])[CH2:21][CH2:20]3)[C:16]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH:30]=1
Reactant: C#CCBr
Reactant: COc1ccc2c(c1)Oc1ccc(C)cc1C(N1CCNCC1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: C#CCN1CCN(C2Cc3ccc(OC)cc3Oc3ccc(C)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.8 G. of sodium carbonate are added to a solution of 10 g. of 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazine in 55 ml. of butanol and then a solution of 2.5 ml. of propargyl bromide in 20 ml. of butanol is added dropwise. Then, the mixture is stirred for 20 hours at room temperature and the solvent is removed by distillation under reduced pressure. After working-up in an analogous manner to that described in Example 13, there is isolated crude 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazine in the form of an oil. The dihydrochloride, prepared in ethanol and recrystallized from methanol/ether, melts at 210°-212° C. (with decomposition).