Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:8][C:7]2[CH:9]=[CH:10][S:11][C:6]=2[C:5](=[O:12])[CH:4]=1.[Br:13]Br.ClCCl.C(OCC)(=O)C>C(O)(=O)C>[Br:13][C:4]1[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[S:8][C:3]=1[S:2][CH3:1]
Reactant: BrBr
Reactant: CSc1cc(=O)c2sccc2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1sc2ccsc2c(=O)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
5-Methylthio-7-oxo-7H-thieno[3,2-b]thiopyran (2.14 g, 10 mmol) was dissolved in acetic acid (140 ml) and added dropwise with bromine (0.96 ml). The reaction mixture was stirred at 50° C. for 16 hours. The resulting precipitates were collected by filtration, washed with water and dried. The reaction product was purified by column chromatography(Wako Gel™ C-200: dichloromethane-ethyl acetate=15:1) to obtain 1.98 g (yield: 67%) of 6-bromo-5-methylthio-7-oxo-7H-thieno[3,2-b]thiopyran.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4]C1C([N+]([O-])=O)=CC=CC=1S([O-])(=O)=O.[OH:18][C:19]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:28][C:19]=1[O:18][CH2:4][C@@H:2]1[CH2:3][O:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1C[C@H]1CO1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A mixture of 2(S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (518 mg, 2.0 mmol), methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (576.6 mg, 2.0 mmol) and cesium carbonate (Cs2CO3) (812.5 mg, 2.5 mmol) in dimethylformamide (10 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the subtitled compound (600 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[Cl:19].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:6][C:5]=1[Cl:19]
Reactant: CC(C)(C)NCC(=O)c1cc(F)c(N)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 206°-208° C. (decomp.), was prepared from 4'-amino-2-tert.butylamino-3'-chloro-5'-fluoro-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:28])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>O1CCOCC1.C(Cl)Cl.CO.[Cu]I.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>[CH3:38][Si:39]([C:42]#[C:43][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:28])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1)([CH3:41])[CH3:40]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cnc(Br)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[Si](C)(C)C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Temperature: 100 °C

Procedure:
A mixture of 6′-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine (100 mg, 0.23 mmol), copper (I) iodide (4.3 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) in anhydrous 1,4-dioxane (2.5 mL) was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.02 mmol) and (trimethylsilyl)acetylene (0.16 mL, 1:1 mmol) were added and the reaction was heated at 100° C. for 5 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia in ammonia)) to afford a brown residue that was taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: COC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.8 %

Procedure:
To a solution of methyl 2-methoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.22 g) in methanol (10 ml) was added 1N-NaOH (1.5 ml). The mixture was heated for 6 hours under reflux. The reaction mixture was concentrated to dryness and to the residue was added water. The mixture was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization from methanol-chloroform gave colorless needles (0.17 g, 77%), m.p. 208-209° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:21]=[C:20]([Cl:19])[CH:25]=[C:24]([Cl:26])[CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(Cl)cc(Cl)c4)cc3CC[C@@H]12
Yield: 59.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,5-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (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 (ethyl acetate eluent), followed by recrystallization from ethyl acetate to give 145 mg (60%) of the title compound as a white solid. mp 172° FDMS: m/e=374 α[D]589 =+70.91 (c=0.55, chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=O)=[CH:17][CH:18]=3)[N:13]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:12]=2)[CH:3]=1.[CH:36]1([C:39]#[C:40][CH2:41][NH2:42])[CH2:38][CH2:37]1>>[CH:36]1([C:39]#[C:40][CH2:41][NH:42][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[NH:20][C:16]2[CH:15]=[C:14]3[C:19]([C:11]([CH:10]=[CH:9][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=4)=[N:12][N:13]3[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:18][CH:17]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: NCC#CC1CC1
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Was prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4,6-dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid E and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (CDCl3): δ 9.51 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.81 (1H, d, J=16.6 Hz), 7.51–7.42 (3H, m), 7.34–7.29 (2H, m), 7.16 (1H, s), 7.11 (1H, dd, J=9.0,1.9 Hz), 6.85 (1H, s), 6.81 (1H, dt, J=7.2, 1.1 Hz), 6.23 (1H, t, J=7.2 Hz), 5.61 (1H, dd, J=9.0, 2.6 Hz), 4.17 (2H, dd, J=5.3, 2.3 Hz), 4.07–4.00 (1H, m), 3.75–3.66 (1H, m), 2.63–2.50 (1H, m), 2.54 (3H, s), 2.32 (3H, s), 2.20–2.02 (2H, m), 1.79–1.62 (3H, m), 1.29–1.19 (1H, m), 0.77–0.67 (4H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:24])[CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:11]([C:10]1[C:9]([CH3:24])=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:13]=1)#[N:12]
Reactant: Cc1cc(N)c(Sc2ccc(F)cc2F)cc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (2.2 ml) was added dropwise to an ice-cooled solution of 4-amino-5-(2,4-difluorophenylthio)-2-methylbenzonitrile (3.9 g) and triethylamine (3.9 ml) in pyridine (40 ml). The mixture was stirred overnight at room temperature and concentrated to dryness. To the residue were added pyridine (10 ml) and 5% aqueous solution of sodium hydroxide (50 ml). The resulting mixture was stirred for 2 hours and washed with toluene (50 ml). The aqueous layer was acidified with hydrochloric acid, and the precipitates obtained were recrystallized from a mixture of ethanol and ethyl acetate to give a pale brown powder of 4'-cyano-2'-(2,4-difluorophenylthio)-5'-methylmethanesulfonanilide (2.6 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([O:34][CH2:59][CH2:58][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Reactant: OCCN1CCOCC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)OCCN3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 10.3 mg (0.08 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[N:31][OH:32])[CH2:29][CH3:30])=[CH:24][CH:23]=1.[C:33]([O:40][CH2:41][CH3:42])(=[O:39])[C:34]([O:36]CC)=O>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](=[N:31][OH:32])[CH:29]([CH3:30])[C:34](=[O:36])[C:33]([O:40][CH2:41][CH3:42])=[O:39])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Diisopropylamine (18.2 mL, 129 mmol) was added to 60 mL of THF and cooled with an external ice bath. Butyllithium (50 mL, 126 mmol, 2.5 M in hexanes) was added and the mixture was stirred at 0° C. for 30 min, and brought to room temperature. The resulting LDA solution was added to a mixture of 1-(4-fluorophenyl)propan-1-one oxime (10 g, 59.9 mmol) and THF (50 mL) at 0° C. Following the addition, the reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (41 mL, 299 mmol) and THF (150 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 200 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-35% EtOAc/hexanes) to give 10.1 g of the title compound. MS: (+) m/z 268.36 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]3=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccn2CCNC(C)=O)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: COc1ccc(-c2ccc3n2CCN=C3C)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
N-[2-[2-(p-Methoxyphenyl)-pyrrol-1-yl]ethyl]-acetamide (2.1 g) was treated with 10 ml of phosphorus oxychloride under argon and boiled for 1/2 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 50 ml of 28% sodium hydroxide solution, diluted with 600 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.0 g of a total of 2.0 g of crude product was dissolved in a 40-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.6 g (42%) of 3,4-dihydro-6-(p-methoxyphenyl)-1-methyl-pyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 167°-169° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccccn3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-picolylchloride hydrochloride as described for compound 105. Crystallized from diethyl ether. M.p. 181°-182° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C1COCC1.O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[N:7]=1
Reactant: CN
Reactant: Clc1ncnc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: CNc1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,4-dichlor-[1,3,5]triazine (2.25 g, 15 mmol; WO 2004/072063, Expl. 9) in 20 ml of THF, MeNH2 (15 ml of 2 M solution in THF) is added. After 1 h the mixture is diluted with 15 ml of water and concentrated partially in vacuo. The precipitated title compound can be filtered off, washed with ice-water and dried: ESI-MS: 143 [M−H.
Reaction SMILES: [OH:1][CH:2]([CH3:30])[CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]2)=[O:6].[Cr](O)(O)(=O)=O.C(O)(C)C>C(O)(=O)C>[C:2]([CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]2)=[O:6])(=[O:1])[CH3:30]
Reactant: CC(O)CN(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)CN(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
In 3 ml of acetic acid is dissolved 0.2 g of 6-{4-[N-(2-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}carbostyril. Thereto is dropwise added 0.3 ml of an aqueous solution containing 0.07 g of chromic acid at room temperature. The mixture is stirred for 1 hour, and 0.3 ml of isopropyl alcohol is added. Acetic acid is removed by evaporation under reduced pressure. The residue is made alkaline with sodium bicarbonate and then extracted with chloroform. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The residue is purified by means of a silica gel column chromatography (eluent; chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 0.07 g of 6-[4-(N-acetylmethyl-N-cyclohexylmethylaminocarbonyl)butoxy]carbostyril.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH3:9])[C:5]([O-:7])=[O:6].[Na+].[CH2:18](Br)[C:19]#C.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[O:3]=[C:4]([CH:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH2:9][C:18]#[CH:19])[C:5]([OH:7])=[O:6]
Reactant: C#CCBr
Reactant: Cc1ccc(C(C)C(=O)C(=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CCC(C(=O)C(=O)O)c1ccc(C)cc1
Yield: 52 %

Procedure:
A 3N aqueous solution (0.9 ml) of sodium hydroxide and 5.0 ml of tetrahydrofuran were added to 0.50 g (2.6 mmoles) of sodium 2-oxo-3-(p-methylphenyl)butanoate, and the mixture was stirred until a completely uniform solution formed. Then, 0.20 ml (2.7 mmoles) of propargyl bromide and 26 mg of triethylbenzylammonium chloride were added, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ether. The ether layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated. The resulting solid was purified to obtain 2-oxo-3-(p-methylphenyl)-5-hexynoic acid in a yield of 52 %.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[OH-].[Na+]>O>[NH2:1][CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CCN=[N+]=[N-])c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2nc3cc(CCN)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
A mixture composed of the above tert-butyl {8-(2-azidoethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}carbamate (31 mg), triphenylphosphine (23 mg), tetrahydrofuran (0.9 ml) and water (0.1 ml) was stirred at room temperature for five hours. A 0.2 N sodium hydroxide solution (2.5 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and then the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH silica used, ethyl acetate-chloroform) to obtain the title compound (17 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.O.[NH4+:11].[Cl-]>[Zn].CC(=O)OCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:11][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[O-:3]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cl-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: [O-][N+](=Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
0.204 mL (2.0 mmol) of nitrobenzene and either of 17.2 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-1 synthesized in Example 3 or 14 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-2 synthesized in Example 4 were put into a 50 mL, two-neck flask equipped with a water cooler, and the resulting mixture was stirred at a nitrogen atmosphere for 20 minutes to swell the the polymer supported reagent with the reactant. To this were added 0.262 g (4.0 mmol) of Zn powders, 0.214 g (4.0 mmol) of NH4Cl, and 15 mL of distilled water, and then the reduction reaction was conducted at 80° C. for 200 minutes. After the completion of the reaction, 30 mL of an organic solvent, EA was added thereto and stirred at room temperature for 30 minutes. The resulting mixture was then filtered to separate firstly the solid mixture and the liquid mixture solution. The liquid mixture solution as obtained was put into a separating funnel to separate a water layer and an EA layer. To the separated water layer was added 20 mL of EA and stirred to extract the product remained in the water layer. This procedure was repeated 3 times. To the EA solution as combined was added 1.0 g of anhydrous magnesium sulfate and the resulting mixture was stirred for 30 minutes and then filtered. From the filtered EA solution, an excessive amount of EA was evaporated by using an evaporator to obtain azoxybenzene as a main product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:22][NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: NNC(=O)c1cccnc1
Solvent: CCO
Product: O=C(NN=Cc1ccnc2ccccc12)c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 7.86 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 6.86 gm (0.05 mole) of nicotinic acid hydrazide and 100 ml of ethanol is refluxed 2 hr. The reaction mixture is cooled to room temperature. The solid which sepatates is collected, washed with water and dried; 14.4 gm (quantitative) to give the title compound; mp. 99.6° C. The product is recrystallized from ethanol to give 11.54 gm (83%) of the title compound, having a melting point of 192.7° C.