Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH:32](N(C(C)C)CC)(C)[CH3:33].C(I)C>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[CH2:32][CH3:33])=[O:11])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1C(c2ccc(Cl)cc2)C(c2ccccc2)CN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide (Example 3) in 5 ml of dimethylformamide was added 0.5 ml (3.0 mmole) of diisopropylethylamine and 0.25 ml (3.0 mmole) of ethyl iodide. The mixture was heated at 60° C. for 18 hours and then partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the expected compound, a foam. NMR 1.3 t 3H, 3.1 q 2H, 4.1 dd 1H, 4.3 dd 1H, 4.4 t 1H, 6.7 d 2H, 6.9 m 2H, 7.1 m 5H, 7.5 s 4H, 8.4 s 1H.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])C.C([O-])(=O)C.[NH4+:17].C(OCC)(=O)C.O>C(N(CC)CC)C>[N+:10]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[NH2:17])([O-:12])=[O:11]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 74.9 %

Procedure:
A 25 ml round bottom flask was fitted with a reflux condenser and magnetic stirrer and placed in an oil bath. The flask was charged with 1.0 g (5.95 mmol) of 4-ethoxy-3-nitropyridine and 5.0 g (65 mmol) of ammonium acetate. The reaction mixture was heated at 120° C. to provide a homogeneous liquid. The progress of the reaction was followed by thin layer chromotography employing a 10:1 ethyl acetate:triethylamine solvent system. After 21/2 hours the reaction mixture was cooled and poured into water. The yellow precipitate was collected by filtration, washed with water and dried in vacuo at 60° C. over phosphorus pentoxide. A total of 620 mg of 3-nitro-4-aminopyridine was obtained and chromatographically verified by comparison to an authentic reference standard. Yield 75%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:19]([NH:8][C:7]1[C:2]([CH3:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=O
Reactant: Cc1c(N)cccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 57.1 %

Procedure:
To a solution of 2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.32 g, 1.26 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added butyraldehyde (0.114 mL, 1.26 mmol), followed 10 min later by sodium triacetoxyborohydride (0.374 g, 1.76 mmol) and acetic acid (72 μL, 1.26 mmol). The resultant mixture was stirred for 22 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL), then extracted with CH2Cl2 (2×20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (221 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5](O)=[O:6].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH2:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[N:10]=1)[C:5]([N:32]([O:31][CH3:27])[CH3:33])=[O:6])[CH:12]([CH3:14])[CH3:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 2-methyl-6-(2-methyl-propyl)-isonicotinic acid (3.80 g, 16.5 mmol) in DCM (50 mL), DIPEA (10.7 g, 82.7 mmol) followed by TBTU (6.37 g, 19.9 mmol) is added. The mixture is stirred at rt for 10 min before N,O-dimethylhydroxylamine (1.94 g, 19.9 mmol) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silic gel eluting with heptane:EA 1:1 to give 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (3.37 g) as a colourless oil; LC-MS: tR=0.61 min; 1H NMR (CDCl3): δ 0.95 (d, J=6.8 Hz, 6H), 2.06-2.18 (m, 1H), 2.60 (s, 3H), 2.69 (d, J=7.3 Hz, 2H), 3.37 (s, 3H), 3.57 (s, 3H), 7.13 (s, 1H), 7.18 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:8]=1.C[CH:14]([S:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1)[C:15]1[CH2:16][S:17][C@@H:18]2[C@H:38]([NH:39]C(=O)CC3SC=CC=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CO>C(Cl)Cl>[NH2:39][C@@H:38]1[C:37](=[O:48])[N:19]2[C:20]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:15]([CH2:14][S:49][C:50]3[N:54]([CH3:8])[N:53]=[N:52][N:51]=3)[CH2:16][S:17][C@H:18]12
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 81.5 %

Procedure:
A suspension of phosphorus pentachloride (416 mg) in dry methylene dichloride (10 ml.) was stirred at 23° and a solution of pyridine (0.16 ml) added. The warm suspension was stirred for 10 minutes, and cooled to 0°, and treated, over 10 minutes, with a solution of diphenylmethyl 3-(1-methyltetrazol-5-ylthiomethyl)-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (619 mg) in methylene dichloride (15 ml.). After stirring for a further 45 minutes, during which time the temperature was allowed to rise to 23°, the solution was added, over 5 minutes, to a stirred and cooled (0°) mixture of methanol (5 ml.) and methylene dichloride (15 ml.). The resulting solution was stirred for a further 10 minutes, and washed with N-hydrochloric acid (20 ml.), and stirred for 30 minutes with saturated sodium bicarbonate sodium (50 ml.). The organic phase was separated, and washed with saturated aqueous sodium bicarbonate (25 ml.), and treated with some charcoal. The mixture was filtered through a pad of kieselguhr, and the filtrate evaporated to a gum (640 mg.), which was triturated with ether (20 ml) to give the amine as an off-white solid (403 mg, 81.5%), λmax. (CHCl3) 268.5 nm (ε 7,700), νmax. (CHBr3) 3416 and 3350 (NH2), 1780 (β-lactam), and 1720 cm.-1 (CO2R), τ (CDCl3) values include 5.00 and 5.15 (C-6H and C-7 H, two doublets, J 5 Hz.), 6.14 (CH3 --), and 7.59 (NH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:4]3[C:3]4[C:26](=[CH:25][CH:29]=[CH:7][CH:2]=4)[CH2:27][C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1Cc1ccccc1-2
Yield: 81 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (298 mg), indanone-2 (132 mg) and NaH (41 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; yield 81%; mp 130-132° C.; ESMS 369 (M++1); IR (KBr) 2216 cm−1 (CN).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][CH:41]=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[O:27]1[C:31]2([CH2:32][CH2:33][CH:34]([N:37]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:39]4[N:40]=[CH:41][N:42]=[C:38]34)[CH2:35][CH2:36]2)[O:30][CH2:29][CH2:28]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.9 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.6 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[N:11]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][NH2:11]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1c(Cl)cc(F)cc1Cl
Reaction time: 1 h
Yield: 70.8 %

Procedure:
9.0 g (0.05 mol) of 2,6-dichloro-4-fluoroaniline was added to 50 ml of concentrated hydrochloric acid, and a solution of 3.8 g (0.055 mol) of sodium nitrite in 25 ml of water was dropwise added thereto at a temperature of from 0° to 5° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 1 hour. Insolubles were removed by filtration, and the filtrate was dropwise added at a temperature of from 0° to 10° C. to a solution of 33.8 g (0.15 mol) of stannous chloride dihydrate in 50 ml of concentrated hydrochloric acid. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 2 hours. The precipitated hydrochloride was collected by filtration, and 50 ml of water was added thereto. The mixture was made alkaline with an addition of 20% sodium hydroxide, and the precipitated solid was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue thereby obtained was washed with cold n-hexane to obtain 6.9 g (yield: 70.4%) of the desired compound as white feather-like crystals. Melting point: 117°-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][S:13]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:17][CH:18]([OH:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:15][CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
2-(2-Methyl-4-nitrophenylimino)-1,3-thiazolidine was prepared in a manner analogous to that described in method C2a and was alkylated with 1-bromo-3,3-dimethyl-2-butanone in a manner analogous to that described in Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-1,3-thiazolidine. To a solution of 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-1,3-thiazolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) was added NaBH4 (0.0096 g, 0.26 mmol) in portions. The resulting mixture was stirred at room temp for 4 h, then was separated between EtOAc (10 mL) and H2O (5 mL) and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hexane) to yield 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-hydroxybutyl)-1,3-thiazolidine (0.024 g, 92%); FAB-MS m/z 338 ((M+H)+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:40])[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:18][CH:17]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution containing about 1.26 g of Compound 39 in about 20 ml anhydrous DMF under nitrogen was cooled in an ice-salt bath. About 0.55 ml of N-methylmorpholin was added to the cooled solution, followed 5 minutes later by about 0.65 ml isobutylchloroformate. After stirring for a period of about 20 minutes, 1.20 g diethyl-L-glutamate hydrochloride was added, followed immediately by about 0.55 ml N-methylmorpholin. The reaction mixture was warmed to room temperature and stirred for 12 hours. At this time, the activation cycle was repeated using 1/2 the amounts of reagents indicated above, after which the reaction mixture was warmed to room temperature and stirred for an additional 12 hours. The solvents were removed under reduced pressure, and the residue was dissolved in about 100 ml CH2Cl2, washed with about 75 ml water, 50 ml 0.1 NHCl, and about 50 ml saturated NaCl. The organic layers were dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed on silica gel (2.4×24 cm), eluting first with CH2Cl2 and then with 1% methanol in CH2Cl2. Fractions showing a single spot corresponding to the product were pooled and evaporated under reduced pressure to yield about 1.29 g of Compound 34.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=O.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C#N)cc2OC)CCc2cncn21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1C1(CO)CCc2cncn21
Temperature: -10 °C

Procedure:
5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.100 g, 0.336 mmol) is dissolved in THF (3 mL) and cooled to −10° C. A THF solution of lithium borohydride (0.08 mL, 2 M) is then added. The solution is removed from the cold bath and allowed to warm to room temperature before being heated to 40° C. at which time additional lithium borohydride (0.08 mL, 2 M) is added. The solution is maintained at that temperature for 1.5 h before being allowed to cool to room temperature and being quenched by the addition of 1 M HCl. Following aqueous workup the residue is warmed to 80° C. in ethanolamine/CH3CN (1:3) for 1 h. The solution is then concentrated and the residue purified via prep HPLC (reversed phase; 5-100% CH3CN/H2O and 0.1% TFA). Conversion to the free base provided 4-(5-hydroxymethyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxybenzonitrile as a white solid. MS (ESI) m/z 270.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.55-2.67 (m, 1H), 2.78-2.96 (m, 3H), 3.91 (s, 3H), 4.10 (d, J=11.6 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.73 (s, 1H), 7.13-7.18 (obs m, 1H), 7.16 (s, 1H), 7.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:25]=[CH:24][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:22][N:21]=3)([CH3:19])[CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1.[Cl:35][C:36]1[N:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:35][C:36]1[N:37]=[N:38][C:39]([C:23]2[CH:22]=[N:21][C:20]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:5]4[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:10][CH:11]=3)([CH3:19])[CH:16]([CH3:17])[CH3:18])=[CH:25][CH:24]=2)=[CH:40][CH:41]=1
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(B4OC(C)(C)C(C)(C)O4)cn3)C(C)C)cc2)c1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4ccc(Cl)nn4)cn3)C(C)C)cc2)c1
Temperature: 95 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (700 mg, 0.960 mmol) was added to a stirred solution of 4a (2.20 g, 4.80 mmol), 3,6-dichloropyridazine (1.40 g, 5.80 mmol) and sodium carbonate (4.80 mL of a 2.0 M aqueous solution, 9.60 mmol) in EtOH:toluene (25.0 mL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 95° C. for approximately 2 h. After cooling to rt, the reaction mixture was filtered through a short column of CELITE®, eluting with EtOAc. The filtrate was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-60% EtOAc/hexanes as eluent) to furnish the title compound 4b. m/z (ES) 445 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.19 (d, 1H, J=2.1 Hz), 8.46 (d, 1H, J=1.6 Hz), 8.36 (dd, 1H, J=2.5, 8.5 Hz), 8.29 (d, 1H, J=2.8 Hz), 7.86 (d, 1H, J=8.9 Hz), 7.62 (d, 1H, J=8.9 Hz), 7.52 (m, 4H), 7.46 (d, 1H, J=8.2 Hz), 7.37 (m, 1H), 3.93 (s, 3H), 3.21 (m, 1H), 1.80 (s, 3H), 0.93 (d, 3H, J=6.9 Hz), 0.89 (d, 3H, J=6.9 Hz).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15]Br)=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](#[N:28])[CH3:27]>C(N)C>[CH2:26]([N:28]1[CH2:15][C:13]2[CH2:14][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:19])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][C:12]=2[CH2:17]1)[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Reactant: CC#N
Agent: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CC2=C(C1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of 1-p-toluene sulfonyl-3,4-bis (bromomethyl)-3-pyrroline (3.41 g) in acetonitrile (43 ml), 0.73 ml of 70% ethylamine and anhydrous potassium carbonate (8 g) were added and stirred at room temperature for one hour. The solid was filtered off and the filtrate was purified by silicagel column chromatography (CHCl3 --MeOH) to give 3-ethyl-7-p-toluene sulfonyl-3,7-diazabicyclo [3.3.0]oct-1(5)-ene (0.95 g, yield 39%). 0.9 g of this compound was hydrolysized in 20 ml of 48% hydrobromic acid with 1 g of phenol. The hydrolysate was washed with chloroform (30 ml×3) and decolorized with active carbon. The solvent was concentrated and washed with ethanol to give the title compound (0.57 g, yield 62%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC1C=CC(S(O[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][CH:27]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 4-hydroxyphenyl methanesulfonate (7.04 g @ 82% strength, 30.6 mmol, (prepared by methanesulfonylation of quinol)) dissolved in acetonitrile (72 mL) was added to a mixture of 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (prepared as described in WO 99/62871) (12.0 g, 30.6 mmol) and potassium carbonate (6.42 g of −325 mesh, 46.0 mmol) under nitrogen and the resulting mixture gently stirred. Acetonitrile (36 mL) and water (12 mL) were added, the stirring rate increased and the reaction mixture was boiled under reflux (80° C.) for 11 to 24 hours. After cooling back to 60° C., the solvent volume was reduced by 6 volumes (˜72 mL) by distillation at reduced pressure. Toluene (108 mL) and water (24 mL) were added and the mixture stirred for 5 minutes at 60° C. The solution was filtered through Celite™ (and/or 5% w/w charcoal) and returned to the reaction vessel at 60° C. The phases were allowed to separate and the lower aqueous phase run off and discarded. Dilute aqueous sodium hydroxide solution (10.2 mL of 2.5%, 0.625 M) was added and the mixture stirred at 60° C. for 5 minutes. The phases were allowed to separate and the lower aqueous phase was run off and discarded. Water (24 mL) was added and stirred at 60° C. for 5 minutes, before the phases were allowed to separate and the lower aqueous phase was run off and discarded. The solvent volume was reduced by distillation at atmospheric pressure until a still-head temperature of ˜110° C. was achieved. Fresh toluene was added to make the total volume up to 8 volumes (96 mL). The solution was cooled to 60° C., filtered and then cooled to 45° C. Iso-hexane (143 mL) was added dropwise over 1 hour, maintaining the temperature at 45° C., and then the solution cooled to 20° C. at 1° C./minute. The resulting solid was isolated by filtration, washed by displacement with iso-hexane (29 mL) and dried in a vacuum oven at 50° C. to yield the title compound as a buff solid (9.9 g, 79%). HPLC (Rt 10.9 mins); m.p. 117-118° C.; 1H NMR (400 MHz, d6-DMSO) δ 9.22 (˜1H, s), 7.36 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 6.98 (2H, d, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.29 (3H, s), 2.93 (2H, t, J=6.6 Hz), 1.44 (9H, s); 13C NMR (100.6 MHz, d6-DMSO) δ 157.18, 152.77, 142.44, 137.80, 131.62, 129.04, 124.01, 123.28, 118.15, 115.45, 78.83, 68.69, 36.89, 34.14 and 28.10; MS (ES+) 425 (M+NH4+, 5%), 308 (10%), 120 (100%).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:15]([O-])=[O:16].[Na+].C(OC(=O)C)(=O)C>C(O)=O>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[O:16])=[CH:10][CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(c1ccc(N)cc1)n1ccnc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(c1ccc(NC=O)cc1)n1ccnc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
(a-4) To a stirred solution of 15 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-benzenamine and 2.7 parts of sodium formate in 60 parts of formic acid is added dropwise a solution of 9 parts of acetic acid anhydride in 24 parts of formic acid at 50° C. The reaction mixture was stirred for 1 hour at 100° C. and the solvent was evaporated. The residue was dissolved in a small amount of ice water and the solution was treated with ammonium hydroxide while cooling. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized twice from tetrahydrofuran, yielding 13.8 parts (80%) of N-[4-[1-(1H-imidazol-1-yl)ethyl]phenyl]-formamide; mp. 129.4° C. (int. 115).