Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][NH:17][CH3:18])[CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:18])[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: CNCc1csc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1csc(Br)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
1.6 ml (13 mmol) of benzoyl chloride are added dropwise to a solution of 2.3 g (11 mmol) of (5-bromothiophen-3-ylmethyl)methylamine and 3 ml (22 mmol) of triethylamine in 30 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 1 hour, filtered, diluted with ethyl acetate and washed with water. The organic phase obtained is dried over sodium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 3.1 g (80%) of N-(5-bromothiophen-3-ylmethyl)-N-methylbenzamide are obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)=[O:7])#[N:2].[CH2:16]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:35])[CH2:31][C:32](=[O:34])[CH3:33])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31]([C:32](=[O:34])[CH3:33])=[CH:11][C:10]2[CH:9]=[C:8]([CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:7])=[O:35])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)CC(=O)N1CCCN(Cc2ccccc2)CC1
Reactant: N#CCCOC(=O)c1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)C(=Cc1cccc(C(=O)OCCC#N)c1)C(=O)N1CCCN(Cc2ccccc2)CC1

Procedure:
1.12 g (5.00 mmol) of 3-(2-cyanoethoxycarbonyl)benzaldehyde, 1.38 g (5.03 mmol) of 1-(4-benzyl[1,4]-diazepane-1-yl)butane-1,3-dion and 0.05 ml (0.51 mmol) of piperidine were stirred in 50 ml of benzene at 105° C. overnight. Ethyl acetate was added to the reaction mixture. After drying over anhydrous sodium sulfate, the product was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6](O)[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([O:14][C:15](=[O:17])[CH3:16])(=O)[CH3:12].[N+]([O-])(O)=[O:19]>>[CH3:16][C:15]([O:14][C@H:11]1[C@H:1]2[O:5][CH2:4][C@H:3]([O:8][C:7]([CH3:6])=[O:19])[C@H:2]2[O:10][CH2:12]1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: CC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(C)=O
Reaction time: 1.25 h

Procedure:
Either one of the above residues containing the mixture of the 2-acetate, 5-acetate and 2,5-diacetate of 1,4:3,6-dianhydro-D-glucitol is nitrated. The preferred nitration method is to add slowly the residue over a period of 0.1 to 5 hours to a solution at -5° to 25° C, preferably 0° to 5° C, of one to 20 molar equivalents, preferably three to five molar equivalents, of acetic anhydride and one to ten molar equivalents, preferably one to two molar equivalents, of nitric acid. After the addition is completed, the reaction mixture is stirred for about 0.5 to 2 hours at -5° to 25° C, preferably 0° to 5° C, in order to complete the nitration. In this manner a solution containing a mixture of 1,4:3,6-dianhydro-D-glucitol 5-acetate 2-nitrate, 1,4:3,6-dianhydro-D-glucitol 2-acetate 5-nitrate and 1,4:3,6-dianhydro-D-glucitol 2,5-diacetate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:13]=[C:12]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:10][C:8]=1[NH2:9])=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](O)=[O:41])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:41])[NH:9][C:8]3[CH:10]=[CH:11][C:12]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][C:7]=3[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 2-(2-methoxycarbonylethyl)-4-tert-butoxycarbonylaminomethylaniline (3.4 g), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (2.80 g, 9.5 mmol), triethylamine (2.43 g, 24 mmol), and Bop-Cl (2.42 g, 9.5 mmol) in dichloromethane (40 mL) was stirred for 2 h at room temperature and diluted with ethyl acetate (800 mL). The mixture was washed with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residue was recrystallized from acetone-ethyl acetate to give 3.22 g of the title compound. The mother liquid was concentrated and the residue was purified by silica gel column chromatography with ethyl acetate to 1% AcOH/ethyl acetate to give additionally 0.8 g of the title compound (72%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH2:12]([OH:14])[CH3:13].C([O-])([O-])OC.[CH3:20][C:21]1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH:6]([O:14][CH2:12][CH3:13])[O:7][CH2:20][CH3:21])=[C:8]([F:10])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: CCO
Agent: COC([O-])[O-]
Agent: c1cc[nH+]cc1
Product: CCOC(OCC)c1c(F)cc(Br)cc1F

Procedure:
4-Bromo-2,6-difluorobenzaldehyde (22 g, 0.1 mol) was dissolved in ethanol (46 g, 1 mol). Methyl orthoformate (17.76 g, 0.12 mol) and PPTS (2.52 g, 0.01 mol) were added, and then the mixture was heated to reflux for 7 hours. Upon completion, the reaction mixture was directly concentrated in vacuo. The resulting oily solid was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound. No further purification was performed. 1H NMR (300 MHz, CDCl3): δ 7.00 (d, 2H), 5.60 (s, 1H), 3.68 (q, 2H), 3.49 (q, 2H), 1.17 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:19])=O>>[ClH:1].[Cl:19][CH2:15][C:11]1[CH:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Product: Cl
Product: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Yield: 98 %

Procedure:
A solution of [5-(3,4-dichloro-phenyl)-pyridine-3-yl]-methanol (470 mg, 1.9 mmol) in thionyl chloride (4.9 ml) was stirred at 20° C. for 15 h. Evaporation of the thionyl chloride and drying under high vacuum at 50° C. for 2 h afforded the title compound (558 mg, 98%) as a light yellow solid. MS: m/e=271.0 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>C(Cl)Cl.O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(C)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-methyl piperazine (5.7 g; 57 mmol; 2 eq) in dry DCM (150 mL) are added Et3N (5.75 g; 57 mmol; 2 eq) and 1-(bromomethyl)-4-methoxy-2-nitrobenzene (7 g; 28.5 mmol; 1 eq). The mixture is stirred at room temperature for 8 h then diluted with water (150 mL). The organic phase is washed with brine and dried. The solvent is removed under vacuum to afford 6.5 g (86%) of the title compound as a viscous liquid. 1H NMR (CDCl3, 400 MHz) δ 7.46-7.44 (m, 1H), 7.34 (s, 1H), 7.08-7.05 (m, 1H), 3.86 (s, 3H), 3.73 (s, 2H), 2.54-2.46 (very br s, 8H), 2.29 (s, 3H). LC/MS (ES+): 266.0.
Reaction SMILES: O[C:2]1[C:3](=[O:18])[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][C:6]=1[C:7](=O)[CH:8]([CH3:10])[CH3:9].Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1.C[O-].[Na+]>C(O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:2]3[C:3](=[O:18])[N:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][C:6]=3[C:7]([CH:8]([CH3:10])[CH3:9])=[N:28]2)=[CH:23][CH:22]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]3[C:2]([C:3](=[O:18])[N:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5]3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: CC(C)C(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Reactant: NNc1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1c2c(nn1-c1ccc(F)cc1)C(=O)N(c1ccccc1)C2
Product: CC(C)c1nn(-c2ccc(F)cc2)c2c1CN(c1ccccc1)C2=O

Procedure:
A mixture of 3-hydroxy-4-isobutyryl-2-oxo-1-phenyl-2,5-dihydropyrrole (0.350 g, 1.43 mmole), 4-fluorophenylhydrazine hydrochloride (0.245 g, 1.50 mmole) and sodium methoxide (39 mg, 0.72 mmole) in ethanol (10 ml) was heated to reflux. After 16 hours the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a silica column using 1:3 ethyl acetate/hexane as eluent to give 210 mg of the title compound along with 80 mg of the 2-(4-fluorophenyl)-3-isopropyl-6-oxo-5-phenyl-4,6-dihydro-2H-pyrazolo[3,4-c]pyrrole regioisomer (M.P. 223°-224° C.). The title compound was recrystallized from ether to give a pale yellow solid. M.P. 150°-151° C.; 1H NMR (250 Mhz, CDCl3) δ 1.38 (d, J=7.0 Hz, 6H), 3.18 (heptet, J=7.0 Hz, 1H), 4.78 (s, 2H), 7.15 (dd, J=8.3, 9.1 Hz, 2H), 7.21 (m, 1H), 7.43 (t, J=7.9 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 8.20 (dd, J=4.8, 9.1 Hz, 2H); MS m/z (M+) 336.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH2:33])=[O:28])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Yield: 51 %

Procedure:
Following the procedure for 243, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid, ammonium chloride, HATU, diisopropylethylamine and DMF were reacted to give 104. Yield 51%. MS: 407.0. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.74 (d, J=7.0, 1H), 7.69-7.54 (m, 4H), 7.47 (s, 1H), 7.44-7.36 (m, 2H), 4.48 (d, J=7.6, 4H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][O:36]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: mp 137-141° C.; 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.30-7.10 (m, 3H), 6.42-6.37 (m, 1H), 6.32 (s, 1H), 4.88 (d, J=9.63 Hz, 1H), 4.70-4.63 (m, 1H), 4.46 (t, J=8.6 Hz, 2H), 4.18-4.05 (m, 1H), 3.85-3.52 (m, 4H), 2.93 (t, J=8.5 Hz, 2H), 2.01-1.67 (m, 3H), 1.64-1.49 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.5 (2), 162.2, 161.8, 145.7, 130.9, 130.2 (2), 126.6, 119.9 (2), 119.0 (2), 118.9 (2), 118.1, 92.5, 77.5, 76.3, 76.1, 72.5, 67.7 (2), 65.4, 58.7, 44.5, 29.0 (2), 28.7, 25.5; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].O=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][CH:20]1[C:25](OCC)=[O:26].Cl>C(O)C>[OH:10][C:9]1[C:8]2[C:19]3[CH2:24][CH2:23][S:22][CH2:21][C:20]=3[C:25](=[O:26])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCOC(=O)C1CSCCC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h

Procedure:
A solution of 6.4 g (0.027 mole) of 5-(3-methyl-2-octyl)resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate (Bennett and Scorah, J. Chem. Soc., 194 (1922)) in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured onto a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the compound of formula XXXII, m.p. 153°-155°C. ##SPC30##
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=O)[CH2:8][C:9]1[N:13]2[CH:14]=[C:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)C.FC(F)(F)C(O)=O.C(N1C=CN=C1)([N:32]1C=CN=C1)=O>O1CCOCC1.O>[CH3:20][N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([CH2:8][C:7]([NH2:32])=[O:6])=[CH:10][N:11]=2)[CH:14]=1)[CH3:21]
Reactant: CCOC(=O)Cc1cnc2ccc(CN(C)C)cn12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc2ncc(CC(N)=O)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (55 mg, 1.31 mmol, 1.5 equiv) is added to a solution of (6-dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (240 mg, 0.87 mmol) in dioxane (10 ml) and water (10 ml). After 1 hour at room temperature, the reaction mixture is concentrated in vacuo. The residue is taken up in N,N-dimethylformamide (10 ml) and treated with trifluoroacetic acid (0.34 ml, 4.5 mmol, 4.5 equiv). Carbonyldiimidazole (167 mg, 0.98 mmol, 1.0 equiv) is added, and the mixture is stirred at room temperature for 1 hour. After removal of the solvent, concentrated aqueous ammonia (10 ml) is added to the activated acid. The mixture is stirred at room temperature for 30 minutes. Volatiles are removed in vacuo, and purification of the residue via flash chromatography (CH2Cl2/MeOH 7:3) affords the title compound (186 mg, 76%). 1H NMR (400 MHz, d4-MeOH): δ=8.31 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J=9.0/1.5 Hz, 1H), 3.95 (s, 2H), 3.71 (s, 2H), 2.42 (s, 6H). MS (ES+): 233 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)CCc2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and 3-phenylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 2.56-2.67 (m, 2H), 2.90 (t, J=7.6 Hz, 2H), 6.99 (dd, J=7.0, 3.9 Hz, 1H), 7.17-7.31 (m, 5H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.74 (s, 1H); MS (DCI) m/z 323 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH2:20].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:20]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)[CH:19]=[CH2:18]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCc1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
In toluene (4 mL) was dissolved 200 mg (0.797 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 305 mg (0.921 mmol) of allyl-(tributyl)tin, and then, 96.8 mg (0.0838 mmol) of tetrakis-(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, and then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 62.1 mg (0.243 mmol, Yield: 30.5%) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[Na+].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mL of dioxane was added 500 mL of 1N sodium hydroxide aq., and then 218 g of tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane under ice-cooling. After stirring for 6 hours at room temperature, the mixture was left overnight. The mixture was concentrated to 1/2 volume by evaporation, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography (eluent: chloroform) to give a solid, which was then washed with diethyl ether to give 68.4 g of N-tertbutoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:34][C:11]1([CH3:35])[CH2:10][C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH2:23][CH2:22]2)[CH:16]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cccc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.10 g, 0.21 mmol), lithium hydroxide hydrate (88 mg, 2.1 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×20 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (30 mg, 31%) as a white solid: LC/MS m/e calcd for C29H33N3O2 (M+H)+: 456.6, observed: 456.3.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]1[CH2:29][CH2:30][CH2:31][N:25]1[C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[CH:8][CH:9]=1)=[O:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: OC[C@@H]1CCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC[C@H]2CO)cn1
Yield: 84 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using L-prolinol instead of 3-amino-1-propanol, to the title compound (122 mg, 84%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][NH2:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:28])([F:27])[C:15](=[O:26])[CH2:16][C:17](=O)[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:14]([F:28])([F:27])[F:13])=[CH:16][C:17]([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:14]([F:28])([F:27])[F:13])([OH:26])[CH2:16][C:17]([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(CC(=O)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(NN)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(-n2nc(C(F)(F)C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Product: Cc1cc(N2N=C(C(F)(F)C(F)(F)F)CC2(O)C(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
(3-Methyl-4-nitro-phenyl)-hydrazine (2.0 g) and 1,1,1,5,5,6,6,6-octafluoro-2,4-hexanedione (3.1 g) were dissolved in toluene and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitro-phenyl)-3-pentafluoroethyl-5-trifluoromethyl-1H-pyrazole (IX-3) (3.0 g) and 2-(3-methyl-4-nitro-phenyl)-5-pentafluoroethyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-ol (IX-4) (0.5 g), respectively.