Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14]([N:17]([C:19]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26]([OH:33])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2)[CH3:18])(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:40]([O:33][C:26]1[C:27]([C:29]([O:31][CH3:32])=[O:30])=[N:28][C:19]([N:17]([CH3:18])[S:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])=[O:15])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of methyl 5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-8-hydroxy-1,6-naphthyridine-7-carboxylate (Example 2.2; 5.44 mmol), and Cs2CO3 (10.9 mmol) in DMF (11 ml) was added benzyl bromide (10.9 mmol). The mixture was stirred overnight. The crude mixture was extracted with AcOEt/water, dried over MgSO4 and concentrated. The product was purified by SiO2 column chromatography (1:1, AcOEt:Hex), to give the target compound in 75% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCN1
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Yield: 56.4 %

Procedure:
The 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine was prepared under the conditions of Example 35 but starting from 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 2.7 g of piperazine. After recrystallizing once from 40 cm3 of propan-2-ol, 1 g of 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine is obtained in the form of a yellow solid melting at 256° C.
Reaction SMILES: FC1C=C(F)C=CC=1C(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:16]1[O:25][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=2[N:15]=1
Reactant: Cc1cc(NC(=O)c2ccc(F)cc2F)c(OC(=O)c2ccc(F)cc2F)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3ccc(F)cc3F)oc2cc1C
Yield: 63.1 %

Procedure:
A suspension of 2-(2,4-difluorobenzamido)-4,5-dimethylphenyl 2,4-difluorobenzoate (90 mg, 0.22 mmol) and 4-methylbenzenesulfonic acid (82 mg, 0.43 mmol) in xylene (2 mL) was heated at reflux for 16 h. After cooling, the solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:15 v/v to afford 36 mg (64%) of the title compound (LCMS RT=7.81 min, MH+ 260.0)
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][C:29](=[O:31])[CH3:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[C:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:52])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(=O)N[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 96 %

Procedure:
The title compound II-bd was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-acetamidoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.61 (d, 1H), 3.67 (m, 1H), 2.51-0.68 (m, 20H), 1.78 (s, 3H), 1.04 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:32][CH3:33])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([O:32][CH3:33])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 2-propen-1-yl [3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate (40 g, 99 mmol) in DCM (500 mL), acetic acid (11.3 mL, 197 mmol) and Pd(PPh3)2Cl2 (1.3 g, 1.64 mmol) were added. Then tri-n-butyl tin hydride (37.3 mL, 145 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by slow addition of saturated NaHCO3 (200 mL). The two layers were separated. The aqueous layer was extracted with DCM (400 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound of Step B (26.1 g, 79.1% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=5.5 Hz, 1H), 7.01 (dd, J=7.5 Hz, 8.1 Hz, 1H), 6.83 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.68 (dd, J=1.5 Hz, 7.5 Hz, 1H), 6.61 (d, J=5.5 Hz, 1H), 3.86-3.95 (br, 2H), 3.78-3.82 (m, 4H), 3.58-3.63 (m, 4H), 3.56 (s, 3H).
Reaction SMILES: Cl[C:2]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[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])N(CCC)[C:4](=[O:49])[CH:3]=1.[CH2:50]([NH2:53])[CH2:51][CH3:52]>C(O)C>[CH2:50]([N:53]1[C:4](=[O:49])[CH:3]=[C:2]([NH:7][CH2:2][CH2:3][CH3:4])[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]1=[O:45])[CH2:51][CH3:52]
Reactant: CCCN
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Solvent: CCO
Product: CCCNc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 173.2 %

Procedure:
A solution of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (1.0 g) and propylamine (0.19 g) in ethanol (20 ml) was heated under reflux for 18 hours with stirring. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-dilute hydrochloric acid. The organic layer was washed with water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow powders (0.58 g, 83%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC
Reactant: c1ccccc1
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC

Procedure:
When the dispersion of the solid polymer electrolyte was added to organic solvents having a dielectric constant of less than 3, such as n-hexane, benzene, toluene, p-xylene and dodecane having dielectric constants of 1.89, 2.28, 2.38, 2.27 and 2.02, respectively, the solid polymer electrolyte produced a white precipitate and the polarization characteristics of the cells could hardly be taken out.
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:3].[CH3:20][N:21]([CH3:24])[CH:22]=O>>[CH3:20][N:21](/[CH:24]=[N:1]/[C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:3])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=S)C1
Reactant: CN(C)C=O
Product: CN(C)/C=N/C(=S)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1,1-dimethylethyl 3-(aminocarbonothioyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I112) (99 mg, 0.349 mmol) in N,N-dimethylformamide (DMF) dimethyl acetal (3 ml, 22.41 mmol) was stirred at room temperature for 1 h. The mixture became red/orange and never went to a clear solution. The DMF dimethyl acetal was evaporated and the product triturated with ether to give an orange solid of desired product in 118 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccn2c1COCC2
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 2a) (8.2 g, 42 mmol) in anhydrous dichloromethane (50 ml) was added trichloro-acetyl chloride (15.2 g, 84 mmol). The resulting mixture was stirred at room temperature for 3 days, and then evaporated to dryness. The crude product was purified by silica gel chromatography (eluting with 5 to 50% ethyl acetate in heptane) to give 11.3 g of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.36 min; m/z=340.08 (M+H+).
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23]Cl)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]>[Zn]>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH3:23])=[O:22])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)CCl
Agent: [Zn]
Product: CC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C

Procedure:
15 (1.1 g, 1.91 mmol) was treated as described for 18 using acidic acid (5.3 ml) and zinc (1.31 g).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[N:19][N:20]([C@H:22]4[CH2:27][CH2:26][C@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]4)[CH:21]=2)=[CH:13][C:12]([C:36]2[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[ClH:52]>C1COCC1>[ClH:42].[ClH:52].[NH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:20]2[CH:21]=[C:17]([NH:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:36]5[CH:37]=[C:38]([Cl:44])[C:39]([OH:43])=[C:40]([Cl:42])[CH:41]=5)[CH:13]=4)[N:8]=[CH:7][C:6]=3[C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (trans-4-(4-((3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)cyclohexyl)carbamate (23 mg, 0.036 mmol) in THF (3 mL) was added trifluoroacetic acid (2 mL). The resultant mixture was heated at 65° C. for 16 h. The mixture was then cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (5 mL) and HCl (2 M in diethyl ether, 2.0 mL, 4 mmol) was added. The resultant solution was concentrated to give the desired product (11.1 mg, 50%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.50 (br s, 1H), 8.22 (d, J=8.7 Hz, 1H), 8.13 (br s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.63 (s, 2H), 7.36 (br s, 2H), 4.35-4.31 (m, 1H), 3.26-3.17 (m, 1H), 2.97-2.89 (br s, 1H), 2.28-2.16 (m, 4H), 2.04-1.91 (m, 2H), 1.70-1.58 (m, 2H), 1.33-1.20 (m, 4H). ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 96.0% (AUC), tR=11.44 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][N:17]1[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]2[C:13]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: c1ccc(COCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)COCc1ccccc1
Yield: 80 %

Procedure:
Freshly distilled benzyl-glycidylether (60 g, 0.365 mmol), phthalimide (49.2 g, 0.304 mmol) and potassium carbonate (3.34 g, 24 mmol) were refluxed with stirring in ethanol (500 ml) for 27 hours. TLC indicated full conversion of the starting material. Ethanol was removed in vacuo. The residual oily material was transferred to a 2 l separation funnel and distributed between ethyl acetate (800 ml) and water (500 ml). The aqueous phase was extracted with ethyl acetate (200 ml), and the combined organic phases were washed with water (300 ml), dried over magnesium sulphate, filtered and concentrated in vacuo. The residual oily material (115 g) was diluted with an equal amount (w/v) of ether (115 ml) and allowed to stand for several days. Crystals were collected on a glass sinter and air dried with suction for 1 hour; then dried under vacuum to constant weight. Yield: 81.5 g (72%). The mother liquor was diluted with ether and seeded with crystals from the first crop. Total yield: 80%. TLC indicated one spot. Structure was confirmed by NMR and IR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C@H](C3C=CC=CC=3)C)[CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]([N:14]1[CH2:15][CH2:16][C@@H:12]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:10]2)[CH2:13]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Yield: 75.4 %

Procedure:
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine (1.70 g, 5.15 mmol) was dissolved in dichloromethane (34 ml), and benzylchloroformate (1.10 ml, 7.73 mmol) was added dropwise while stirring and cooling with ice. The reaction solution was then stirred at room temperature for 2.5 hours and then stirred at 40° C. for 1.5 hours. After letting the reaction solution cool, the reaction solution was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 1.40 g (75%) of the title compound was obtained in the form of a colorless syrup from an n-hexane:ethyl acetate=2:1 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: C1COCC1.C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.9 %

Procedure:
To a solution of THF (50 mL) of 4-(pyridin-2-ylmethoxy)-benzoic acid methyl ester (4.9 g) described in Manufacturing Example 25-1 was added LAH (1.0 g) at 0° C., which was stirred for 20 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (heptane:ethyl acetate=1:1, then ethyl acetate) to obtain the titled compound (1.6 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]1.[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=2)[CH3:18])[C:13]([CH3:20])=[N:12]1
Reactant: CC(=O)c1c(C)nn(-c2ccc3ccccc3n2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc4ccccc4n3)N=C2C)cc1
Yield: 30.5 %

Procedure:
2.0 mL of an isopropyl alcohol solution of 28.7 mg (0.11 mmol) of 1-(1-(quinolin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone, 20.8 mg (0.11 mmol) of 4-methoxycarbonylbenzhydrazide and 6.1 mg (0.03 mmol) of p-toluenesulfonic acid monohydrate was refluxed with heating for 48 hours. After cooling, the precipitate was collected by filtration and washed with methanol and acetonitrile to obtain 14.9 mg of the desired product as a purple solid (yield 31%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[CH2:2]1.[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[CH3:18][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: ON=C1COc2ccccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1COc2ccccc21
Yield: 42 %

Procedure:
3.7 g of benzofuran-3-one oxime are dissolved in 15 ml of dimethylformamide. At 20° C., 1 g of sodium hydride (60%) is added and the mixture is stirred until the evolution of gas ceases. 3.15 g of dimethyl sulphate are then added dropwise and the mixture is stirred at 20° C. for 24 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using n-hexane/acetone (4:1). 1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31](O)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:31]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[CH:8]=[CH:9][C:10]=4[CH3:34])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=2)=[O:32])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Example 54 step iii) (0.1 g), 4-amino-N-boc-piperadine (0.05 g) and N,N-diisopropylethylamine (0.25 mL) in tetrahydrofuran (10 mL) was added HATU (0.16 g) and the mixture stirred at room temperature for 3 hours. The reaction mixture was then concentrated to dryness and the crude product purified HPLC to give the sub-title compound (0.09 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:37](O)CCO.CC1C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:37][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCCCO
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCCO1

Procedure:
The title compound was prepared from 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 1, step (h), 0.58 mmol), 1,3-propanediol (882 mg, 11.6 mmol) and catalytic PTSA according to the procedure in Example 1, step (h) (147 mg, 49%). Mass spectrum (ESI, m/z): Calcd. for C28H38N4O4Si, 523.2 (M+H), found 523.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:20][CH:19]3[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:22][N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:20]2
Reactant: CN1C2CCC1CC(N1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1C2CCC1CC(N1CCNCC1)C2

Procedure:
A solution of 1-benzyl-4-(N-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine (4.75 g, 15.88 mmol) in 50 ml methanol was hydrogenated at a pressure of 2.0 atm in the presence of 20% palladium hydroxide on carbon (470 mg) for 30 h. The mixture was then filtered through a pad of celite. The filtrate was concentrated to afford a pale yellow solid quantitatively, which is pure enough for subsequent use.