Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCO2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][CH2:12][O:11]4)[C:7]([C:8]#[N:9])=[C:2]([CH3:1])[N:3]=3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: Cc1nc(S)c(C#N)c(C2CCCCO2)c1C#N
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(C2CCCCO2)c1C#N

Procedure:
50 mg (0.14 mmol) of the compound from Example 41A, 40 mg (0.16 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 45 mg (0.54 mmol) of sodium bicarbonate are reacted in 2.8 ml of dry DMF analogously to the preparation of the compound of Example 14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[CH2:8][NH:7][CH2:6][CH2:5]2.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CC=C[CH:23]=1>>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][NH:7][CH2:8]2)=[CH:3][C:2]=1[O:1][CH3:23])([CH3:20])[CH3:19]
Reactant: COc1cc2c(cc1O)CCNC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1ccncc1
Product: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2

Procedure:
To a solution of 19.2 g of 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline in 425 mL of pyridine is added 48.4 g of t-butyl-dimethylsilylchloride and 0.5 g of 4-N,N-dimethylaminopyridine. The solution is heated to reflux for 3.5 hours and the volatiles removed at 70° C. by distillation. The residue is partitioned between aqueous potassium bicarbonate and ethyl acetate. The organic layer is washed with water, dried (magnesium sulfate) and the volatiles removed in vacuo. The residue is suspended in diethyl ether, filtered and washed with hexane. The filtrate is evaporated and the residue distilled via Kugelrohr at 150 mm and 120°-130° C. to afford 26.2 g of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:27])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]([CH3:16])=[C:13](I)[CH:14]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[N:41]([C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=3)[N:40]=[CH:39][CH:38]=2)O1.CN(C)C=O>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.C(O)(C)C>[C:46]([C:45]1[CH:44]=[CH:43][C:42]([N:41]2[C:37]([C:13]3[CH:14]=[C:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:28])[CH3:1])=[O:8])[C:10](=[O:27])[N:11]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[C:12]=3[CH3:16])=[CH:38][CH:39]=[N:40]2)=[CH:49][CH:48]=1)#[N:47]
Reactant: Cc1c(I)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C#N)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
A mixture of N-[3-(dimethylamino)propyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (10 g, 19.71 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (8.9 g, 29.55 mmol), water (0.71 g), N,N-dimethylformamide (100 mL) and diispropylethylamine (7.64 g, 59.14 mmol) was purged with nitrogen for 10 minutes. To the above mixture was charged 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (“Pd-118” ex. Johnson Matthey, 642.38 mg, 985.62 moles) and the mixture heated to 40° C. for 12 h. The reaction mixture was cooled to room temperature and was added to a mixture of isopropanol (100 mL) and water (200 mL). The resulting mixture was stirred for 18 h. The precipitate was filtered, washed with water (50 mL) and dried under vacuum at 50° C. for 12 h to afford the title product as a brown solid (6.2 g, 56%); 1H NMR (400 MHz, DMSO-d6) δ 9.33 (t, J=5.77 Hz, 1 H), 8.07 (s, 1 H), 7.92-7.98 (m, 3 H), 7.91 (s, 1 H), 7.82-7.89 (m, 2 H), 7.72 (d, J=8.03 Hz, 1 H), 7.67 (d, J=8.53 Hz, 2 H), 6.73 (d, J=1.51 Hz, 1 H), 3.26 (q, J=6.86 Hz, 2 H), 2.25 (t, J=6.78 Hz, 2 H), 2.13 (s, 6 H), 1.75 (s, 3 H), 1.59 (p, J=7.03 Hz, 2 H); LCMSm/z: 549 [M+]
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Cl.[C:8]([O-:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[K+].[I-].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][O:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])c1ccccc1
Reactant: COC(CCl)OC
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(COC(=O)c1ccccc1)OC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Chloroacetaldehyde dimethyl acetal (50.0 g), potassium benzoate (70.7 g), potassium iodide (6.66 g) and DMF (N,N-dimethylformamide) (250 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (250 mL) and ethyl acetate (250 mL) were added thereto, followed by stirring. After filtration, the filtrate was extracted with ethyl acetate (500 mL). The organic layer was subjected to vacuum concentration and then to vacuum distillation at 132-135° C. and at 5 mmHg and thereby yielded the target compound (61.0 g) in a yield of 72%.
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[Cl-].[O:29]1[CH:33]=[N:32][C:31]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:30]1>C1OC1CC>[CH3:27][C@@:3]1(/[CH:1]=[CH:34]/[C:31]2[N:32]=[CH:33][O:29][N:30]=2)[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: c1ccc([P+](Cc2ncon2)(c2ccccc2)c2ccccc2)cc1
Agent: CCC1CO1
Agent: [Cl-]
Product: C[C@@]1(/C=C/c2ncon2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
1.14 g (3.0 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 15 ml of 1,2-butylene oxide, treated with 1.38 g (3.6 mmol) of (1,2,4-oxadiazol-3-yl)methyl-triphenylphosphonium chloride and refluxed for 10 hours. Subsequently, the mixture was filtered, the filtrate is evaporated and the residual brown oil was chromatographed over silica gel (0.040-0.063 mm particle size) with methylene chloride as the eluent. Yield: 280 mg (21%) of colorless crystals MS: (M+NH4)+ 465.3 IR (KBr): 1792, 1753, 1658, 1492, 1200, 991 cm-1
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[Cl-].[CH3:8]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:52]=[CH:51][C:48](C=O)=[C:47]([CH3:53])[CH:46]=2)=[C:41]([CH:54]([CH3:56])[CH3:55])[CH:40]=[N:39]1>C1COCC1>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:52]=[CH:51][C:48]([CH:1]=[CH:2][O:4][CH3:8])=[C:47]([CH3:53])[CH:46]=2)=[C:41]([CH:54]([CH3:55])[CH3:56])[CH:40]=[N:39]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.6 %

Procedure:
To an ambient temperature suspension of potassium tert-butoxide (668 mg, 5.96 mmol) in THF (20 mL) is added (methoxymethyl)triphenyl phosphonium chloride (2.04 g, 5.96 mmol) and is stirred at room temperature for 20 min. Solid 4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-benzaldehyde (400 mg, 0.992 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is quenched with sat. aq. NH4Cl and concentrated. The residue is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (SiO2 120 g, 0% to 30% EtOAC/Hex) to yield the title compound (302 mg, 73%) as a mix of E/Z isomers. 1H NMR (400 MHz, CDCl3) (major isomer) δ 7.70 (s, 1H), 7.43-7.38 (m, 2H), 7.33-7.26 (m, 1H), 7.08 (d, 1H, J=8.4 Hz), 6.72 (d, 1H, J=12.8 Hz), 6.60-6.52 (m, 2H), 5.82 (d, 1H, J=12.8 Hz), 4.78 (s, 2H), 3.66 (s, 3H), 3.00 (sept, 1H, J=7.0 Hz), 2.22 (s, 3H), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:30]1([CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[N:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:38](=[O:39])[CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccccc1)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinamine dihydrochloride (4.46 g, 13.0 mmol) and potassium carbonate (6.67 g, 52.0 mmol) are dissolved in methylene chloride (60 mL) and water (30 mL) and the mixture is cooled with an ice bath. A solution of 3-phenylpropionyl chloride (2.72 g, 16.2 mmol) in methylene chloride (15 mL) is added dropwise over 15 min, and the mixture is stirred at room temperature for 2 hr. The phases are separated, and the organic phase is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated. Chromatography of the residue on silica gel followed by recrystallization from acetonitrile affords the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]([C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)=[O:19])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O1CCOCC1>CO.O>[CH3:25][C:22]1[S:23][CH:24]=[C:20]([C:18]([NH:17][C:4]2[CH:3]=[C:2]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:19])[N:21]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(C(=O)Nc2cc(-c3ccncc3)cc3[nH]ncc23)cs1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A microwave vial was charged with N-[6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (50 mg), Solvias catalyst (7 mg), tripotassium phosphate (76 mg), 4-pyridinylboronic acid (15 mg), 1,4-dioxane (0.5 ml) and water (0.1 ml). The mixture was heated under microwave irradiation for a total of 60 min at 80° C. 4-Pyridinylboronic acid (15 mg) was added and the mixture was heated for 30 min at 80° C., then 30 min at 120° C. The reaction mixture was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried in vacuo. The residue was extracted with DCM/water, dried through a hydrophobic frit and dried in vacuo. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method E). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol and a few drops of 2M HCl (aq) were added and the reaction was stirred for 30 min. The reaction mixture was passed through an aminopropyl cartridge, preconditioned with methanol, washing with methanol, then dried to give title compound, (19 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:14]([F:17])([F:16])[F:15])(O)[CH2:11][C:10]([C:18]3[O:19][CH:20]=CC=3)=[N:9]2)=[N:6][CH:7]=1.FC(F)(F)C(=O)C=C(C1OC=CC=1)OC.BrC1C=C[C:42]([NH:45][NH2:46])=NC=1.BrC1C=CC(Br)=CN=1.[OH2:55].NN>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:10]([C:18]3[O:19][C:20](=[O:55])[N:45]([CH3:42])[N:46]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: O
Reactant: NNc1ccc(Br)cn1
Reactant: OC1(C(F)(F)F)CC(c2ccco2)=NN1c1ccc(Br)cn1
Agent: Brc1ccc(Br)nc1
Agent: COC(=CC(=O)C(F)(F)F)c1ccco1
Agent: NN
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Step-1: 1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-ol: To a stirred solution of 1,1,1-trifluoro-4-(furan-2-yl)-4-methoxybut-3-en-2-one (129 g, 585 mmol; prepared by following the procedure described in Tett Lett., 2002, 43, 8701) in chloroform (600 mL) was added solid 5-bromo-2-hydrazinylpyridine (prepared by the reaction of 2,5-dibromopyridine with hydrazine hydrate, 110.0 g, 585 mmol) in 10 portions at 0° C. over a period of 30 min. The reaction was stirred for 1 h at room temperature, and then at 50° C. for 36 h. The reaction was cooled to 0° C. before the addition of water (200 mL) and chloroform (500 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (5% ethyl acetate-hexanes system as eluent) to afford 90 g (40%) of the title compound as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.17 (d, J=2.5 Hz, 1H), 7.96 (s, 1H, D2O Exchangeable), 7.75 (dd, J=2.5 & 8.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.41(d, J=8.5 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 6.54 (dd, J=1.5 & 2.5 Hz, 1H), 3.71(d, J=18.5 Hz, 1H), 3.56 (d, J=18.5 Hz, 1H); ESI-MS (m/z) 376, 378 [(MH)+, Br79,81].
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([NH2:40])=[O:39])[CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[ClH:31].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([NH2:40])=[O:39])[CH2:33]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1CCCNC1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: NC(=O)C1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a stirred solution of 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1.44 g, 0.0057 mol, prepared similarly as described in example 2) and triethylamine (1.46 g, 0.014 mol) in toluene (40 ml) at 0° C., methanesulfonyl chloride (0.88 ml, 0.011 mol) was added dropwise over 10 minutes. The resulting mixture was stirred at 0° C. for 1.5 h. Toluene (50 ml) and water (100 ml) were added, and the phases were separated. The aqueous phase was extracted with toluene (50 ml), and the combined organic phases were washed with brine (2×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (20 ml) and 3-piperidinecarboxamide (1.09 g, 0.0085 mol) and potassium carbonate (1.76 g, 0.013 mol) were added. The mixture was heated at reflux temperature for 4 h, and stirred at room temperature for 40 h. Water (20 ml) was added, and the product was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. Water (20 ml) and concentrated hydrochloric acid (3.0 ml) were added, and the mixture was extracted with dichloromethane (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was redissolved in a mixture of warm ethyl acetate (10 ml) and methanol (1.0 ml), and after standing for 5 h at room temperature, a precipitate was filtered off and dried, affording 1.56 g (64%) of the title compound.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8]([CH3:14])([CH2:9][CH:10]=C(C)C)[CH:7]([CH3:15])[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:23]=[O+][O-].[BH4-].[Na+]>C(O)C>[CH3:2][CH:3]1[C:8]([CH3:14])([CH2:9][CH2:10][OH:23])[CH:7]([CH3:15])[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)=CCC1(C)C(C)CCN(Cc2ccccc2)C1C
Reactant: O=[O+][O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CCN(Cc2ccccc2)C(C)C1(C)CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2,3,4-trimethyl-3-(3-methyl-2-buten-1-yl)-1-(phenylmethyl)piperidine hydrochloride (24.7 g, 76.7 mmol) was dissolved in ethanol (500 mL) and cooled to -78° C. ozone was bubbled into the reaction mixture until the solution turned blue and the mixture was purged with oxygen, then nitrogen until the solution turned colorless. Sodium borohydride (14.5 g, 383 mmol) was added to the reaction mixture while maintaining the temperature at -78° C. and the solution was stirred at -78° C. for 1 hour. The mixture was slowly warmed to room temperature over a period of 2 hours, 6 H HCl was added to acidify the solution and the solvent was removed in vacuo. The white residue was taken up in water, washed with ether (3×100 mL), basified with aqueous NAOH and extracted with methylene chloride (3×200 mL) The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The residue was taken up in ether (500 mL), dried over anhydrous MgSO4 and the solvent was removed in vacuo to afford 19.1 g (95%) of 2,3,4-trimethyl-1-(phenylmethyl)-3-piperidineethanol.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:35]3[N:34]=[C:32]([NH2:33])[NH:31][C:29](=[O:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:36][CH2:37][CH2:38][OH:39])[C@@H:21]1[OH:40])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](C)(C)Cl.[C:52](Cl)(=[O:56])[CH:53]([CH3:55])[CH3:54]>CCOC(C)=O.O>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:35]3[N:34]=[C:32]([NH:33][C:52](=[O:56])[CH:53]([CH3:55])[CH3:54])[NH:31][C:29](=[O:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:36][CH2:37][CH2:38][OH:39])[C@@H:21]1[OH:40])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCO)c(=O)[nH]1
Temperature: 5 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Dried 5′-O-t-butyldiphenylsilyl-2′-O-(hydroxyethyl)-guanosine (55.9 g, <69 mmol) as a crude product was dissolved in anhydrous pyridine (494 mL, 6.11 mol) with cooling to 5° C. and trimethylchlorosilane (62.7 mL, 494 mmol) was added slowly to give a suspension. The reaction mixture was allowed to slowly warm to ambient temperature, and after 1 hour was again cooled to 5° C. Isobutyryl chloride (51.8 mL, 494 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was cooled to 5° C. and cold water (100 mL) was slowly added. After stirring for 12 hours, the solvent was evaporated in vacuo at 40° C. to give an oil which was dissolved in EtOAc (2000 mL) and water (200 mL). The mixture was shaken, the organic was separated, washed twice with water (2×200 mL), then with brine (200 mL), and dried with MgSO4. The solvent was evaporated in vacuo to a volume of about 500 mL after which there was a flocculent white solid which was filtered, washed with cold EtOAc (3×5 mL), and dried in vacuo (0.5 torr) at 45° C. with P2O5 for 28 hours to afford the title compound as a white solid (26.74 g, 60%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[O:21])=[CH:16][CH:15]=1.[CH2:24]=O.[OH-].[Na+]>CO.Cl.O>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:24][CH2:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:23])=[CH:15][CH:16]=1)=[O:21]
Reactant: C=O
Reactant: CNCc1cccc2ccccc12
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)CCN(C)Cc2cccc3ccccc23)cc1

Procedure:
17.1 g of methyl-(1-naphthylmethyl)amine are dissolved in 200 ml of methanol and 10 ml of concentrated hydrochloric acid, 13.4 g of 4-tolylmethylketone and 100 ml of 35% formaldehyde solution are sequentially added. The mixture is refluxed for 11/2 hours, with stirring, cooled, diluted with 1 liter of water, made alkaline with 30% sodium hydroxide solution and exhaustively extracted with chloroform. The organic extract is dried and evaporated to dryness and the oily residue is dissolved in petroleum ether and allowed to crystallise in the cold, to obtain the heading compound, m.p. 92°-95°.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:5]1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]1
Reactant: CCOC(=O)c1cn(CCF)c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(=O)O)cn(CCF)c3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The ethyl 1-(2-fluoroethyl)-7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate (254 mg, 0.613 mmol) obtained in (A) was dissolved in a mixed solution of methanol, tetrahydrofuran and water (1:1:1), added with 1 N aqueous sodium hydroxide (1.23 ml, 1.23 mmol), and then the mixture was stirred at room temperature for 8 hours. The reaction mixture was added with 1 N hydrochloric acid (1.23 ml, 1.23 mmol) to neutralize the system, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (174 mg, 73%) as yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(O)C.C([O-])(=O)C.[Na+].[ClH:23].[NH2:24]O>O.C(OCC)(=O)C>[ClH:23].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]([NH2:24])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CCC(=O)c1cccc(S(C)(=O)=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(N)c1cccc(S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 1-(3-methane sulfonylphenyl)propan-1-one (188 g), ethanol (4.7 ml), sodium acetate (1.09 g), and hydroxylamine hydrochloride (0.68 g) were added and the mixture was stirred at 90° C. for 3 hours. Ethyl acetate and water were added to the reaction solution, the mixture was separated, then the organic layer was successively washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The obtained 1-(3-methane sulfonylphenyl)propan-1-one oxime was used instead of the starting material compound 1-(4-aminophenyl)propan-1-on oxime of Reference Example 109 for the similar procedure as with Reference Example 109 to obtain the title compound.