Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=[CH:9][C:8]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:20][CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([NH2:6])=[C:8]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[CH:9]=2)[CH:14]=[N:15]1)(=[O:4])=[O:3]
Reactant: Nc1ncc(-c2cnn(CCO)c2)cc1-c1nc2ccccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (0.072 ml) was added to 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethanol (150 mg, Example 28), triethylamine (0.130 ml) dissolved dichloromethane (5 ml) at 0° C. The resulting suspension was stirred at 0° C. for 2 hours. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl methanesulphonate (150 mg) as a solid. NMR Spectrum: (CDCl3) 3.11 (s, 3H), 4.49 (t, 2H), 4.62 (t, 2H), 7.41-7.49 (m, 2H), 7.68 (bs, 2H), 7.78-7.82 (m, 1H), 7.83-7.87 m, 1H), 8.01 (d, 1H), 8.31 (d, 1H), 8.43 (d, 1H), 8.53 (d, 1H); Mass spectrum: M+H+ 400.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].F[C:6]1[C:11]([CH3:12])=[C:10]([I:13])[C:9]([CH3:14])=[CH:8][N:7]=1.CC(OC)(C)C.O>C(O)C.C1COCC1>[CH2:2]([O:1][C:6]1[C:11]([CH3:12])=[C:10]([I:13])[C:9]([CH3:14])=[CH:8][N:7]=1)[CH3:3]
Reactant: Cc1cnc(F)c(C)c1I
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOc1ncc(C)c(I)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20% solution of sodium ethoxide in ethanol (123 mL) was added to a solution of 2-fluoro-4-iodo-3,5-dimethylpyridine obtained in Preparation Example 29(2) (400 mg) in THF (5 mL), and the mixed solution was stirred at room temperature overnight. The reaction mixture was cooled at 0° C., and MTBE (20 mL) and water (20 mL) were then added. The organic layer was separated. The organic layer was washed with brine. The combined aqueous layers were extracted with MTBE. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (423.8 mg).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>CCO.[Pd]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([NH2:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: N=C1CCCCC(Cc2ccc([N+](=O)[O-])cc2)N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(Cc2ccc(N)cc2)N1
Yield: 176.1 %

Procedure:
The product from Example 273 (0.55 g, 1.8 mmol) in 30 mL of EtOH was reduced with 5% Palladium on carbon under 5 psi of hydrogen. Solvent removal in vacuo followed by lyophilization in water gave 0.46 g (97%) of the title material.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[N:29][CH:28]=1.[F-].[Cs+].CO>C(#N)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14]([C:27]2[S:31][C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[N:29][CH:28]=2)[CH:15]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4o3)c2)OC1(C)C
Reactant: CN1CCN(c2ncc(Br)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CC#N
Product: CN1CCN(c2ncc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)s2)CC1
Temperature: 120 °C
Yield: 45.8 %

Procedure:
Compound [5] was prepared as follows. 3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (150 mg), 1-(5-bromothiazol-2-yl)-4-methyl-piperazine (117 mg), bis(triphenylphosphine) palladium (II) chloride (15.61 mg) and caesium fluoride (169 mg) were weighed out in a microwave vial and sealed. Methanol (1.5 ml) was added and argon was bubbled in the resulting suspension for 10 minutes. The resulting mixture was heated in the 300 W microwave at 120° C. for 20 minutes. The crude product was purified by flash chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane then 3% to 5% methanolic ammonia 7N in dichloromethane. The solvent was evaporated to dryness to afford the product, which was stirred at room temperature for 1 h in acetonitrile (3 ml), collected by filtration, washed with acetonitrile and dried under vacuum at 40° C., to give 3-(1,3-benzoxazol-2-yl)-5-[2-(4-methylpiperazin-1-yl)thiazol-5-yl]pyridin-2-amine (80 mg). NMR Spectrum: (CDCl3) 2.39 (s, 3H), 2.54-2.65 (m, 4H), 3.56-3.65 (m, 4H), 6.96 (m, 2H), 7.35 (s, 1H), 7.36-7.40 (m, 2H), 7.61 (dd, 1H), 7.74 (dd, 1H), 8.31-8.35 (m, 2H); Mass spectrum: M+H+ 393. There was no deprotection step.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.O.[ClH:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[ClH:32].[C:1]1([C:12](=[O:29])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH3:23])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)CCCc1ccc(C(C)N2CCCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(c1ccc(CCCC(=O)c2ccccc2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenylmagnesium bromide (2 mol/l THF solution, 1.6 ml) in toluene (7 ml) was added dropwise a solution of N-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamide (200 mg, 0.66 mmol) obtained in Reference Example 89 in toluene (3 ml) under a nitrogen atmosphere under ice-cooling. After stirring at room temperature for 1 hr, the reaction solution was poured into water (40 ml), and extracted with ethyl acetate (40 ml×2). The extract was washed successively with 10% sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (developing solvent; hexane:ethyl acetate=10:1) to give a colorless oil. The oil was dissolved in ethyl acetate (10 ml), and 4N-hydrochloric acid (ethyl acetate solution; 0.2 ml) was added dropwise under ice-cooling. The mixture was stirred for 5 min., and the solvent was evaporated under reduced pressure. The residue was powderized with isopropyl ether and hexane, and washed with hexane to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:17]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC1(c2cccc(O)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C)CCOCC4)c3)ccc21
Yield: 40 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-(3-hydroxyphenyl)-4-methyltetrahydropyran to give 4-methyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 40% yield, m.p. 107°-108° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29]([O:32][C@@H:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:31])[CH3:30]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:34](=[O:35])[C@@H:33]([O:32][C:29](=[O:31])[CH3:30])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)[C@H](C)OC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (Example 373, step 2) and (S)-(−)-2-acetoxypropionyl chloride. 1H-NMR (CDCl3) δ: 10.03 (1H, br s), 8.26 (1H, d, J=1.81 Hz), 8.21 (1H, d, J=8.74 Hz), 7.62 (1H, s),7.30 (1H, dd, J=8.74 Hz, 1.81 Hz), 7.28 (1H, s), 5.38 (1H, q, J=6.92 Hz), 4.99 (2H, s), 4.12 (2H, q, J=7.09 Hz), 2.08 (3H, s), 2.04 (3H, s), 1.59 (3H, d, J=6.92 Hz), 1.26 (3H, t, J=7.09 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.[F-].[Na+].O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][OH:9]
Reactant: COC(=O)c1cccc(F)c1NCCN(C)C
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCNc1c(F)cccc1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of methyl 2-(2-(dimethylamino)ethylamino)-3-fluorobenzoate (749 mg, 3.117 mmol) in Et2O (30 mL) at −20° C. was treated with LAH (166 mg, 4.374 mmol). After 1.5 hours, additional LAH (15 mg, 0.3952 mmol) was added and the reaction was warmed to 0° C. After 1 hour at 0° C., the reaction was diluted with Et2O (70 mL) and NaF and water were added with vigorous stirring until the reaction was quenched and a white ppt formed. The clear solution was decanted and evaporated under vacuum. The crude material was purified on a 12 g ISCO redisep column (0-10% MeOH in CH2Cl2 as eluent) to yield 543 mg (82%) of (2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)methanol as a clear oil. FIA: 213.08 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[O:5])C.N(C1C=CC=CC=1OC)=[C:15]=O.CNC>>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[N:3]([CH3:15])[CH3:1]
Reactant: COc1ccccc1N=C=O
Reactant: CCNC(=O)Nc1ccccc1O
Agent: CNC
Product: CN(C)C(=O)Nc1ccccc1O
Yield: 54 %

Procedure:
The subtitled compound was prepared using the procedure as described for Example 25 for N-ethyl-N′-(2-hydroxyphenyl)urea from 1-isocyanato-2-methoxybenzene and dimethylamine (2M solution in THF). Yield 54%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of ethyl 2-propoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.23 g) in ethanol (4 ml) containing 1N-NaOH (1.5 ml) was heated at 80° C. for 2 hours. The reaction mixture was concentrated to dryness and the residue was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization from ethyl acetate-methanol afforded colorless crystals (0.15 g, 69%), m.p. 174°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])=[N:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(COc2ccc(N)nc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2ccc(NS(=O)(=O)c3ccc(C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 5-[(4-methoxybenzyl)oxy]pyridin-2-amine (24 g, 104 mmol) in pyridine (210 mL) was added 4-methylbenzenesulfonyl chloride (20.9 g, 110 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, the residue was washed with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to give the title compound (37 g, 93%) as a pale-red solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CC([O-])=O.[K+].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Pd]>[C:1]([O:4][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A one-liter flask is charged with 450 grams of acetic acid, 92 grams of toluene and a catalyst mixture containing 34.1 grams of 5 wt. % palladium on charcoal, 100 grams of KOAc and 14 grams of stannous acetate. While the flask containing the reaction mixture is constantly stirred at about 100° C., air is continuously blown through the reaction mixture at a rate of about 0.5 liter/min. measured at 25° C. and 760 mm Hg for about 9 hours. Gas chromatographic (G.C.) analysis of the reaction mixture shows that about 80 mol % of toluene is converted to form approximately 91.5 mol % of benzyl acetate, 7.5 mol % of benzyl aldehyde and 1 mol % of benzyl diacetate.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.F[B]F.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([O:33][CH3:34])[C:31]=1F)[N:28]([C@@H:35]1[CH2:37][C@@H:36]1[F:38])[CH:27]=[C:26]([C:39]([OH:41])=[O:40])[C:25]2=[O:42]>CS(C)=O>[NH2:3][C@H:4]1[C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]([C:31]2[C:30]([O:33][CH3:34])=[C:29]3[C:24]([C:25](=[O:42])[C:26]([C:39]([OH:41])=[O:40])=[CH:27][N:28]3[C@@H:35]3[CH2:37][C@@H:36]3[F:38])=[CH:23][C:22]=2[F:21])[CH2:5]1
Reactant: N[C@@H]1CNCC12CC2
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Agent: F[B]F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2C[C@@H](N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 10 h
Yield: 61.4 %

Procedure:
(7S)-7-Amino-5-azaspiro[2.4]heptane dihydrochloride (61.4 g; 0.332 mol) was dissolved in dimethylsulfoxide (800 ml), and triethylamine (138 ml; 0.994 mol) was added to the resultant solution under a nitrogen atmosphere at room temperature, followed by stirring for 10 hours. 6,7-Difluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid difluoroboron chelate (100 g; 0.276 mol) in powder form was slowly added to the reaction mixture, followed by stirring for 40 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethanol (90%: 1000 ml) and triethylamine (20 ml) were added thereto, followed by refluxing for 2.5 hours. The reaction mixture was left to cool, and crystals that precipitated were collected by filtration. The crystals were sequentially washed with ethanol and ether, followed by drying under reduced pressure at 70° C. for 16 hours, to thereby yield 72.5 g of the title compound (as 0.5 hydrate) as a pale yellow powder (yield: 61.4%). Solvents were removed from the filtrate under reduced pressure, and water (2000 ml) was added to the residue. An aqueous sodium hydroxide solution (3N) was added to the mixture so as to adjust the pH value to 10.0 while being stirred under ice cooling. Subsequently, an aqueous hydrochloric acid solution (3N) was added to the mixture so as to adjust the pH to 7.4, followed by stirring for 16 hours at room temperature. Crystals that precipitated were collected by filtration, washed with water, and dried under reduced pressure at 70° C., to thereby yield 19.2 g of the title compound (as 0.5 hydrate) as a pale yellow powder (yield: 33.6%).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: NC1CCOCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(NC2CCOCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(tetrahydro-pyran-4-yl-amino)-nicotinamide was prepared starting from intermediate E and 4-aminotetrahydropyran. MS calcd. for C27H25ClN4O3 [(M+H)+] 489.2, obsd. 489.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.CI>C(#N)C>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: CI
Solvent: CC#N
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A solution of (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (261 mmol) in acetonitrile (1000 ml) was cooled on ice. Diazabicycloundecene (156.0 ml, 1044 mmol) was added thereto and methyl iodide (65.0 ml, 1044 mmol) was added drop wise to the solution. The reaction mixture was warmed to room temperature, and stirred for 14 hours. The reaction mixture was cooled on ice, diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added, then, the mixture was stirred at room temperature for 1.25 hours. The reaction mixture was again cooled on ice, and diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added. After stirring at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (400 ml) and water (400 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml), the organic layers were combined and sequentially washed with 1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800 ml) and saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2000 g; ethyl acetate:hexane=1:3), the fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 190 g; ethyl acetate:hexane=1:3) to give methyl (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (25) (110.4 g, 233.5 mmol, 89.5%) as colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[O:6])C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:14]1([S:13][C:10]2[CH:9]=[CH:8][C:7]([C:5](=[O:6])[C:4]([OH:17])=[O:3])=[CH:12][CH:11]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)c1ccc(SC2CC2)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 41.8 %

Procedure:
In a flask (4-cyclopropylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (9.19 g, 36.71 mmol) was dissolved in toluene (20 mL) and heated to 50° C. in an oil bath. To this heated solution was then added an aqueous sodium hydroxide solution (3 M solution, 15.17 mL, 45.52 mmol) dropwise keeping the temperature of the reaction below 60° C. The reaction was then stirred at 50° C. for 1.5 h. After this time the reaction was removed from the oil bath and concentrated hydrochloric acid (3.5 mL, 42.2 mmol) was added dropwise while the reaction was still at 50° C. It was then allowed to cool to 25° C. and stirred for 16 h. The solids were filtered off and washed with water (10 mL) and toluene (10 mL) to afford (4-cyclopropylsulfanyl-phenyl)-oxo-acetic acid (3.41 g, 42%) as a white solid and used without purification.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:21]([C:25](O)=[O:26])[CH:22]([CH3:24])[CH3:23].CC(C)N=C=NC(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]1([C:7]2([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:25]([CH:21]([NH:20][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH:22]([CH3:24])[CH3:23])=[O:26])=[CH:17][CH:18]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reaction time: 19 h

Procedure:
To a stirred solution at room temperature of 4-(1-phenylcyclohexyl)phenol (311 mg, 1.23 mmol) in dry THF (2 mL) was added BocValOH (295 mg, 1.36 mmol) dissolved in THF (2 mL). A solution of DIC (231 μL; 1.48 mmol) in THF (2 mL) was added drop wise, which caused precipitation after a few minutes. After 5 min DMAP (166 mg; 1.36 mmol) was added and stirring was continued for 19 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (eluent: EtOAc (0-10%) in heptane) affording 517 mg (1.14 mmol; 93%) of colourless oil. LC-MS purity (UV/MS): 100/100%, Rt 6.77 min, M+18: 469.53.