Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=O.[Li+].[Cl-].Cl.[OH-].[Na+]>O.CS(C)=O>[I:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ncnc3ccc(I)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1ccc2ncnc(C3CCNCC3)c2c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(6-iodo-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (14.21 g, 28.6 mmol), prepared as described in the preceding step, LiCl (2.38 g, 56.1 mmol), water (1.54 mL, 85.8 mmol), and DMSO (14 mL) was stirred at 150° C. under air for 3 h in a 500 mL flask fitted with a lightly capped Liebig condenser to minimize loss of reagent water while allowing gas escape. The reaction was then allowed to cool to rt, 2 M HCl (aq) (100 mL) was added, and the mixture was stirred at 100° C. for 10 min (Caution: Gas evolution). The reaction was cooled on an ice bath, 2.5 M NaOH (100 mL) was added, and the reaction was extracted with DCM (1×250 mL and 1×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated to provide a 60:40 mixture of the title compound and its methyl ester, contaminated with DMSO, as a dark green oil (10.5 g). This material was resubjected to Krapchow decarboxylation conditions using LiCl (2.41 g, 63 mmol), water (1.54 mL, 85.8 mmol), and DMSO (4 mL) (˜7 mL total DMSO) for an additional 5 h at 150° C. After a total of 8 h at 150° C., the reaction was allowed to cool to rt, and 3 M HCl (100 mL) was added (gas evolution) and the reaction stirred at 100° C. for 15 min. The reaction was then stirred at 0° C. while 2.5 M NaOH (120 mL) was added slowly over ˜30 s to pH >12 (paper), and the cream-colored opaque slurry was extracted with 9:1 DCM/MeOH (4×100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a clear dark green oil contaminated with DMSO and an aromatic impurity (5.97 g). 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.52 (d, 1H), 8.12 (dd, 1H), 7.78 (d, 1H), 3.68-3.55 (m, 1H), 3.36-3.27 (m, 2H), 2.92 (td, 2H), 2.1-1.8 (m, 5H). LC/MS (ESI): calcd mass 339.0, found 340.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:6]1[CH2:21][CH2:22][O:23][CH:5]1[C:4]1[CH:7]=[CH:8][C:9]([O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: OCCO
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1F)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(C2OCCO2)cc1F)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Into a 5 L 3-neck flask equipped with a condenser and a Dean-Stark trap add 3-fluoro-4-triisopropylsilanyloxybenzaldehyde (Example 737, Part A) (90.14 g, 0.3041 mol), ethylene glycol (188.75 g, 3.041 mol), and p-toluenesulfonic acid (0.58 g, 0.003041 mol) in toluene (3.155 L). Beat to boil and reflux until 130 mL of H2O (lower layer) is collected in the Dean-Stark trap (5 hrs). Cool to room temperature, wash with 10% aqueous potassium carbonate solution (2×1 L) and brine (2×1 L), and dry over sodium sulfate. Filter and concentrate to give the crude product.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+].[CH3:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([N+:34]([O-:36])=[O:35])[CH:26]=1)(=[O:24])=[O:23].O=C1C2CC(CC2)C(OC(=O)C2C=CC(S(C)(=O)=O)=CC=2[N+]([O-])=O)=C1>C(#N)C.C(OCC)(=O)C>[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:1]=1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][C:27]=1[N+:34]([O-:36])=[O:35]
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)C3CCC2C3)c([N+](=O)[O-])c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
2.76 g (0.02 mol) of 93% 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 4.45 g (0.044 mmol) of triethylamine are stirred for 7 hours at room temperature in 50 ml of acetonitrile in the presence of 130 mg (2 mmol) of potassium cyanide. 4.22 g (0.16 mol) of freshly prepared 4-methanesulfonyl-2-nitrobenzoyl chloride are then introduced and stirring is carried out for 12 hours at a temperature of 20° C. If, according to monitoring by thin-layer chromatography, relatively large amounts of the intermediate 4-methanesulfonyl-2-nitrobenzoic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (known from U.S. Pat. No. 5,801,120) are still detectable, then a further 130 mg (2 mmol) of potassium cyanide are added and stirring is continued for a further 2 hours until conversion is complete. The reaction mixture is then taken up in ethyl acetate and extracted at a pH value of 13 against water. The aqueous phase is then acidified using hydrochloric acid and extracted at a pH value of approximately 4 using fresh ethyl acetate, dried over Na2SO4 and concentrated to a slight extent. The product, dissolved in warm ethyl acetate, is treated with activated carbon and filtered off with suction (suction filter) through a small amount of silica gel, then concentrated further and caused to crystallise by adding a small amount of hexane. 1.69 g of pure 4-hydroxy-3-(4-methanesulfonyl-2-nitrobenzoyl)-bicyclo[3.2.1]oct-3-en-2-one having a melting point of 170–170.5° C. are obtained. Further product (1.65 g) can be obtained from the mother liquor by recrystallisation. Total yield: 3.34 g, or 49.1% based on the starting material 4-methylene-3-oxabicyclo[3.2.1]octan-2-one used or 57.1% based on the starting material 4-methanesulfonyl-2-nitrobenzoic acid used. 1H-NMR (CDCl3): 15.94 ppm, s, 1H, 8.74, s, 1H, 8.24 ppm, d, 1H, 7.48 ppm, d, 1H, 3.20 ppm, m, 1H, 3.19 ppm, s, 3H, 2.84 ppm, m, 1H, 2.0–2.3 ppm, 4H, 1.6–1.8 ppm, 2H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:16](=[CH2:17])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19](Cl)(Cl)[C:20](Cl)=[O:21].C(=O)([O-])O.[Na+]>CCOCC.C(COC)OC.[Cl-].[NH4+].CO.[Zn].[Cu].[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[C:16]3([CH2:19][C:20](=[O:21])[CH2:17]3)[CH:14]([CH2:13][CH2:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1C2CCCC1CN(C(=O)OC(C)(C)C)C2
Agent: [Cu]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2CCCC(C1)C21CC(=O)C1

Procedure:
To 3.7 g of zinc/copper alloy was added a solution of 1.4 g of 3-(tert-butoxycarbonyl)-9-methylene-3-azabicyclo[3.3.1]-nonane in dry ether (30 ml). Subsequently, a solution of 2.6 ml of trichloroacetyl chloride in dry dimethoxyethane (50 ml) was dropped thereinto and the resulting mixture was reacted at room temperature for 3 hours. Then a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture while maintaining the mixture at 0° C. or below. After filtering off the zinc/copper alloy, the filtrate was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.5 g of a yellow oily substance. This product was dissolved in 40 ml of a saturated solution of ammonium chloride in methanol. After adding 1.7 g of zinc, the resulting mixture was reacted at room temperature for 24 hours. After filtering off the zinc, water was added to the residue. Next, it was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 0.8 g of the title compound as a colorless oily substance.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:6]=1[O:12][CH3:13].[Li+].[BH4-].CCOC(C)=O>C1COCC1>[Br:11][C:7]1[C:6]([O:12][CH3:13])=[C:5]([CH2:4][CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(Br)cccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl[3-bromo-2-(methyloxy)phenyl]acetate (8.20 g, 31.7 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2-[3-bromo-2-(methyloxy)phenyl]ethanol
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH2:15])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH:15][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=3)[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3cccc(OC)c3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid ethyl ester (compound A1) and 3-methoxybenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)([CH3:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH3:15][C:2]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)([CH3:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OCC(C)(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C

Procedure:
305 mg of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanol dissolved in 15 ml THF were treated with 338 mg of triphenylphosphine, 196 mg of methyl 4-hydroxybenzoate and 0.21 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was partitioned in 100 ml of 1:1 ethyl acetate/sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), giving 160 mg of methyl 4-[2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoate as a colorless oil. The ester (160 mg), dissolved in 4 ml THF/0.8 ml H2O, was treated with 50 mg of lithium hydroxide hydrate. The mixture was heated at 60° C. for two hours. The mixture was acidified to pH 2 with 1N hydrochloric acid then partitioned in 10 ml ethyl acetate/10 ml sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparation tlc (SiO2, 40% ethyl acetate/hexanes), giving a white foam. 1H NMR (CDCl3): 8.03 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.1 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 3.96 (s, 2H), 1.67 (s, 4H), 1.46 (s, 6H), 1.27 (s, 12H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)=O)C.CC(C[AlH]CC(C)C)C.O>C(Cl)Cl>[CH:11]([C:9]1[N:10]=[C:6]([CH:4]=[O:3])[S:7][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)c1csc(C=O)n1
Reaction time: 1 h

Procedure:
A solution of 2.1 g (11 mmol) of 4-isopropyl-thiazole-2-carboxylic acid ethyl ester (J. Med. Chem., 1998:602-617) in CH2Cl2 (50 mL) was cooled to −78° C. under nitrogen and treated dropwise with DIBAL (12 mL of 1.0 M in CH2Cl2; 12 mmol). The mixture was stirred at low temperature for 1 hour and then treated with another 7 mL of DIBAL. The solution was stirred for 30 minutes at −78° C. H2O was added, and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Chromatography of the residue over silica gel, eluting with 3:1 hexane:EtOAc, gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11](OC3C=CC=CC=3)=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32].Cl.CN.C(=O)([O-])[O-].[K+].[K+].[CH3:42][N:43](C)C=O>O>[CH3:42][NH:43][C:11]([C:6]1[C:5]2[C:4]3([C:31]4[C:22](=[CH:23][C:24]5[O:29][CH2:28][CH2:27][O:26][C:25]=5[CH:30]=4)[O:21][CH2:20]3)[C:3](=[O:32])[N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)Oc3ccccc3)cccc21
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CNC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 100 °C
Yield: 32 %

Procedure:
Phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (0.30 g, 0.70 mmol), methylamine hydrochloride (0.12 g, 1.8 mmol), potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0 mL) were added to a microwave reaction vessel. The reaction was heated at 100° C. for 0.5 h in a microwave reactor. Further, methylamine hydrochloride (0.20 g, 3.0 mmol) was added and the mixture was heated at 100° C. for an additional 45 min in a microwave reactor. The mixture allowed to cool to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The product was precipitated from dichloromethane with diethyl ether and subsequently recrystallized from ethyl acetate to afford N,1′-dimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.08 g, 32%) as a colorless solid: mp 120-122° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.41-7.31 (m, 1H), 7.25-7.19 (m, 1H), 6.98-6.93 (m, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 5.19 (d, J=3.2 Hz, 1H), 4.87 (s, 2H), 4.21-4.08 (m, 4H), 3.26 (s, 3H), 2.64 (d, J=4.9 Hz, 3H); MS (ES+) m/z 366.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.[CH3:39][O:40][CH2:41][CH:42](O)[CH3:43].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+]>O1CCCC1.CO>[CH3:39][O:40][CH2:41][CH:42]([CH3:43])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Reactant: COCC(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.7 %

Procedure:
To a solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.5 g), tributylphosphine (2.79 g) and 1-methoxypropan-2-ol (1.24 g) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (3.48 g) at 60° C. The whole was stirred at 60° C. for 1.5 h and then concentrated in vacuo. Diisopropyl ether was added to the residue and insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio) and then by basic silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio) to give a colorless oil. A mixture of the oil, 1M aqueous sodium hydroxide solution (15 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 20 h. The mixture was washed with diethyl ether. The organic layer was extracted with 1M aqueous sodium hydroxide solution. The water layers were combined, acidified by 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with hexane to give the title compound (1.50 g, 52%) as colorless crystals. MS 421 (MH+).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[CH2:40][OH:41]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][OH:41])=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCC[C@H]1CO
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3CO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (S)-[1-(4-amino-butyl)-pyrrolidin-2-yl]-methanol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.62-3.56 (m, 2H), 3.29-3.23 (m, 2H), 3.02 (m, 1H), 2.78 (m, 1H), 2.83 (m, 1H), 2.51 (m, 2H), 2.24 (d, 3H, J=1.6 Hz), 2.02 (m, 1H), 1.88-1 .56 (m, 7H) ppm; MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[CH2:5][CH2:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.[ClH:33].C(OCC)C>ClCCl>[ClH:33].[ClH:33].[NH:16]1[CH2:17][CH2:18][CH:13]([N:3]2[CH2:4][CH2:5][C:6]3[N:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2]2=[O:1])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ncccc3NC2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cccnc2CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
tert-Butyl 4-(2-oxo-4,5-dihydro-1H-pyrido[3,2-d][1,3]diazepin-3(2H)-yl)piperidine-1-carboxylate (0.814 g, 2.350 mmol) was dissolved in dichloromethane (8.0 ml). Trifluoroacetic acid (2.0 ml, 26.0 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 4 hours. All volatiles were removed and the residue was dissolved in dichloromethane (10 mL). 2M Hydrogen chloride in diethyl ether (4.11 ml, 8.22 mmol) was added to the mixture. The reaction was stirred at room temperature for 15 minutes and all volatiles were removed. The resulting off-white solid was washed 4 times with anhydrous diethyl ether. Title compound was obtained as white solid in 88% yield. 1H NMR (500 MHz, D2O) δ ppm 8.28 (d, J=4.88 Hz, 1 H) 8.05 (d, J=8.24 Hz, 1 H) 7.74-7.82 (m, 1 H) 4.30-4.41 (m, 1 H) 3.71-3.78 (m, 2 H) 3.51-3.62 (m, 2 H) 3.34-3.41 (m, 2 H) 3.09-3.20 (m, 2 H) 1.98-2.14 (m, 4 H).
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH:17]([OH:20])[CH2:18][Cl:19]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][CH:17]([O:20][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][Cl:19]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: OC(CCl)CCl
Solvent: Cc1ccccc1
Product: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Yield: 79.5 %

Procedure:
A stirred solution of 508 g (2.5 mol) of diphenylmethylchloride and 387 g (3 mol) of 1,3-dichloro-2-propanol in 700 mL of dry toluene was heated at reflux temperature for 72 hr. The reaction mixture was concentrated in vacuo and the residual oil distilled to give 587 g (80%) of colorless oil; bp 137°-140° C./0.1 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1.Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:21]2([OH:23])[CH2:20][CH2:19][O:18][CH:17]([CH3:16])[CH2:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CC1CC(=O)CCO1
Agent: Cl
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
Using the procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, a Grignard reagent was prepared from 3-benzyloxybromobenzene (10.5 g) and 2-methyltetrahydropyran-4-one (2.28 g) was added. The mixture was stirred at ambient temperature for 3 hours, acidified by the addition of 2N hydrochloric acid solution and extracted with ethyl acetate. Column chromatography, using a 10:3 v/v mixture of toluene and ethyl acetate as eluent, gave a less polar isomer, (2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (2.45 g, 41%), as an oil,
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: COC[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1(C1C=CC=CC=1)[OH:16]>C1C=CC=CC=1>[C:2]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:1]=[CH:8][CH:7]=[CH:6][CH:15]=1
Reactant: OC1(c2ccccc2)c2ccccc2CCC1Cl
Reactant: CC[Mg]Br
Solvent: c1ccccc1
Product: O=C1c2ccccc2CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 187.8 %

Procedure:
Step C Add ethylmagnesium bromide (1.76 mL, 5.27 mmol, M in) dropwise to a 0° C. solution of 2-chloro-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol (1.36 g, 5.27 mmol) in dry benzene (20 mL). Stir the solution at 0° C. for 30 min and heat to reflux for 5 hours. Cool the mixture to room temperature and quench with saturated NH4Cl (aqueous). Extract with ether, combine the ethereal extracts, wash with water and brine, dry over Na2SO4 and concentrate to provide 1.1 g (94%) of the title compound.