Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1ccccc1
Reaction time: 18 h
Yield: 93.1 %

Procedure:
Benzaldehyde (2.2 g, 21.0 mmol) was added to a stirred solution of 3-amino-4-methoxy-N-phenyl-benzamide (5.0 g, 21.0 mmol) in dichloromethane (250 mL) under an inert atmosphere at room temperature, followed by acetic acid (1.26 g, 21.0 mmol). After 1 hour sodium triacetoxyborohydride (4.7 g, 21.0 mmol) was added in one portion. After 18 hours, saturated aqueous sodium bicarbonate (200 mL) was added and the mixture stirred for 2 to 3 hours. The layers were separated, the organic phase was washed with water then saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to afford the product (6.5 g); m.p. 164-165° C. after recrystallization from ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.C1(C(OC(C)(C)C)=O)CC1.BrCCCC[Cl:31].[Li+].CC([N-]C(C)C)C>>[Cl:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: ClCCCCBr
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Agent: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1

Procedure:
Compound 104a was prepared, likewise the procedure described for 103b, starting from t-butyl cyclopropanecarboxylate (Kohlrausch, K. W. F. et al. Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285) (12.5 g, 88 mmol), 1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and LDA (prepared from BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) and iPr2NH (12.3 mL, 88 mmol, distilled from NaOH)) to give, after purification by fractional distillation under reduced pressure, 104a (10.73 g 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR: δ 3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: δ 173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1=COCCC1
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and 10-camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:3])[CH3:2].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:12]1[CH:13]=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]2[C:11]=1[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: CC(=O)Oc1cccc2c1CCC(=O)N2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Reaction time: 0.5 h

Procedure:
20.5 Grams of 5-acetyloxy-3,4-dihydrocarbostyril was dissolved in 200 ml of acetic acid, into this solution, 16 g of bromine dissolved in 60 ml of acetic acid was added dropwise under water-cooled condition with stirring for 30 minutes and the reaction was continued for 2 hours at the same temperature. Then 300 ml of water added to this reaction mixture and allowed to stand for 3 hours, and crystals formed in the mixture were obtained by filtration and recrystallized from methanol. 21 Grams of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril was obtained as in the form of colorless needle-like crystals. Melting point: 237°-239° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1>>[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:2]([NH:1][CH:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)=[O:3])[CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C=NC1CCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)NC5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from isocyanatocyclopentane and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=563.3.
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[NH:18][C:17]3[C:12]([O:13][CH2:14][C:15](=[O:19])[N:16]=3)=[CH:11][N:10]=2)C=CC=CC=1.[O:20]1CCOCC1>O.C(Cl)Cl.O=[Os](=O)(=O)=O>[O:19]=[C:15]1[CH2:14][O:13][C:12]2=[CH:11][N:10]=[C:9]([CH:8]=[O:20])[NH:18][C:17]2=[N:16]1
Reactant: O=C1COC2=CN=C(/C=C/c3ccccc3)NC2=N1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: O
Product: O=CC1=NC=C2OCC(=O)N=C2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-[(E)-2-phenylethenyl]-1H-pyrimido[5,4-b][1,4]oxazin-7(6H)-one (106 mg, 0.418 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added NaIO4 (357 mg, 1.67 mmol) and OsO4 (00.1 mL, 4% wt in water) and the reaction mixture was stirred at room temperature. After 2 h, and additional 3 mL of 1,4-dioxane and 180 mg of NaIO4 were added. After a total of 7.5 h, the reaction was capped and stored in a freezer for the weekend. After warming to room temperature, additional OsO4 (0.1 mL, 4% wt in water) was added and the reaction was stirred for an additional 4 h. The solvent was evaporated to give a white solid which was dissolved in DCM and water. The aqueous layer was extracted with 10% MeOH-DCM (6×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give a light tan solid (92 mg) which was not purified further.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1Br)(=[O:9])=[O:8])(=[O:5])=[O:4].[Na].CN(C=O)C.[Na][Na]>CO.[Cu]>[F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[C:11]([C:11]2[C:10]([S:7]([NH:6][S:3]([C:2]([F:1])([F:18])[F:19])(=[O:4])=[O:5])(=[O:9])=[O:8])=[CH:15][C:14]([Br:16])=[CH:13][CH:12]=2)=[CH:12][CH:13]=[C:14]([Br:16])[CH:15]=1)(=[O:9])=[O:8])(=[O:5])=[O:4]
Reactant: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1Br
Agent: [Cu]
Agent: [Na]
Agent: [Na][Na]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)NS(=O)(=O)C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Inside a glove box, a 250 mL round-bottom flask equipped with a stirring bar, reflux condenser, and a septum was charged with N-trifluoromethanesulfonyl-2,5-dibromo-benzene-sulfonamide, sodium salt (19.45 g, 50 mmoles), activated copper powder (40 g), and DMF (80 mL). The flask was heated to 120° C. under nitrogen and stirred overnight. The solution was cooled to room temperature, filtered, and the solids washed with DMF. The solvent was evaporated by distilling under high vacuum and the resulting solids were dried under vacuum. The dark solids were dissolved in water by heating to a reflux and adding hydrochloric acid to give pH of 1. Residual dark solids were filtered off then the solution was neutralized using aqueous sodium hydroxide, which gave a yellow-brown precipitate that was removed by filtration. The mixture was saturated with sodium chloride and concentrated at reflux to 400 mL. Upon cooling, magenta solids precipitated from solution. The solids were collected by vacuum filtration and dried under vacuum to give 13.2 g (68% crude yield). The solids were dissolved in methanol at a reflux, treated with decolorizing carbon, filtered, evaporated, and dried in a vacuum oven at 150° C. under nitrogen purge. The solids were recrystallized from dioxane (50 mL) inside the glove box after filtering off residual solids. The crystals were collected and washed with dioxane to remove much of the remaining magenta color. The recrystallization was repeated inside the glove box to give colorless crystals, which were dried in a vacuum oven at 150° C. under nitrogen purge and transferred to a glove box for storage and handling to give 10.78 g (55% yield) of N,N′-bis(trifluoromethanesulfonyl)-4,4′-dibromo-biphenyl-2,2′-disulfonamide, disodium salt. 19F NMR (DMSO-d6): −78.31 (s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1C
Yield: 100.5 %

Procedure:
This compound was prepared in a manner analogous to Step E, Example 1. Here, 8.2 grams (0.0206 mole) of methyl 6-chloro-2-methyl-3-[6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl]benzoate was combined with 5.7 grams (0.410 mole) of potassium carbonate and 4.4 grams (0.309 mole) of methyl iodide in 200 mL of THF. The reaction product was purified by column chromatography on silica gel using mixtures of EtOAc and hexane as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 7.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:34]1[CH2:33][CH2:26][CH2:36][C@@H:35]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 134-138° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.29 (dd, J=7.8, 7.8 Hz, 1H), 7.14-7.01 (m, 3H), 6.58 (s, 1H), 6.36 (s, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.18 (m, 2H), 4.12-4.04 (m, 2H), 4.01-3.68 (m, 5H), 2.21-1.85 (m, 5H), 1.77-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.8, 156.8, 153.0, 146.3, 143.0, 142.9, 132.3, 132.2, 128.94, 128.90, 123.9, 123.8, 123.4, 123.34, 123.28, 116.14, 116.10, 109.8, 109.6, 103.5, 80.58, 77.1, 76.9, 70.9, 68.4, 68.3, 58.04, 58.02, 44.7, 32.3, 29.4, 29.1, 25.9, 25.7; MS (ES+) m/z 394.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: OCc1ccc(Cl)cc1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 4-chlorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>[Pt].C(N(CC)CC)C>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 95.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.5 g of 1% Pt/C, 0.05% load) and triethylamine (0.2 g, 0.4% load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])(C)(C)C.C(Cl)CCl>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NCCCNC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with (3-Amino-propyl)-carbamic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 392. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H) 8.35-8.5 (m, 3H) 8.1 (d, 1H) 7.7 (m, 1H) 7.48 (d, 1H) 7.2 (d, 2H) 6.68 (d, 2H) 3.8 (m, 2H) 3.55 (m, 2H) 3.05 (m, 2H) 2.9 (m, 4H) 2.0 (t, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[C:34]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:33][C:32]([OH:43])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:43][C:32]3[CH:33]=[C:34]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: Oc1cc(CCc2ccccn2)n(-c2ccccc2)n1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc(CCc3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.30 g), 1-phenyl-5-[2-(pyridin-2-yl)ethyl]-1H-pyrazol-3-ol (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethyl)pyridine as a colorless oil (0.47 g, yield 76%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[NH2:11].CN(C)[C:14]1[O:15][C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:19][C:14]1=[O:15]
Reactant: Nn1ccc2c(Cl)cccc21
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ccc2c(Cl)cccc21
Reaction time: 4.5 h

Procedure:
A mixture of 169A, glacial acetic acid (30 mL) and 2-dimethylamino-4-trifluoromethyl-[1,3]oxazin-6-one (2.76 g, 13.3 mmol) is stirred for 4.5 h under reflux, whereupon the acetic acid was removed in vacuo. The residue is diluted with ethyl acetate, washed with water and subsequently dried over sodium sulfate. The crude product (3 g) is obtained after removal of the drying agent by filtration and evaporation of the solvent. The product (0.88 g) is obtained as a brown oil after flash chromatography (ethyl acetate/petrol ether 2/8).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([OH:21])[CH2:20][CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:23](F)(F)C(O)=O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([O:21][CH3:23])[CH2:20][CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(O)CCCSC2)cc1OC1CCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(C2(OC)CCCSC2)cc1OC1CCCC1
Reaction time: 8 h

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-thiopyran (2 g; which is prepared as described in Example 7) methanol (175 mL) is treated with trifluoroacetic acid (0.5 mL) and the mixture is allowed to stand at room temperature overnight. The mixture is concentrated in vacuo, and it is then treated with diethyl ether (175 mL) and washed with saturated aqueous sodium bicarbonate solution (25 mL) and water (25 mL) and dried over magnesium sulphate. The solvent is removed and the resulting oily residue is subjected to flash chromatography on silica gel, using a mixture of pentane and ethyl acetate (9:1 v/v) as eluent, to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-methoxy-3,4,5,6-tetrahydro-2H-thiopyran (1.16 g), in the form of a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([NH:32][C:33]([C:35]3[S:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[O:34])[S:31][C:27]=2[C:26](N2CCOCC2)=[CH:25][CH:24]=1>>[CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][N:5]([C:26]2[C:27]3[S:31][C:30]([NH:32][C:33]([C:35]4[S:36][C:37]([CH3:40])=[CH:38][CH:39]=4)=[O:34])=[N:29][C:28]=3[C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:4]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: CN(C)C1CCNC1
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCC(N(C)C)C2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
The title compound is synthesized starting from 3-(dimethylamino)pyrrolidine and 4-bromo-2-nitroanisole as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and was obtained as yellow solid in 10% overall yield, MS: m/e=417 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:26])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(tert-butyl)benzene (85 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (73 mg, 40%) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1)=O)C.[NH3:14].CO>>[C:4]([C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1)(=[O:3])[NH2:14]
Reactant: N
Reactant: CCOC(=O)c1cn2cncc2s1
Solvent: CO
Product: NC(=O)c1cn2cncc2s1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 294 mg potion of 2-ethoxycarbonylimidazo[5,1-b]thiazole was dissolved in 8 ml of a 2M ammonia/methanol solution, and the mixture was then stirred at room temperature for 4 days. After concentration under reduced pressure, 3 ml of dichloromethane was added to the resulting residue, and the precipitate was collected by filtration, washed with dichloromethane, and then dried under reduced pressure to obtain 226 mg of the title compound.