Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 982 %

Procedure:
tert-Butyl methyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclohexyl)carbamate (0.60 g, 0.13 mmol) was treated with 20% TFA solution (31 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 hours at 0° C. The solution then was neutralized with 10% NH4OH, the organic layer separated and evaporated. The crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:4) to give the final product as a yellow solid (0.45 g, quantitative). 1H-NMR (DMSO-d6) δ 1.51-1.60 (m, 3H), 1.69-1.77 (m, 3H), 1.83-1.91 (m, 1H), 1.96-2.07 (m, 1H), 2.40 (s, 3H), 3.24-3.51 (m, 3H), 6.20 (brs, 2H, NH), 6.63 (d, 1H, J=10.2 Hz), 7.02 (d, 2H, J=10.4 Hz), 7.09 (dd, 1H, J=3.6, 4.8 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.59 (s, 1H, NH); ESI-MS (m/z, %) 353 (MH+, 80), 322 (100), ESI-HRMS (MH+) calc. for C20H25N4S (MH+), calculated: 353.1794. found: 353.1812.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16]O)[O:11][C:10]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>>[Cl:27][CH2:16][CH2:15][CH2:14][CH:12]1[O:11][C:10](=[O:18])[N:9]([N:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: O=C1OC(CCCO)CN1N=Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(CCCCl)CN1N=Cc1ccccc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 3-phenylmethyleneamino-5-(3-hydroxy) propyl-2-oxazolidinone (10.88 g, 0.0438 mole) CHCl3 (200 ml), and pyridine (4.25 ml, 4.16 g, 0.0526 mole, 1.2 eq.) is stirred at ambient temperature. Thionyl chloride (11.2 ml, 18.2 g, 0.1533 mole, 3.5 eq.) is added dropwise over 30-45 minutes while at ambient temperature (slight exotherm observed). After complete addition, the solution is heated to reflux. Reflux is maintained for 2 hours. After cooling, the solution is concentrated under reduced pressure to a solid residue, which is azeotroped with toluene (2×50 ml). The solid is dissolved in CH2Cl2 (250 ml), then washed with H2O (3×100 ml). The CH2Cl2 is dried over MgSO4, filtered, then concentrated under reduced pressure to give 5-(3-chloropropyl)-3-phenylmethyleneamino-2-oxazolidinone (11.2 g, 0.0420 mole) as a solid residue.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]=1[OH:16].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:30]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]=1[OH:16])=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1cc(CN)c(O)c(S(C)(=O)=O)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCc1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.79 g (0.003 mol) of 2-aminomethyl-4-ethyl-6-methylsulfonylphenol hydrochloride is reacted with0.42 g of hexamethylenetetramine in 6 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:10]1[C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 0.025 mol) in CHCl3 (100 mL) was added NBS (6.733 g, 0.038 mol) portion wise at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via by flash column chromatography using 25% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford 4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (4.6 g, 65%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12].Cl.C([O:19]CC)C>>[CH3:10][CH:11]([CH3:13])[CH2:12][C:8]([C:7]1[CH:6]=[N:5][CH:4]=[CH:3][C:2]=1[CH3:1])=[O:19]
Reactant: Cc1ccncc1C#N
Reactant: CC(C)C[Mg]Br
Reactant: CCOCC
Agent: Cl
Product: Cc1ccncc1C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methylnicotinonitrile (5.00 g) in diethyl ether (75 ml) was cooled to 5C and a solution (ca. 0.8 M, 78 ml) of isobutylmagnesium bromide in diethyl ether was gradually added thereto. The mixture was heated under reflux for 24 hrs. and added to 1N hydrochloric acid (400 ml). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized, and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=3:1) for purification to give the title compound (3.20 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([O-:7])=[O:6])=[CH2:3].[K+:10].[K+].[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH:13]=[CH2:14].[C:22]([O-])(=O)[C:23](C)=[CH2:24].[K+].[CH2:29]([C:32]1[CH:37]=[CH:36][C:35](O)=[C:34](OC)[CH:33]=1)[CH:30]=[CH2:31]>>[C:1]([O:9][CH2:31][CH2:30][CH2:29][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:12][CH2:13][CH3:14])(=[O:8])[C:2]([CH3:4])=[CH2:3].[C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([O-:7])=[O:6])=[CH2:3].[K+:10].[K+:10].[CH2:24]([O:21][C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:23]=[CH2:22]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: C=CCc1ccccc1O
Reactant: C=C(C)C(=O)[O-]
Agent: C=C(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Product: C=CCOc1ccccc1

Procedure:
The procedure for preparing the copolymer in Example 1 was repeated except that potassium itaconate and o-allylphenol were used in place of potassium methacrylate and 4-allyl-2-methoxyphenol, respectively to obtain a copolymer of stearyl methacrylate, potassium itaconate and O-allyl phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](O)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1CCC(N=C=NC2CCCCC2)CC1.[N:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]([NH:41][NH2:42])=O)=[CH:38][C:33]=2[NH:32][CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][CH2:11][C:12]1[S:52][C:39]([C:37]2[CH:36]=[CH:35][C:34]3[NH:30][CH:31]=[N:32][C:33]=3[CH:38]=2)=[N:41][N:42]=1
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1Cl

Procedure:
The compound was synthesized starting from 3-(3-chloro-4-methoxyphenyl)propionic acid (215 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.032 g (8.6%); MS m/z: 371.1/373.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.05 (t, 2H, 3J=7.5 Hz); 3.44 (t, 2H, 3J=7.5 Hz); 3.81 (s, 3H); 7.05 (d, 1H, 3J=8.7 Hz); 7.22 (dd, 1H, 4J=2.1 Hz, 3J=8.7 Hz); 7.39 (d, 1H, 4J=2.1 Hz); 7.83 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.22 (d, 1H, 4J=1.7 Hz); 8.93 (s, 1H); HPLC (METHOD [A]): rt 13.65 min (98.9%)
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[Cl:17][C:12]1[C:11](/[C:2](/[NH:27][CH:25]([C:22]2[CH:23]=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH3:26])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Reactant: CC(N)c1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\NC(C)c1ccc(Cl)nc1)c1cccnc1Cl
Yield: 73 %

Procedure:
To a solution of ethyl 3-chlor-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.150 g, 0.55 mmol, 1 eq.) in 3 ml of acetonitrile was added 1-(6-chloropyridin-3-yl)ethanamine (0.103 g, 0.66 mmol, 1.2 eq.) followed by triethylamine (TEA) (0.167 g, 1.66 mmol, 3 eq.). The reaction was microwaved (130° C., 600 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-3-{[1-(6-chloropyridin-3-yl)ethyl]amino}-2-cyanoacrylate (0.157 g, 68% yield) as a mixture of 2 atropoisomers.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:22](=[O:23])[C:21]([Cl:26])([Cl:25])[Cl:20])[N:13]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(C(=O)C(Cl)(Cl)Cl)c2ccccc2)n1

Procedure:
A solution of 2-anilino-4,6-dimethylpyrimidine (5 g) in toluene was added to a suspension of sodium hydride in oil (0.75 g of an 80% suspension) in toluene (100 ml) and the mixture was heated under reflux until evolution of hydrogen ceased. A solution of trichloroacetyl chloride (2.8 ml) in toluene (20 ml) was added dropwise at room temperature and the mixture heated at 80° for one hour. It was then worked up by filtration through silica using dichloromethane as eluent. The solvent was evaporated and the residue, after solidification, was recrystallised from ethyl acetate/diisopropyl ether to give N-(4,6-dimethylpyrimidin-2-yl)-N-phenyltrichloroacetamide, m.p. 125.5°-7°. (Compound 8).
Reaction SMILES: O[Li].O.C([O:7][C:8]1[C:13]([CH3:14])=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[O:11][C:10](=[O:24])[C:9]=1[CH3:25])(=O)C>CO>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=[C:15]1[C:12]1[O:11][C:10](=[O:24])[C:9]([CH3:25])=[C:8]([OH:7])[C:13]=1[CH3:14]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccccc3o2)oc(=O)c1C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An aqueous solution (30 ml) of LiOH-hydrate (465 mg) was added to a solution of 4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one (3.00 g) in MeOH (100 ml) at 0° C., and after stirring at room temperature for 2 hours, the MeOH was distilled off under reduced pressure. The residue was rinsed with Et2O, and then a KHSO4 aqueous solution was added at 0° C. for adjustment to pH 2.0. The precipitated crystals were filtered off and thoroughly rinsed with water and Et2O in that order and then dried to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CN1c2ccccc2Sc2ccc(CC(=O)O)cc21
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2

Procedure:
18.0 g of (10-methyl-10H-phenothiazin-2-yl)acetic acid are dissolved in a mixture of 400 ml of toluene and 200 ml of ethanol, and 5 ml of concentrated sulfuric acid are added. In a water separator filled with molecular sieve, the reaction mixture is heated at the boil under reflux for twelve hours. The reaction mixture is then cooled in an ice bath, and 200 ml of water are added. The mixture is then neutralized by addition of solid sodium carbonate. The product is then extracted five times with in each case 250 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane=>n-heptane:ethyl acetate=10:1. This gives 17.0 g of ethyl (10-methyl-10H-phenothiazin-2-yl)acetate as a yellow oil. C17H17NO2S (299.39), LCMS (ESI): 300.1 (M+H+), Rf (n-heptane:ethyl acetate=3:1)=0.34.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:30][CH2:31][C@H:32]1[C@H:37]([OH:38])[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(O)(C)C>CC(C)=O.C(OCC)(=O)C>[CH2:14]([O:30][CH2:31][CH:32]1[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCOCC1OCCCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of Jones reagent (1.34 g as chromic anhydride) were added, whilst ice-cooling, to a solution of 4.30 g of dl-trans-2-hexadecyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 2) in 20 ml of acetone. The mixture was then stirred at room temperature for 2 hours, after which 2 ml of isopropanol were added. The reaction mixture was then stirred for a further 10 minutes, after which it was diluted with 50 ml of ethyl acetate and then washed, in turn, with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was removed by distillation. The resulting oily residue, 4.5 g, was subjected to column chromatography through 100 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:10 to 3:20 by volume gave 3.73 g of the title compound, melting at 42°-43.5° C. (hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]C(CC)C.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: COc1ccccc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
27 ml (240.62 mmol) of 2-fluoroanisole is dissolved in 700 ml of tetrahydrofuran. At −70° C., 200 ml of sec-BuLi (1.3 M solution in cyclohexane) is added in drops. It is stirred for one hour at −70° C., and then 152 ml of N,N-dimethylformamide, dissolved in 50 ml of tetrahydrofuran, is added in drops at this temperature. After another hour of stirring at −70° C., 380 ml of hydrochloric acid (w=10%) is added in drops. In this case, the batch slowly comes to room temperature. After stirring overnight at room temperature, methyl tert-butyl ether is added, and the organic phase is separated after vigorous stirring. The aqueous phase is extracted two more times with methyl tert-butyl ether. The combined organic extracts are washed with brine and dried. After the desiccant is filtered off, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 25.66 g (69.2%) of the desired compound is isolated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OCC[O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C@@:25]2(C3[C:34](=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.BrCCC[CH2:49][O:50][CH3:51].BrCCCCC>>[CH3:34][O:33][CH2:32][CH2:25][CH2:26][CH2:27][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:51][O:50][CH2:49][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COCCCCBr
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: COCCCCN1C(=O)C2(COc3cc4c(cc32)OCOC4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-bromo-4-methoxybutane to replace 1-bromopentane, 1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.30-6.86 (m, 4H), 6.45 (s, 1H), 6.18 (s, 1H), 4.72 (ABq, 2H), 4.18-4.04 (m, 4H), 3.88-3.63 (m, 2H), 3.44-3.37 (m, 2H), 3.30 (s, 3H), 1.88-1.56 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.3, 138.2, 132.5, 128.8, 123.9, 123.1, 121.1, 111.4, 108.6, 99.3, 80.1, 72.0, 64.5, 63.9, 58.6, 57.9, 40.0, 26.9, 24.3; MS (ES+) m/z 381.9 (M+1).
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][OH:23]>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][O:23][C@@H:15]1[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OCc1c(Cl)cccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3c(Cl)cccc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.1 %

Procedure:
To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.06 g of 2,6-dichlorobenzyl alcohol in 25 ml of diethyl ether was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and then the mixture was stirred at room temperature for 4 days. The colourless crystals which had precipitated were filtered off, giving 1.582 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, melting at 123°-124° C. Triethylamine was then added to the mother liquor and the resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography through silica gel, in essentially the same manner as described in Example 1(a), to give 338 mg of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran and 306 mg of cis-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([OH:18])[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([O:18][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
A solution of 14.5 g. of (1S,5R,6S,7R)-6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one, 6 ml. of dihydropyran, and 40 mg. of p-toluenesulfonic acid in 300 ml. of absolute methylene chloride as agitated for one hour at 5°. Then the solution is diluted with ether, shaken with 4% sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Yield: 21 g. of the tetrahydropyranyl ether as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCC4)cc3)c2cc1OC
Yield: 69.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclobutylmethanol (22 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 64%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16]([O:18]CC)=[O:17])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[OH-].[Na+].C1COCC1.Cl>O.C(O)C>[CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nn2ccccc2c1-c1cc(-c2ccccc2)c(C(=O)O)s1
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A mixture of ethyl 5-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-3-phenylthiophene-2-carboxylate (119 mg, 0.327 mmol), a 8N aqueous solution of sodium hydroxide (5 mL), THF (5 mL) and ethanol (10 mL) and water (1 mL) was stirred for 1 h at 70° C. The mixture was allowed to cool to 0° C. To the mixture, was added a 6N aqueous solution of hydrogen chloride to adjust ca pH 3-4. The mixture was extracted with EtOAc-THF mixed solvent and the organic phase was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and dried under vacuum to yield the title compound (112 mg, over yield) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ: 12.83 (br s, 1H), 8.80-8.65 (m, 1H), 8.00-7.93 (m, 1H), 7.61-7.53 (m, 2H), 7.44-7.36 (m, 4H), 7.28 (s, 1H), 7.02-6.95 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[O:12][C:13](=[O:16])[CH2:14][NH2:15]>>[CH:1]1([NH:15][CH2:14][C:13]([OH:16])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: COC(=O)CN
Product: O=C(O)CNC1CCc2ccccc21

Procedure:
Alternatively, 1-indanone was reductively aminated with glycine methyl ester, followed by saponification of the ester.