Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-Bromobenzyl alcohol (50.00 g, 267.3 mmol), tert.-butyldimethylsilyl chloride (52.38 g, 347.5 mmol), and imidazole (23.66 g, 347.5 mmol) were dissolved in anhydrous DMF (300 mL). This solution was allowed to stir at room temperature overnight and then poured into ice-water (600 mL). The organic layer was separated off and washed with saturated aqueous sodium bicarbonate (2×200 mL) and water (2×200 mL). We obtained colorless oil (71.9 g, 88%): 1H NMR (CDCl3): δ 0.10 (s, (CH3)2Si), 0.94 (s, (CH3)3C), 4.7 (s, CH2O), 7.20 (d, J=7.8 Hz, C6H4), 7.45 (d, J=7.8 Hz, C6H4); 13C NMR (CDCl3): δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][C:14]#N)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.COCCO.[OH-:22].[K+].[OH2:24]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][C:14]([OH:24])=[O:22])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CC#N
Reactant: O
Agent: [K+]
Solvent: COCCO
Product: Cc1oc(-c2cccc(Br)c2)nc1CC(=O)O
Yield: 60 %

Procedure:
The crude [2-(3-bromophenyl)-5-methyloxazole-4-yl]-acetonitrile (assume 0.22 mol) was combined with 2-methoxyethanol (630 mL) and 85% solid KOH (74.6 g, 1.33 mol) in water (360 mL) was added to the reaction. The mixture was heated to reflux for 3 h, cooled, quenched with 2 M HCl (500 mL), and extracted with CH2Cl2. The organic layer was dried (MgSO4), and the solvent removed in vacuo, using toluene to azeotropically remove residual 2-methoxyethanol. The crude product (57.3 g) was recrystallized from toluene (450 mL) to give 39.8 g (60%) of 2-(3-bromophenyl)-5-methyl-4-oxazoleacetic acid as an off-white powder. 1H NMR (300 MHz, d6-DMSO) δ 7.99 (t, J=1.83 Hz, 1H), 7.88 (dt, J=8.1, 1.5 Hz, 1H), 7.65 (ddd, J=8.1, 1.8, 1.5 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 3.50 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=O)(=O)[CH3:5]>CO>[CH3:1][N:2]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:7]=2[C:4]([CH3:5])=[N:3]1
Reactant: CNN
Reactant: CC(=O)C1C(=O)CCCC1=O
Solvent: CO
Product: Cc1nn(C)c2c1C(=O)CCC2
Temperature: 0 °C

Procedure:
A solution of 11 ml of methylhydrazine in 50 ml of methanol was added dropwise to an ice-cold solution of 30 grams of 2-acetyl-1,3-cyclohexanedione in 200 ml of methanol and the reaction mixture was heated at reflux for 90 minutes. The solvent was removed under reduced pressure and the residue was triturated in hexane and cooled to give a clammy tan solid. This crude product was recrystallized from a mixture of toluene and hexane to give 1,5,6,7-tetrahydro-1,3-dimethyl-4H-indazol-4-one as a yellow crystalline solid melting at about 82.5°-84° C.
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:8]([CH:11](O)[CH2:12][CH3:13])[CH2:9][CH3:10])[CH3:7].[C:15]([NH:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH2:16][CH2:17][CH3:18].C([O-])([O-])=[O:29].[K+].[K+]>CN(C=O)C>[CH2:6]([N:8]([CH2:11][CH2:12][CH2:13][O:29][CH:17]([CH3:18])[CH2:16][C:15]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])[CH2:9][CH3:10])[CH3:7]
Reactant: CCCC(=O)Nc1cccc(O)c1
Reactant: O=C([O-])[O-]
Reactant: CCC(O)N(CC)CC
Agent: CS(=O)(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOC(C)CC(=O)Nc1ccccc1
Yield: 88.9 %

Procedure:
The mesylate of N,N-diethylaminopropanol (6 mmol), prepared as described in Example 18 above, was mixed with 3-butyramidophenol (5.0 mmol), and K2CO3 (10 mmol) in anhydrous DMF (10 mL) and the reaction is performed following general procedure B. The crude product is purified using silica gel column chromatography 5% MeOH/DCM as eluent to yield 3-(N,N-diethylaminopropoxy)butyranilide (1.3 g).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:7]([O:18]CC2C=CC=CC=2)=[CH:6][C:5]=1[CH2:26][C:27]#[N:28])([O-])=O.C.C(O)C>[Pd].O>[OH:18][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[OH:10])[NH:28][CH:27]=[CH:26]2
Reactant: N#CCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Oc1cc2cc[nH]c2cc1O
Temperature: 80 °C

Procedure:
The reaction mixture is prepared in an autoclave by adding 0.04 mole (15 g) of 2-nitro-4,5-dibenzyloxyphenylacetonitrile, 1.5 g of palladium at a concentration of 10% on charcoal and 1.5 g of charcoal to 120 ml of ethanol containing 3 ml of water. These are heated to 80° C. for 2 hours, with stirring, under a hydrogen pressure of 4.105Pa. After cooling, the reaction mixture, which is treated in the same manner as previously, produces 5,6-dihydroxyindole in an equivalent yield.
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[Cl:15][C:5]1[CH:6]=[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])[C:2]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: FC(Cl)C(F)(F)Oc1cc(Cl)cnc1Br
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2OC(F)(F)C(F)Cl)cc1

Procedure:
9.75 g (30 mmol) of 2-bromo-5-chloro-3-(2-chloro-1,1,2-trifluoroethoxy)pyridine, 6.94 g (33 mmol) of ethyl 4-hydroxyphenoxypropionate and 6.6 g of anhydrous potassium carbonate in 40 ml of absolute dimethyl sulfoxide were stirred for 9 hours at 80° C. under argon. After cooling, the mixture was diluted with 300 ml of diethyl ether, the potassium carbonate was filtered off, and the organic phase was washed with 5% strength KOH and subsequently with water until neutral. After drying, the compound of Example 1 was obtained in a crude yield of 13.4 g (98% of theory).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1.[CH3:17]OC(OC)N(C)C.Cl.[NH2:26][C:27]([NH2:29])=[NH:28].N12CCCN=C1CCCCC2>CC(O)C.CN(C)C=O>[NH2:28][C:27]1[N:29]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:17][N:26]=1
Reactant: N=C(N)N
Reactant: Cn1cc(CC(=O)c2ccco2)ccc1=O
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 86.5 %

Procedure:
To 5-(2-furan-2-yl-2-oxo-ethyl)-1-methyl-1H-pyridin-2-one (8) (402.0 g, content 397.6 g, 1.83 mol) obtained in Example 2 were added dimethylformamide (0.4 L) and N,N-dimethylformamide dimethyl acetal (654.4 g, 5.49 mol), and the reaction mixture was stirred at 60° C. for 10.5 hours and then at room temperature for 13.5 hours. To the reaction mixture were added guanidine hydrochloride (524.56 g, 5.49 mol) and 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) (821 mL, 5.49 mol), and the reaction mixture was stirred for 7.8 hours at 70° C. Next, to the reaction mixture was added 2-propanol (12.0 L), followed by stirring for 2 hours in an ice bath. The precipitated crystals were collected by filtration, washed with 2-propanol (1.0 L), and then air-dried at 60° C. for 13 hours to give 424.9 g of the title compound as pale yellow crystals (content 413.0 g, yield 84.1%).
Reaction SMILES: [Cl-:1].[OH:2][CH2:3][P+:4](CO)([CH2:7][OH:8])[CH2:5][OH:6].[CH:11]([OH:14])(C)C.[OH-].[K+:16]>O>[OH:2][CH2:3][P:4]([CH2:7][OH:8])[CH2:5][OH:6].[CH2:11]=[O:14].[Cl-:1].[K+:16]
Reactant: CC(C)O
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=O
Product: OCP(CO)CO

Procedure:
The catalyst is removed using tris-(hydroxymethyl)phosphine (“THMP”) which is prepared by adding 245 g of tetrakis-(hydroxymethyl)phosphonium chloride (1.03 mol, Strem) and 500 mL of isopropyl alcohol (IPA) to a 2 L round-bottomed flask, degassing the mixture with nitrogen for 20 minutes, slowly adding 64 g (1.03 mol, 90% purity, Aldrich) of potassium hydroxide over 30 minutes to the vigorously stirring solution, while under a nitrogen atmosphere, and, after the potassium hydroxide has been added, stirring the reaction for an additional 30 minutes. This reaction is exothermic, and produces THMP, formaldehyde, potassium chloride, and water. The catalyst is then removed using the THMP by adding 25-100 mol equivalents of THMP per mole of ruthenium catalyst, stirring vigorously at 60-70° C. for 18 to 24 hours, under nitrogen, adding degassed water or methanol (˜150 mL/L of reaction mixture) and vigorously stirring for 10 minutes, and centrifuging the mixture for phase separation. The oil may have to be heated to remove the residual water or methanol. The aqueous phase will contain small amounts of IPA, formaldehyde, and potassium chloride, and will need to be purged or cleaned for recycling.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3,5-trimethylphenol (10.0 g), ethyl 4-bromobutyrate (12.6 ml), potassium carbonate (12.2 g), and dimethylformamide (DMF, 100 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate (AcOEt) and water. The separated organic phase was washed with a saturated aqueous solution of sodium hydrocarbonate (sat. NaHCO3aq.), water, and brine, and was dried over magnesium sulfate (MgSO4). After evaporation, the resulting residue was purified by chromatography over silica gel (CHCl3 as eluent) to give ethyl 4-(2,3,5-trimethylphenoxy)butyrate (16.35 g) as an oil compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.[CH2:32]([NH:34][CH3:35])[CH3:33].[OH2:36]>CN(C=O)C>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][C:26]([N:34]([CH2:32][CH3:33])[CH3:35])=[O:36])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: CCNC
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)Cc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 13 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.25 g, 0.43 mmol) was dissolved in DMF (1.5 ml). Ethylmethylamine (0.186 ml, 2.16 mmol) and water (0.5 ml) were added and the reaction mixture was heated for 2 hours to 90° C. More ethylmethylamine (0.2 ml, 2.33 mmol) was added and it was heated for another 1.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Chromatography on silica gel with toluene/ethanol (5:1) and then with hexanes/acetone (1:2) gave 27 mg (13%) of the title compound as a colourless solid.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:9])[C:6]([CH3:8])=[CH2:7].C1(C)C=CC=CC=1>CS(O)(=O)=O.O>[C:5]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:16]=1)(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C
Reactant: C=C(C)C(=O)Oc1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1ccc(OC(C)(C)C)cc1
Yield: 65 %

Procedure:
Under ice cooling, isobutene was introduced into a mixture of 17.8 g of 4-hydroxyphenyl methacrylate, 0.3 g of methanesulfonic acid, and 100 g of toluene over 4 hours. To the reaction solution, 50 g of water was added to quench the reaction, from which the organic layer was recovered. The organic layer was washed with water, sodium bicarbonate water, and saturated saline solution in sequence and concentrated. The concentrate was purified by distillation, obtaining 152 g (yield 65%) of 4-tert-butoxyphenyl methacrylate, designated Monomer 1.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:26]([NH2:28])[CH3:27])[CH:22]=[C:23]([CH3:25])[CH:24]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH:26]([C:21]3[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([O:18][CH2:17][CH:16]([F:15])[F:29])[CH:20]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(OCC(F)F)cc(C(C)N)c1
Agent: Cl
Product: Cc1cc(OCC(F)F)cc(C(C)N2Cc3c(ccnc3Cl)C2=O)c1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-30, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1CF
Temperature: 25 °C

Procedure:
2-(S)-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (5.62 g, 21.2 mmol) was treated with tetrabutylammonium fluoride (1 M solution in THF, 191 mL) under N2, heated to reflux for 1 hour, cooled to ambient temperature, concentrated to 50 mL, treated with water (100 mL) and extracted with ethyl acetate (2×250 mL). The combined ethyl acetate layers were washed with 0.25 M HCl (100 mL), washed with NaHCO3 solution, washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (10:1 and then 5:1 hexane:ethyl acetate) to provide 2.9 g (72%). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H) 2.26 (m, 2H) 3.84 (t. J=7.46 Hz, 2H) 4.35 (m, 1H) 4.42 (ddd, J=46.36, 9.92, 2.71 Hz, 1H) 4.72 (ddd, J=48.31, 10.00, 3.05 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C@@H:11]([NH2:15])([CH2:13][CH3:14])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH2:13][CH3:14])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC[C@H](C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)Nc1ccc([N+](=O)[O-])cn1

Procedure:
2-Bromo-5-nitropyridine (341 mg, 1.68 mmol), (S)-(+)-sec butylamine (123 mg, 1.68 mmol), and finely ground potassium carbonate (707 mg, 5.1 mmol) were heated to 80° C. in 15 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and purified by flash chromatography to yield 233 mg. ES-MS calcd for C9H13N3O2 (m/e) 195.22, obsd 196.1 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: CN(C)CCO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCOC(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A 391 mg (2.5 mmole) portion of phenyl chloroformate was added dropwise to a solution of 223 mg (2.5 mmole) of N,N-dimethylethanolamine and 253 mg (2.5 mmole) of triethylamine in 5 ml of methylene chloride under ice-cooling with stirring, followed by stirring further under ice-cooling for 10 minutes and then at room temperature for 30 minutes. The reaction solution was diluted with methylene chloride, and the solution was washed with 1% aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was distilled off, and there was obtained 465 mg of the crude 2-dimethylaminoethyl phenyl carbonate in the form of a colorless oil. 880 mg (2.2 mmole) of the compound as obtained in Example 80 was added to the compound, followed by warming at 90° C. for 2 hours. The reaction solution was subjected to separation and purification by chromatography on a column of silica gel (40 g). After impurities were removed with n-hexane-ethyl acetate (1:4) as an eluent, there was obtained the objective compound in the form of a colorless powder from the eluate of chloroform-methanol (10:1). Yield of 800 mg (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[C:26]([CH2:28]OS(C1C=CC=CC=1)(=O)=O)#[N:27].CS(C)=O>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH2:28][C:26]#[N:27])[C:8]([CH3:14])([CH3:15])[CH2:7]1
Reactant: CC1(C)CC(Oc2ccc(Cl)c(Cl)c2)CC(C)(C)N1
Reactant: N#CCOS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(Oc2ccc(Cl)c(Cl)c2)CC(C)(C)N1CC#N
Product: Cl
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 4-(3,4-dichloro-phenoxy)-2,2,6,6-tetramethyl-piperidine (1.22 g, 3.9 mmol), potassium carbonate (6.9 g, 50 mmol), cyanomethylbenzenesulfonate (7.5 ml, 40 mmol) and DMSO (20 ml) was stirred at 70° C. for 15 h. Water (100 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). Chromatography on silica gel with ethyl acetate:petroleum (1:1) gave the title compound. Hydrochloric acid in ether was added and the hydrochloric acid salt was precipitated and stirred for 10 min, followed by filtration. Yield 0.23 g, (16%). Mp >200° C. (Dec.).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:20]=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CCO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:29][CH:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:14]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Ethyl 2-[6-[[2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]-2-pyridyl]acetate (Example A9; 0.4 g, 0.796 mmol) was taken in THF(12 mL) and EtOH (4 mL), to it was added aqueous solution of LiOH (0.033 g, 0.796 mmol in 4 mL water) and stirred for 1 h at room temperature. Completion of reaction was confirmed by TLC. Organic solvent was removed under reduced pressure. The obtained residue was diluted with water (50 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N HCl to pH 1-2 and extracted with Ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL) dried over anhydrous sodium sulphate and the solvent was removed under vacuum to get the pure product (0.320 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1N
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-(4-methylpiperazin-1-yl)propanamide, and the procedure described in General Procedure F. m/z (M+H)+ 598.4.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33])([CH3:26])[CH3:25].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CC(C)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of 2-isopropylbenzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ1.16 (t, 6H), 2.21-2.35 (m, 3H), 2.60 (m, 1H), 3.21 (m, 1H), 3.42 (q, 2H), 5.88 (d, 1H), 6.56 (t, 1H), 6.94 (t, 1H), 7.13 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]2[O:12][CH:11]([CH3:13])[S:10][C:9]=2[C:14]=1[CH3:15])(=O)C.C[O-].[Na+].O.C(O)(=O)C>CO>[OH:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]2[O:12][CH:11]([CH3:13])[S:10][C:9]=2[C:14]=1[CH3:15]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)SC(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(C)O2
Yield: 82.8 %

Procedure:
2.9 g of 5-acetoxy-2,4,6,7-tetramethyl-1,3-benzoxathiole, prepared as described in Example 22, were dissolved in 30 ml of methanol, 1.3 g of sodium methoxide was added to the solution, and the mixture was allowed to react at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water and the solution was neutralized by adding acetic acid. The separated product was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off. The crude product thus obtained was purified by silica gel column chromatography. From the fraction eluted with a 1:1 by volume mixture of hexane and benzene were obtained 2.0 g of the title compound, melting at 125°-127° C.