Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][OH:8])[CH3:4].FC1C([O:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([C:29]=2[NH:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=O)=C(F)C(F)=C(F)C=1F>CN1CCCC1=O.CO.C(OCC)(=O)C>[CH2:3]([N:5]([CH2:9][CH3:10])[CH2:6][CH2:7][O:8][C:19]([C:21]1[NH:22][C:23]2[C:28]([C:29]=1[NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])[CH3:4]
Reactant: CCN(CC)CCO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCN(CC)CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 0 °C
Yield: 31.1 %

Procedure:
Stir under N2 at 0° C. a suspension of NaH (29 mg, 0.72 mmol of 60% oil dispersion) in 1-methyl-2-pyrrolidinone (15 mL), and slowly add N,N-diethylethanolamine(0.095 mL, 0.72 mmol). Stir for 10 min and then add dropwise 3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid pentafluorophenyl ester (100 mg, 0.24 mmol). Allow the reaction to reach ambient temperature and stir overnight. Quench into water and extract with ethyl acetate. Wash the extract with water, brine, dry (MgSO4), filter and concentrate under vacuum to obtain crude product. Chromatograph on silica gel (10 g, Sepack cartridge) and use 1:1 methanol/ethyl acetate as eluent. Combine like fractions and concentrate under vacuum to obtain 26.3 mg (31%) of the titled compound: MS 353 (M+H).
Reaction SMILES: CS[C:3](=[O:12])[C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5].C(=O)([O-])[O-:14].[Na+].[Na+].Cl>O>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4](=[O:5])[C:3]([OH:12])=[O:14])[N:7]=1
Reactant: CSC(=O)C(=O)c1csc(N)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(C(=O)C(=O)O)cs1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To 10.1 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid methyl ester and 80 ml of water was added 10.6 g of sodium carbonate with ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, the thus obtained reaction mixture was adjusted to pH 2.5 with 6N hydrochloric acid at the same temperature. The deposited crystals were collected by filtration, washed with water, and then dried to obtain 6.2 g (67.8% yield) of 2-(2-aminothiazol-4-yl)glyoxylic acid having a melting point of above 200° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:38])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=1)[C:11]([NH:13][NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:38])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]([F:36])([F:35])[F:37])[CH:27]=1)[C:11]1[O:24][C:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyl-oxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (944 mg, 1.73 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (907 mg, 3.46 mmol), iodine (878 mg, 3.46 mmol) and Et3N (0.96 mL, 6.92 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a light yellow oil (790 mg, 87%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.5, 8.8 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 5.19 (dd, J=7.2, 9.0 Hz, 1H), 4.55 (dq, J=6.1, 7.2 Hz, 1H), 1.47 (d, J=6.1 Hz, 3H), 0.74 (s, 9H), 0.09 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[N:27]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[N:27]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]([OH:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of 1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]phenyl}ethanone (233 mg) in methanol (5 mL) was added sodium borohydride (38 mg), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (225 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:19](I)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was added triethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol), and copper(I) iodide (16 mg, 0.09 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. Then added 30 mL ethyl ether to the dark oil, filtered to remove the dark precipitate. The organic extracts were concentrated and the residue was purified by chromatography (silica gel, ethyl ether/EtOAc) to the title compound as a tan foam (317 mg, 99%).
Reaction SMILES: CI.[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][OH:17])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:19]C(C)([O-])C.[K+]>O1CCCC1>[F:3][C:4]([F:18])([CH2:14][CH2:15][CH2:16][O:17][CH3:19])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCC(F)(F)COCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCCCC(F)(F)COCc1ccccc1
Reaction time: 8 h

Procedure:
Excess methyl iodide (17 g, 120 mmoles) is added to the alcoholate previously prepared from 2,2-difluoro-1-benzyloxy-5-hydroxypentane (9.8 g, 42.6 mmoles) and potassium t-butoxide (5.6 g, 50 mmoles) in dry tetrahydrofuran (50 ml). The reaction mixture is kept at room temperature overnight, concentrated under vacuum, and the residue is deluted with water and ether. Usual extraction gives the title compound which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80, RF: 0.9; 7.4 g, 71%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]([C@@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:15]=2[CH2:14][CH2:13]1)CCC1SC=CC=1.Cl.[CH3:24]OC1C=CC=C2C=1CCC(=O)C2.CCCN>C(O)(=O)C.[H][H].O=[Pt]=O>[CH3:24][O:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:16]2[C:15]=1[CH2:14][CH2:13][CH:12]([NH:4][CH2:3][CH2:2][CH3:1])[CH2:17]2
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: [H][H]
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCN
Product: CCCNC1CCc2c(cccc2OC)C1

Procedure:
Another process for preparing racemic rotigotine hydrochloride, which is disclosed in U.S. Pat. No. 4,564,628, is shown in Scheme 2 below. 5-methoxy-2-tetralon (Compound I) is reacted with 3-propylamine in acetic acid and H2/PtO2 to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthaleneamine (Compound VI). This intermediate then is reacted either with 2-thienylacetic acid in presence of borane trimethylamine complex in xylene or with 2-thienylacetyl chloride and lithium aluminum hydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (Compound IV). Finally, this intermediate is reacted with boron tribromide, then with HCl, to form the racemic rotigotine hydrochloride (Compound V).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)[CH2:17][CH2:16]2)[N:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1cncc(N2CCN(CC3COc4ccccc4O3)CC2)n1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (4.7 g, 20 mmole) and 2,6-dichloropyrazine (3.0 g, 20 mmole) were combined in 200 ml of dimethylformamide and 2.6 g (20 mmole) of diisopropylethylamine was added. The mixture was heated under nitrogen at 60° C. for 24 hours. The solvent was then removed in vacuum and the residue filtered through 75 g of silica gel with chloroform as the eluent. The product-containing fractions were concentrated in vacuum and the residue was crystallized from methanol with addition of 4N isopropanolic HCl and recrystallized from methanol to give 4.26 g of the title compound as the monohydrochloride, m.p. 270°-280° C.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (82 mg) and methanesulfonyl chloride (100 μL) in tetrahydrofuran (3 ml) was added triethylamine (100 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and water was added. The precipitated crystals were collected by filtration, and washed with water. The obtained crystals were recrystallized from tetrahydrofuran to give the title compound (42 mg, yield 36%) as colorless crystals. melting point 251° C.
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:4]([CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:1]=[S:2]
Reactant: S=C=S
Reactant: NCCCN1c2ccccc2Sc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=NCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
4.2 g of carbon disulfide was added dropwise to a solution of 12.8 g of 10-(3-aminopropyl)phenothiazine and 7.7 ml of triethylamine in 100 ml of tetrahydrofuran. After stirring the solution at room temperature for 2 hours, a solution of 11.3 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran was added dropwise thereto, and the reaction was conducted at room temperature for 5 hours. After concentration, ethyl acetate was added to the concentrate, and the crystals precipitated were collected by filtration, and the filtrate was concentrated to obtain 18.6 g of the desired compound (oily).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[H][H]>CC(O)C>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Solvent: CC(C)O
Product: CO[C@@H]1CCCCC1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
Kinetic resolution of racemic 2-methoxycyclohexanone was carried out (see formula (16) below) That is, a reaction was carried out in accordance with the procedures of Example 13 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using 2-methoxycyclohexanone (320 mg; 2.5 mmol) (made by Tokyo Kasei Kogyo Co., Ltd. )as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 1 hours. As a result, (R)-2-methoxycyclohexanone was obtained at isolation yield of 42% (134 mg; 1.05 mmol), (1R, 2S)-2- methoxycyclohexanol was obtained at isolation yield of 50% (164 mg; 1.25 mmol and enantiomeric excess of 91%). GC (column: Chirasil-DEX CB; column temperature:90° C.; injection and detection temperature: 200° C.; helium pressure: 25 kPa; tR of (1R,2S)-2-methoxycyclohexanol: 37.6 minutes(50.8%); tR of 1S, 2S alcohol: 36.5 minutes (2.5%); tR of 2-methoxycyclohexanone:27.0 minutes (46.7%)). enantiomeric excess of (R)-2-methoxycyclohexanone:94% : HPLC (column: CHIRALCEL OB-H; solvent: 200:1 hexane/2-propanol; temperature: 30° C.; UV wavelength: 290 nm; flow rate: 1.0 ml/minute; tR of (R)-2-methoxycyclohexanone: 20.9 minutes (97.2%); tR of Sketone: 17.0 minutes (2.8%). specific rotation of ketone: [α]29D+98.8° (c:2.61; CH2Cl2); absolute structure: R; literature value: [α]22D−112.4° (c:2.08;CH2Cl2),>99%ee(S). specific rotation of alcohol: [α]29D+14.9° (c:1.026; CH2Cl2); absolute structure: 1R, 2S: the absolute structure was determined by HPLC analysis of the product of oxidation of (1R, 2S)-2-methoxycyclohexanol.
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[OH:9])[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.[CH2:16]1[C:21](=[O:22])[N:20]([O:23][C:24](ON2C(=O)CCC2=O)=[O:25])[C:18](=[O:19])[CH2:17]1>C(#N)C.CN(C1C=CN=CC=1)C.CCOCC>[CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:24]([O:23][N:20]1[C:21](=[O:22])[CH2:16][CH2:17][C:18]1=[O:19])=[O:25])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C=CCCC[C@@H]1C[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)ON1C(=O)CCC1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,2R)-2-(pent-4-en-1-yl)cyclopropanol (See International Patent Application Publication No. WO08/057209) (2.13 g; 70% wt) in acetonitrile (20 ml) was added pyridine (1.5 ml), followed by N,N′-disuccinimidyl carbonate (3.74 g) and a crystal of DMAP. The mixture was stirred at 40° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ether and washed with HCl 1N, water and brine and dried over sodium sulfate. The organic layer was filtered and concentrated to provide the desired product (2.88 g) as an oil. 1H NMR (500 MHz, CDCl3): δ (ppm) 4.06-4.03 (m, 1H), 2.87 (s, 4H), 2.28-2.25 (m, 2H), 1.98-1.97 (m, 1H), 1.72-1.65 (m, 2H), 1.46-1.40 (m, 2H), 1.31-1.24 (m, 1H), 1.12-1.08 (m, 1H), 0.72-0.68 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][Cl:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[ClH:12].[C:1]1([S:7]([CH2:10][CH2:11][NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(CCCl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cl
Product: O=S(=O)(CCNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 71.90 g (0.352 mole) of 2-chloroethyl phenyl sulfone, 37.45 g (0.350 mole) of benzylamine and 60 ml of triethylamine in 800 ml of acetonitrile was stirred at room temperature for ≈64 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the volume was reduced in vacuo to 300 ml. Methanol was added followed by an excess of ethereal hydrogen chloride. A white precipitate was collected to give 81.30 g (74.5%) of white, crystalline solid, m.p. 211°-213° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (77 mg, 0.25 mmol) (Example B.2) according to general procedure II. Obtained as a yellow solid (93 mg, 67%). MS (ISP) 556.3 [(M+H)+]; mp 190-191° C.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][CH:12]1[C:20](=O)[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH:20]([NH2:10])[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1
Reactant: NC1CCCc2occc21
Reactant: CC1CCc2sccc2C1=O
Product: CC1CCc2sccc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.12-6.99, 4.13, 3.89, 3.51, 2.86-2.74, 2.13-1.98, 1.75, 1.65, 1.15, 1.07.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[C:9]([C:12]1[CH:13]=[C:14]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:15]=[C:16]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]>C(COC)OC>[C:9]([C:12]1[CH:13]=[C:14]([N:24]([CH3:1])[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH:15]=[C:16]([S:18]([F:22])([F:23])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C

Procedure:
In a microwave insert, N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (0.25 g) was dissolved in absolute dimethoxyethane (7.5 ml), powdered potassium carbonate was added and the mixture was admixed with iodomethane (80 μl). Subsequently, the mixture was heated to 100° C. in the microwave for 40 min. Once further N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4×250 mg) had been converted in the manner described, the five batches were worked up together, having been decanted from the potassium carbonate into 1N hydrochloric acid while cooling with ice. After repeatedly washing the potassium carbonate residue with dimethoxyethane, the aqueous phase was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.03 g of the desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:37])=[C:34]([Pb+3])[CH:35]=1>C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:37])=[C:32]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:31]=1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: Cc1ccc(Cl)cc1[Pb+3]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.504 g, 2.96 mmol) and N,N-dimethylaminopyridine (1.45 g, 11.84 mmol) is added anhydrous chloroform (40 ml). To this solution is added crude 5-chloro-2-methylphenyllead triacetate (2.26 g, 4.44 mmol) in one portion, and the mixture is then heated at 40° C. for 17 hours (analysis), then for a further 23 hours at 45-50° C. The mixture is allowed to cool to room temperature, then diluted with ethyl acetate (100 ml) and washed with dilute aqueous hydrochloric acid (3×30 ml). The organic phase is dried over anhydrous magnesium sulfate, then concentrated to give a yellow gum which is purified by column chromatography (ethyl acetate/hexane/acetic acid 8:18:1 ratio) then triturated with hexanes to afford 4-(5-chloro-2-methylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.53 g) as a white solid.