Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH3:13].[F:14][C:15]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[C:17](F)[C:16]=1[F:24].C1OCCOCCOCCOCCOC1>C(#N)C.CN(C=O)C>[F:21][C:19]1[C:18]([F:22])=[C:17]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH3:13])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:16]([F:24])=[C:15]([F:14])[N:20]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1C
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 22 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.2 mmol, prepared by treatment with sodium methoxide) suspended in 30 ml of acetonitrile was added pentafluoropyridine (0.57 ml, 5.2 mmol) and 1.14 g (5.17 mmol) of 15-Crown-5 and DMF (25 ml), and the resulting mixture was refluxed for 20 hours. The mixture was cooled, concentrated in vacuo, and the residue diluted with water, extracted with methylene chloride, and the organic layer was washed with water and brine. The organic layer was concentrated in vacuo and a crude product was purified by flash chromatography to afford 0.39 g (22%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41](Cl)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:10]4[CH:9]=[N:8][C:7]5[N:6]([N:5]=[CH:4][C:3]=5[CH2:1][CH3:2])[CH:11]=4)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCc1cnn2cc(B(O)O)cnc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(CC)cnn5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the above crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (50 mg, 0.0944 mmol), Pd(PPh3)4 (11 mg, 0.0094 mmol) and 2M potassium carbonate (0.19 mL, 0.378 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C35H35ClN5O3S: 640.2 (M+H+); Found: 640.3 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[N:13]=[C:14]([CH2:21][OH:22])[CH:15]=[C:16]2[CH:20]=[CH:19][O:18][C:17]=12.C(=O)=O.CC(C)=O>C(Cl)Cl>[Cl:11][C:12]1[N:13]=[C:14]([CH:21]=[O:22])[CH:15]=[C:16]2[CH:20]=[CH:19][O:18][C:17]=12
Reactant: OCc1cc2ccoc2c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: O=Cc1cc2ccoc2c(Cl)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Oxalyl chloride (3.1 mL, 35 mmol) is dissolved in 200 mL CH2Cl2 in a dried flask under N2. The flask is placed in a dry-ice/acetone bath at −78° C., DMSO (4.95 mL, 70 mmol) in 10 mL CH2Cl2 is added drop-wise, and the mixture is stirred for 20 min. (7-Chlorofuro[2,3-c]pyridin-5-yl)methanol (C4) (5.5 g, 30 mmol) in 10 mL CH2Cl2 is added, and the reaction is stirred 30 min at −78° C. TEA (21.3 mL, 153 mmol) is then added. The reaction is stirred 30 min in the dry-ice/acetone bath, an ice bath replaces the dry-ice/acetone bath, and the reaction is stirred 1 h and is washed with 100 mL 1:1 saturated NaCl/NaHCO3. The organic layer is dried over anhydrous K2CO3, filtered, and concentrated in vacuo to afford 7-chlorofuro[2,3-c]pyridine-5-carbaldehyde (C6) as a pale yellow solid (97% yield). MS (EI) for C8H4ClNO2 m/z: 181 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:30])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:32][C:33]#[N:34])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:30])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5587 g, 1.2 mmol), prepared in the previous step, bromoacetonitrile (0.10 mL, 1.44 mmol) and potassium carbonate (0.83 g, 6 mmol) in 10 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a brown oil. The oil was chromatographed on a 90 g KP-SIL 60 Δ Biotage column using 5% ethyl acetate in methylene chloride as the eluent. Isolation of the desired product gave 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.48 g, 79%) as a clear oil, MS m/z: 505 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[N:18])=[C:8]([Br:19])[C:7]=2[CH:20]=1.Cl[C:22]1[N:27]2[N:28]=[CH:29][CH:30]=[C:26]2[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=1.[Cl-].C(N(CC)CC)C>C(O)C>[Br:19][C:8]1[C:7]2[CH:20]=[C:3]([CH2:2][NH:1][C:22]3[N:27]4[N:28]=[CH:29][CH:30]=[C:26]4[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=3)[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Reactant: CCc1cc(Cl)n2nccc2n1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1

Procedure:
540 mg (1.65 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) and 300 mg (1.65 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) were heated with reflux in 4 ml dry ethanol for 13 h. In order to complete the conversion of the amine 200 mg of the chloride and 0.24 ml triethylamine in 4 ml dry ethanol were added, and the mixture was heated for additional 21 h. The solvent was removed in vacuo, and the title compound isolated from the residue by chromatography (hexane/acetone 95:5 to 75:25) to give colorless crystals after evaporation to dryness, m.p. 186°-194° C.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:13]1([C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.C([O-])(=O)C.[Na+]>CCOCC.O.C(O)(=O)C>[C:1]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
This compound was synthesized by adapting, to N-isobutyryl-L-cysteine, the tritylation method described by K.-Y. Zee-Cheng and C. C. Cheng, J. Med. Chem., 1970, 13, 414-418. A suspension comprising 4.1 g (21.5 mmol) of N-isobutyryl-L-cysteine [(prepared according to H. Brückner et al., J. Chromatogr., 1989, 476, 73-82), ([α]D20=+84° (c 1, CHCl3))], 5.6 g (21.5 mmol) of triphenylmethanol and 16 ml of glacial acetic acid is stirred at ambient temperature. 4.1 ml (32.2 mmol) of BF3 etherate are added dropwise to the mixture while maintaining the temperature at 20-25° C. After stirring for 3 h, the brown solution obtained is subsequently cooled to 0° C. and then 70 ml of an aqueous sodium acetate solution and 140 ml of water are added. At the end of the additions, the reaction mixture sets solid in the form of a gel. This mixture is left overnight at 0° C. and then 150 ml of ice-cold water and 120 ml of ether are subsequently added with vigorous stirring. The ethereal phase is separated by settling and the aqueous waste liquors are washed with 4×80 ml of ether. The organic phases are combined, washed with 4×60 ml of ice-cold water, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The crude product obtained is purified by washing successively with hexane (5×50 ml) to provide 13 in the form of a gum which is homogeneous by TLC with a yield of 81%. Rf (CH2Cl2/MeOH/AcOH, 9.4/0.6/0.07): 0.53. [α]D20=+21.40 (c 1.12, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])[N:5]=[CH:4][C:3]=1[CH:15]=O.NC1N(C2C=CC=CC=2Cl)N=CC=1C=O.C(O)C.[C:35](OCC)(=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].N1CCCCC1>>[F:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([F:14])[C:7]=1[N:6]1[C:2]2[NH:1][C:35](=[O:42])[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:15][C:3]=2[CH:4]=[N:5]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1c(C=O)cnn1-c1c(F)cccc1F
Agent: Nc1c(C=O)cnn1-c1ccccc1Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cnn(-c3c(F)cccc3F)c2[nH]c1=O
Temperature: 75 °C
Yield: 100 %

Procedure:
In a 500 mL round-bottomed flask was added 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbaldehyde (7.77 g, 35 mmol; prepared in a fashion similar to that described for 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde in Example 1 above) followed by ethanol (100 ml, 35 mmol). To the solution was added diethyl malonate (11 ml, 70 mmol) and piperidine (3.4 ml, 35 mmol) and the mixture was heated to 75° C. overnight. The reaction mixture was concentrated under reduced pressure and the brown residue was treated with 200 mL of a 1:1 solution of EtOAc:Hexanes. The precipitated solid was then filtered through a sintered glass frit and rinsed with hexanes. It was dried under high vacuum to afford the title compound (11.13 g, 100% yield) as a beige crystalline solid. MS (ESI, pos.ion) m/z: 306.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
Ethyl 3-{4-[2-(4-Chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenyl}propionate (49 mg) was dissolved in a mixed solvent of 1 ml of ethanol and 1 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at 60° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, which was then adjusted to neutrality with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration, and washed in water, followed by drying, to produce 30 mg of 3-{4-[2-(4-chlorobenzenesulfonamido)-2(3-pyridyl)ethyl]phenyl}propionic acid. The spectrometric data supports the structure of [25] as follows.
Reaction SMILES: [Br:1]Br.[CH3:3][Si:4]([C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)([CH3:6])[CH3:5]>O1CCCC1.O>[Br:1][CH:16]([CH3:17])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][Si:4]([CH3:5])([CH3:6])[CH3:3])=[CH:14][CH:13]=1)=[O:18]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(Br)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (8.4 g) is slowly added to 1-(4-trimethylsilanylethynylphenyl)propan-1-one (10.0 g) in 100 ml of tetrahydrofuran at 0° C. and subsequently stirred at room temperature for 2 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 19:1 as eluent to obtain 2-bromo-1-(4-trimethylsilanylethynylphenyl)propan-1-one as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](OC)([O:10]C)[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH2:19][CH3:20].[O:21]=[O+][O-]>>[C:14]([C:4]1[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([OH:21])[C:3]=1[O:18][CH2:19][CH3:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C
Reactant: O=[O+][O-]
Product: CCOc1c(O)cc(C(C)=O)cc1C(C)(C)C

Procedure:
1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-ethoxybenzene (O4.010; 19.68 g) was converted analogously to O3.070. 5.15 g of the title compound were obtained.
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C1C=CC=CC=1.[OH:17][CH:18]([CH3:23])[CH2:19][C:20]([O-:22])=O>CS(C)=O.O>[CH2:19]1[C:20](=[O:22])[N:4]([CH2:8][C:7]([NH2:6])=[O:9])[CH2:23][CH:18]1[OH:17]
Reactant: CC(C)CN1CC(=O)NC1c1ccccc1
Reactant: CC(O)CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
A solution of 0.65 g 2-methylpropyl 2-phenyl-4-oxoimidazolidine-β-hydroxybutanoate in 1.5 ml dimethyl sulfoxide and 0.5 ml water is heated at reflux for 16 h. After evaporating, the residue is chromatographed on silica, eluting with 7:3 ethyl acetate/methanol. Oxiracetam is obtained as a white powder, m.p. 167°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[I:14]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.C(O)(=O)C>O>[I:14][C:11]1[S:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(Cc2ccc(I)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of 2-(4-fluorophenylmethyl)thiophene (3.85 g, 20.0 mmol), prepared as described in step 1, and N-iodosuccinimide (4.50 g, 20.0 mmol) in 1:1 chloroform-acetic acid (40 mL) was stirred at ambient temperature for 1 hour and then diluted with an equal volume of water. The organic layer was washed with saturated aqueous NaHCO3 solution (2×50 mL), 10% aqueous sodium thiosulfate solution (2×50 mL) and once with brine. After drying over MgSO4, the organic layer was concentrated in vacuo to give 6.07 g (95%) of 2-iodo-5-(4-fluorophenylmethyl)thiophene as a gold colored oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].CCOC(C)=O>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Reactant: CC1=CC[C@@H](C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid chloride (1.8 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (336 mg, 0.89 mmol) and DMAP (217 mg, 1.8 mmol) were dissolved in dichloroethane (2.2 mL), sealed with a cap and heated to 80° C. After 2 h, the temperature was increased to 90° C., and the solution was stirred 16 h. The reaction mixture was further heated to 100° C., stirred 24 h and partitioned between water and ethyl acetate:hexanes (1:1). The layers were separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% EtOAc:hexanes 5 min then 5-40% EtOAc:hexanes, 20 min, 24 g column) afforded 250 mg (56% yield of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: C([NH:3][C:4]([NH:16][CH2:17][CH2:18][NH2:19])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#N.[ClH:20]>>[ClH:20].[ClH:20].[ClH:20].[NH2:19][CH2:18][CH2:17][NH:16][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])=[NH:3]
Reactant: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC(=N)NCCN

Procedure:
N-Cyano-N'-(2-aminoethyl)-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (1.0 g) (see Example 10) and 1 N hydrochloric acid (20 ml) were refluxed together for 6 hours. Evaporation and recrystallisation from methanol/isopropanol gave the title compound (0.6 g), m.p. 195°-196° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:10][C:9]2[S:11][C:12](=[C:14]3[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][S:15]3)[S:13][C:8]=2[S:7]1.O1CCOCC1.C1COCC1.[NH3:33]>CCOCC>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]1[S:7][C:8]2[S:13][C:12](=[C:14]3[S:18][C:17]([C:19]([O-:21])=[O:20])=[CH:16][S:15]3)[S:11][C:9]=2[S:10]1.[NH4+:33]
Reactant: O=C(O)C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Reactant: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C([O-])C1=CSC(=C2SC3=C(SC(=C4SC=CS4)S3)S2)S1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 14 h
Yield: 92 %

Procedure:
Finely crushed 1 (140 mg, 0.330 mmol) was suspended in a mixed solvent of 1,4-dioxane (31.5 ml), THF (31.5 ml), and Et2O (7.0 ml), and the resultant mixture was irradiated with ultrasonic waves for 15 seconds. The mixture was further charged with 28% aq. NH3 (2.8 ml), and irradiated with ultrasonic waves for 15 seconds. The mixture was vigorously stirred for 14 hours at room temperature, and then left to stand for 1 hour at 5° C. The reaction mixture was then filtered using a membrane filter (H010A047A, Advantec). The filtered product was successively washed with water, THF, and Et2O, and dried under reduced pressure to obtain the target product Compound 1-NH4+ (134 mg, 92%) as a dark red solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:13])([O-:12])[CH3:11].[K+].C(OCC)(=O)C>C(O)(C)(C)C>[C:10]([O:12][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)([CH3:13])([CH3:11])[CH3:9].[C:10]([O:12][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:13])([CH3:11])[CH3:9]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1ccnc(Cl)n1
Product: CC(C)(C)Oc1nccc(Cl)n1
Yield: 50 %
Yield: 16 %

Procedure:
After dissolving 2.00 g of 2,4-dichloropyrimidine in 30 ml of tert-butanol, 1.58 g of potassium tert-butoxide was added while stirring and the mixture was stirred overnight at room temperature. The reaction mixture was poured onto ice and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate), to obtain 2-tert-butoxy-4-chloropyrimidine (0.40 g, 16% yield) and 4-tert-butoxy-2-chloropyrimidine (1.28 g, 50% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N>C(Cl)Cl.CO>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (4.68 gm, 8 mmols) in dry methylene chloride (40 ml) was cooled to -60° under nitrogen. It was charged with dimethylaniline (4.06 gm, 33.5 mmol) and phosphorus pentachloride (3.68 gm, 17.7 mmol) and stirred for 30 minutes at -64° to -56°, during which time the phosphorus pentachloride dissolved. A solution of dry methanol (8.10 ml) in dry methylene chloride (8.10 ml) was then slowly added at -55° to -45°. The reaction mixture was stirred for 20 minutes at -60° to -55° and then poured into 16 ml of ice-water. The pH was adjusted to 1.7 with concentrated ammonia and the layers were separated. The methylene chloride layer was washed with 20 ml of pH 2.0 buffer which was separated and combined with the aqueous layer. Methylene chloride (20 ml) was added to the combined aqueous layers and the mixture was adjusted to pH 6.5 with concentrated ammonia. The phases were separated, the water was washed with 20 ml of methylene chloride, and the combined methylene chloride layers were dried over molecular sieves. After filtration, the solution was concentrated in vacuo to about 20 ml and then added dropwise to 400 ml of stirring heptane. The heptane was decanted from the solid which precipitated and was replaced by 100 ml of fresh heptane. The suspension was thoroughly stirred, filtered, washed, air dried, and finally dried in vacuo. There was obtained 1.66 gm of the title product as a white amorphous solid. The purity was estimated from its nmr spectrum to be about 90%, the remainder being primarily the non-acetylated material.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11](=O)[CH2:12][C:13]([CH3:15])=O)C.C([O-])(=O)C.[NH4+:21]>O>[OH:10][C:11]1[CH:12]=[C:13]([CH3:15])[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: [NH4+]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1cc(O)nc2c1CCCC2
Yield: 4.9 %

Procedure:
98.15 G. (1.0 mole) of cyclohexanone, 130 g. (1.0 mole) of ethylacetoacetate and 77.1 g. (1.0 mole) of ammonium acetate are heated at reflux for 14 hours. The reaction mixture is cooled in ice and diluted with water. The resultant precipitate is collected by filtration, washed with ether and dried in air affording 8.0 g (5%) of 2-hydroxy-4-methyl-5,6,7,8-tetrahydroquinoline, m.p. 250°-252°C.