Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[H-].[Na+].[H][H].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1COCC1>[C:7]([O:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:17]([OH:18])[CH2:16][Cl:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)=C(O)CCl
Reaction time: 4 h

Procedure:
A solution of t-butyl cyanoacetate Compound 1a (32.2 g, 228 mmol, 1.14 M) in THF was added dropwise to a suspension of 60% NaH (9.13 g, 228 mmol) in THF (200 mL) under nitrogen at 0° C. The mixture was stirred until hydrogen gas evolution ceased and the solution became homogeneous. A solution of chloroacetyl chloride Compound 1b (18.5 mL, 228 mmol) in THF (100 mL) was added at a rate sufficiently slow enough to maintain the temperature below 10° C. After stirring for 4 hr, the reaction was quenched at 0° C. with water (25 mL). The resulting precipitate was filtered through Celite 545. The organic solution was then evaporated down to give a residue that was partitioned between ether and 1 M NaOH. The aqueous layer was washed with ether (3×) and adjusted to pH 5 with NaH2PO4. The aqueous layer was extracted with EtOAc, then dried over MgSO4 and evaporated to yield 4-chloro-2-cyano-3-hydroxy-but-2-enoic acid tert-butyl ester Compound 1c (26.3 g) as a light brown foam. 1H NMR (CDCl3) δ 4.34 (br s, 2H), 1.47 (s, 9H). MS 216 (M−).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:23]=1)([CH3:29])[CH3:28]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and 1-Methyl-piperazine following General Procedure C.
Reaction SMILES: [C:1]1([OH:14])[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H][H]>[Pd].C(O)C>[C:1]1([OH:14])[N:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Oc1nnc2ccc3ccccc3n12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1nnc2n1-c1ccccc1CC2
Reaction time: 6 h

Procedure:
s-Triazolo(4,3-a)quinolin-1-ol (2.0 grams) was mixed with 125 milliliters of ethanol, and 1.0 gram of 5 percent palladium on carbon was added. The resulting mixture was hydrogenated at 50 psi hydrogen pressure and a temperature of 50°C., for 6 hours. The mixture was then filtered to remove catalyst, and the filtrate was evaporated to yield the desired 4,5-dihydro-s-triazolo(4,3-a)quinolin-1-ol product, m.p., 181°-2.5°C. Its identity was confirmed by NMR and by microanalysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[F:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)[N:17]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:15][C:16]1[C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=2)=[CH:20][CH:19]=[C:18]([C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)[N:17]=1
Reactant: CCCCCCCc1ccc(Br)cc1
Reactant: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCCc1ccc(-c2ccc(-c3ccc(CCCCCCC)cc3)c(F)n2)cc1
Yield: 39.1 %

Procedure:
A solution of 48 mmol of 1-bromo-4-heptylbenzene in 155 ml of toluene is admixed with 48 mmol of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid, 77 ml of ethanol, a solution of 96 mmol of sodium carbonate in 77 ml of water and 0.5 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 7 h. After cooling, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. The solvents are then removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane as eluent and recrystallization from acetone, giving 8.9 g (39%) of 2-fluoro-3-(4-heptylphenyl)-6-(4-nonylphenyl)pyridine; X 42 S3 56 SC 136.1 S2 136.7 N 137 I.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:33])[CH2:12][CH2:13][N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17])[CH2:7][CH2:6]1.Cl.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].B(F)([O-])[O-].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:35]([O:42][NH:43][C:16](=[O:17])[CH:15]([N:14]([CH2:13][CH2:12][C:11]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][OH:2])[CH2:6][CH2:7]1)=[O:33])[S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH:19]([CH3:20])[CH3:21])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)O)C(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: [O-]B([O-])F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NOCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid hydrochloride (1.10 grams, 2.17 mmol) in methylene chloride (50 mL) and N,N-dimethylformamide (0.5 mL) were added sequentially O-benzylhydroxylamine hydrochloride (0.41 grams, 2.60 mmol), triethylamine (0.91 mL, 6.5 mmol) and (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluoroborate (1.20 grams, 2.71 mmol). The resulting mixture was stirred for 16 hours at room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulfate and concentrated to yield an oil which was chromatographed on silica gel eluting with 3% methanol in chloroform to afford N-benzyloxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide as a clear oil (0.85 grams, 68%). Conversion to the hydrochloride salt was subsequently carried out using anhydrous hydrochloric acid in cold (0° C.) methylene chloride.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[O:14]1[CH2:18][C:17](=O)[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]1=2.Cl>O1CCCC1>[C:12]([CH2:11][C:17]1[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH:18]=1)#[N:13]
Reactant: O=C1COc2ccccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2ccccc12
Temperature: 70 °C
Yield: 98 %

Procedure:
To a suspension of 2.64 gms (0.11 mole) of oil free sodium hydride in 200 ml of tetrahydrofuran (THF) was added dropwise a solution of 19.47 gms (0.11 mole) of diethylcyanomethylphosphonate in 75 mL of THF. After the H2 evolution had ceased, a solution of 13.4 g (0.1 mole) of 3-(2H)-benzo[b]furanone in 100 mL of THF was added. The solution was heated at 70° C. for 1.5 hours, cooled, and poured into 500 mL of 5% HCl, and washed with ether. The ether phase was washed with brine, dried (MgSO4), filtered and concentrated to give 15.4 g of a dark oil. The product was distilled at 96°-100° C./0.075 mm Hg to give 10.85 g of a yellow oil which crystallized upon standing.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:5]1)=[N+:2]=[N-:3].C(O[Na])(C)=O.[Br:23]Br>C(O)(=O)C>[N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:23])[CH:11]=2)[N:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2ccccc21
Reactant: BrBr
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of azide 12 (120 mg, 0.52 mmol) in acetic acid (2 ml) were successively added anhydrous AcONa (212 mg, 1.9 mmol) and Br2 (0.3 mL, 0.52 mmol). The mixture was stirred at 25° C. for 1 h and then quenched with water (30 mL). The resulting solution was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified over column chromatography with petroleum ether/EtOAc (9:1 v/v) to give bromo azide 13 (153 mg) as thick liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=1.CCN(CC)CC.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=2)[CH2:31][CH2:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Br)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-6-(tributylstannyl)pyridine (2.0 g, 4.47 mmol) in Et3N (3.12 mL, 22.37 mmol) and was added 1-methyl piperazine (2 ml, 17.89 mmol). The reaction was heated at 100° C. for 24 h then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layer were washed with brine, dried and concentrated. The residue was purified with silica gel chromatography to give 1-methyl-4-(6-(tributylstannyl)pyridin-2-yl)piperazine (1.4 g, 70.3%). MS (ESI, pos. ion) m/z: 466.2 (M+1); 1H-NMR (CDCl3, 300 MHz) δ 7.3 (1H, t), 6.8 (1H, d), 6.5 (1H, d), 3.6 (4H, t), 2.5 (4H, t), 2.4 (3H, s), 1.5-1.7 (6H, m), 1.2-1.5 (6H, m), 1.0-1.2 (6H, q), 0.8-0.9 (9H, q).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Solvent: Cc1ccccc1C
Product: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Temperature: 25 °C

Procedure:
513 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol, 1.8 l of xylene, 19 g of p-toluenesulfonic acid and 50 ml of ethylene glycol were boiled for 4 hours in a water separator. The reaction solution was cooled to room temperature and washed with 2×200 ml of water. The organic extracts were dried using sodium sulfate, filtered and evaporated to a residue, giving 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1c(=O)oc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.77 g, 0.0138 mol) is added in small portions to a mixture of 4-fluoro-3-methyl-6-nitro-1,3-benzoxazol-2(3H)-one (Step 6, 0.73 g, 3.44 mmol) and ammonium chloride (1.84 g, 3.44 mmol) in ethanol (30 ml) and water (15 ml) at 95° C. The reaction mixture is stirred vigorously and heated for 1 h, cooled to room temperature, and diluted with dichloromethane (150 ml). The mixture is filtered, washed with water and saline, dried (MgSO4) and evaporated to give product as a tan solid suitable for use in the next step (0.64 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (361 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionic acid tert.-butyl ester (Example K12) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (367 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.ClC[CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:5][N:4]=[N:3]1
Reactant: ClCCCSc1ccccn1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCSc1ccccn1
Yield: 57.3 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 2-(3-chloropropyl)thiopyridine (2.0 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol and the product is recrystallized from ethanol to obtain 1-methyl-5-[2-(2-pyridyl)thioethyl]thio-1,2,3,4-tetrazole (1.5 g) as colorless prisms, m.p. 77°-79.5° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:26])[C@@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:17])[C@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[C@@H:5]([CH3:26])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a stirred solution of tert-butyl [(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate (0.56 g, 1.4 mmol) in pyridine (7.3 mL) at 0° C., methanesulfonyl chloride (0.14 mL, 1.9 mmol) was added followed by DMAP (0.04 g, 0.3 mmol). After stirring at 0° C. for 1 h, the mixture was diluted with EtOAc, washed with a saturated aq. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-25% EtOAc in hexanes) to provide the sub-title compound (0.59 g, 88%). LCMS calc. for C13H31N4O4SSi (M+H-Boc)+: m/z=367.2. found 367.2.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br.O[CH2:7][CH2:8][NH:9][C:10](=[O:35])[C@@H:11]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>C(O)(=O)C>[C:1]([O:4][CH2:7][CH2:8][NH:9][C:10](=[O:35])[C@@H:11]([NH2:24])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
A 30% hydrogen bromide acetic acid solution (13.1 mL, 65.9 mmol) was added to an acetic acid (4.4 mL) solution of benzyl (1S)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethylcarbamate (9.36 g, 22.0 mmol) prepared in Reference Example 6 (6b) under ice-cooling with stirring. The mixture was stirred at room temperature for 4 hours, and then ice water (300 mL) was added thereto. The reaction solution was washed with diethyl ether (50 mL, three times), and subsequently the water layer was neutralized with sodium bicarbonate (about 40 g) and extracted with methylene chloride (300 mL, three times). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give 5.89 g of the title compound (yellow solid, yield: 80%).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[C:4]([OH:9])(=[O:8])[CH:5]([CH3:7])[OH:6].[Cl-].[Na+].[OH2:12]>>[C:4]([OH:9])(=[O:8])[CH2:7][C:5]([CH2:7][C:5]([OH:6])=[O:12])([C:4]([OH:9])=[O:8])[OH:6]
Reactant: O
Reactant: CC(O)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
The colouring agent and the flavouring agent were the same as in Example I. The mixture was treated in the same manner but the brine solution was now containing only 80 g of common salt besides 8 g of calcium chloride and having a pH-value which was adjusted at 5.0 by means of lactic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[C:13]([F:34])[CH:12]=2)=[O:9])[C:4](=[O:35])[N:3]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH2:42][CH2:43][CH:44]([OH:46])[CH3:45].[CH3:47]N1C(=O)CCC1>>[F:34][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:5]2[C:4](=[O:35])[N:3]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])[CH:33]=[CH:32][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([N:42]([CH2:43][CH:44]([OH:46])[CH3:45])[CH3:47])=[O:31])[CH:17]=1
Reactant: CN1CCCC1=O
Reactant: CC(O)CN
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N(C)CC(C)O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 60 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and 1-aminopropan-2-ol (16 mg, 0.2 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (20 mL). The precipate was collected by filtration to give the title compound as a white solid (58 mg, 60%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[NH2:9][OH:10]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=[N:9][OH:10])[NH2:8]
Reactant: N#CCc1cccs1
Reactant: NO
Product: NC(Cc1cccs1)=NO
Reaction time: 8 h

Procedure:
290 g. (2.35 moles) of 2-thienylacetonitrile is treated with the equivalent amount of alcoholic hydroxylamine solution and stirred overnight to obtain 2-thienylacetamidoxime. By concentrating, treating the residue with anhydrous chloroform, filtering and again concentrating, the crude amidoxime is obtained in the form of a syrup. The syrupy residue is dissolved in 1000 ml. of anhydrous dioxane and the cooled solution is treated dropwise first with 854 g. of trichloroacetyl chloride then with 380 ml. of pyridine. The mixture is then stirred overnight at room temperature. The dioxane is distilled off in a rotary evaporator and the residue is added to a liter of water. The oily substance which separates is treated with ether. The ether solution is repeatedly washed with water, neutralized with saturated sodium bicarbonate solution, washed several times with water and dried with magnesium sulfate. After concentrating, the residue is treated with 750 ml. of toluene and refluxed in a reflux condensor for about 2 hours. A small amount of water is removed. The toluene solution is treated with activated carbon, filtered, concentrated and the residue is distilled under vacuum. 258 g. of 3-(2-thienylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole are obtained, b.p. 0.01 119°-122°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:20]>CO>[Cl-:20].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([NH3+:13])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(C)(C)C)cc1
Reactant: Cl
Solvent: CO
Product: C[C@H]([NH3+])c1ccc(C(C)(C)C)cc1
Product: [Cl-]

Procedure:
To a solution of (R)—N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (977 mg) in MeOH (1.75 mL) was added conc. HCl (1.75 mL). The reaction was aged at room temperature monitoring disappearance of starting material by analytical reverse-phase HPLC. When the starting material was consumed, the reaction was concentrated in vacuo. The crude residue was resuspended in MeOH (1 mL) and crashed out of solution by the addition of Et2O. Filtration afforded the title compound as a colorless solid (559 mg). ESI-MS (m/z): 161 [M+H—NH3]+, 338 [2M+H—NH3]+