Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(O)(=O)=O.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][N:42]([C:44]([NH2:46])=[O:45])[NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1.N1C=CC=CC=1>C(OCC)(=O)C.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:41][C:36]2[CH:37]=[C:38]([F:40])[CH:39]=[C:34]([F:33])[CH:35]=2)[C:44]([NH2:46])=[O:45])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: NC(=O)N(N)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cc(F)cc(F)c2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 4-[4-(1Ethoxycarbonyl-1-methylethoxy)phenyl]butyric acid (1.0072 g, 3.42 mmol) in ethyl acetate (10 mL) at rt was added DMF (1 pipette drop), followed by oxalyl chloride (0.728 g, 5.73 mmol) dropwise over 5 min. The resulting solution was stirred for 30 min at rt, then concentrated to an oil. The oil was twice reconstituted into toluene (20 mL) and concentrated to an oil, then dissolved in ethyl acetate (3 mL). 1-(3,5-Difluorophenylmethyl)hydrazine carboxamide methanesulfonate (1.025 g, 3.45 mmol) was suspended in ethyl acetate (10 mL) at 0° C., and pyridine (0.65 mL, 636 mg, 8.04 mmol) was added. The solution of acid chloride in ethyl acetate was then added dropwise over 15 min, and the resulting mixture stirred for 30 min at 0° C. The mixture was then diluted with ethyl acetate and washed with 1 N HCl (2×) followed by sat'd aq. NaCl. It was then dried (MgSO4), filtered and concentrated to an oil, which was chromatographed on silica gel (ethyl acetate) to afford the title compound as a solid (1.1436 g, 70%): mp 108.1-109.4° C.; 1H NMR (DMSO-d6, 60° C.) δ 9.73 (s, 1 H), 7.00 (m, 5 H), 6.70 (d, 2 H, J=6.5 Hz), 6.03 (s, 2 H), 4.54 (br s, 2 H), 4.15 (q, 2 H, J=7 Hz), 2.45 (m, 2 H), 2.09 (m, 2 H), 1.74 (m, 2 H), 1.48 (s, 6 H), 1.17 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 162.5 (dd, J=244, 13 Hz), 159.2, 153.8, 144.1, 135.8, 129.7, 119.4, 111.3 (d, J=25 Hz), 102.8 (t, J=26 Hz), 79.2, 51.1, 47.3, 34.3, 33.1, 27.0, 25.7, 14.6; IR (KBr) 3456, 3324, 1726, 1643, 1509, 1445 cm−1; Anal. Calcd. for C24H29N3O5F2: C, 60.37; H, 6.12; N, 8.80; F, 7.96. Found: C, 60.48; H, 6.28; N, 8.67; F, 7.75.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH:19](N1CCCCC1)=[O:20].Cl>C1COCC1>[CH:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1)=[O:20]
Reactant: O=CN1CCCCC1
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(C=O)cc2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (2.0 g, 8.23 mmol) in THF (7 ml) was added n-BuLi (1.61 M solution in hexane, 5.47 ml, 8.8 mmol) at −78° C. under nitrogen, and the mixture was stirred for 2 hour, then allowed to warm up to 0° C. for 30 min. A solution of 1-formylpiperidine (930 mg, 8.23 mmol) in THF (5 ml) was added, and the mixture was stirred for 2 hours. The mixture was made neutral by addition of 1N HCl solution, and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The compound was used for next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[I-:11].[Na+]>[Cu](I)I>[I:11][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: [I-]
Agent: I[Cu]I
Agent: [Na+]
Product: N#CCc1ccc(I)cc1
Temperature: 110 °C

Procedure:
A round bottomed flask fitted with a magnetic stirrer was charged with 1.22 g of copper iodide (Sigma Aldrich), 25 g of 4-bromophenylacetonitrile (Apollo Scientific) and 38.37 g of sodium iodide (Sigma Aldrich) under argon. The round bottomed flask was evacuated and backfilled with argon three times. N,N′-Dimethylethylenediamine (1.38 mL, Sigma Aldrich) and 25 mL dioxane were added and the mixture was heated to 110° C. for 2 hours (h). The reaction was allowed to cool to room temperature (rt) and 125 mL of 30% aqueous ammonia was added. The mixture was then poured onto 500 mL water and extracted three times with dichloromethane (DCM) and the combined organics dried over MgSO4. The solvent was removed under reduced pressure to afford the title compound as brown oil that solidified on standing. Yield: 29.97 g. 1H NMR (400 MHz, CDCl3), δ 7.71 (2H, d, Ar—H), 7.08 (2H, d, Ar—H), 3.66 (2H, s, CH2).
Reaction SMILES: C(C1C=C(C#N)C(=O)NC=1[CH:10]=[CH:11][N:12]([CH3:14])[CH3:13])(=O)C.[C:18]([C:21]1[CH:22]=[C:23]([C:29]#[N:30])[C:24](=[O:28])[NH:25][C:26]=1C)(=[O:20])[CH3:19].COC(OC)N(C)C>CO>[C:18]([C:21]1[CH:22]=[C:23]([C:29]#[N:30])[C:24](=[O:28])[N:25]([CH:10]=[CH:11][N:12]([CH3:14])[CH3:13])[CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: COC(OC)N(C)C
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)n(C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D-3. 5-Acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile--A mixture containing 35.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml of methanol and 30 ml of dimethylformamide dimethyl acetal was heated with stirring on a steam bath for 4 and 1/2 hours and then allowed to cool to room temperature. The precipitated yellow solid was collected, washed with methanol and dried in an oven under reduced pressure at 95° C. to yield 16.4 g of 5-acetyl-1,2-dihyro-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, m.p. 267°-270° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1>[Li+].[OH-]>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(C)c1OCc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-(4-trifluoromethylbenzyloxy)-3-methylbenzoate (1.17 g, 3.61 mmol) is added 10 mL of 1N LiOH. The mixture is stirred at room temperature for 3 days, then concentrated under vacuum. The residue is washed with hexane, then acidified to pH 1 with 6N HCl. A white precipitate forms which is extracted with ethyl acetate. The organic solution is dried over sodium sulfate, filtered and concentrated to give the title acid as a white solid, m.p. 104-106° C.
Reaction SMILES: [C:1]([O:5][N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]#[N:12])([CH3:4])([CH3:3])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[N:13]=[N:14][NH:15][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON1CCCC1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)ON1CCCC1c1nn[nH]n1
Temperature: 95 °C
Yield: 24.4 %

Procedure:
A mixture of tert-butyloxy-2-cyanopyrrolidine (3 g, 15.3 mmol), sodium azide (1.49 g, 23.0 mmol) and ammonium chloride (1.22 g, 23 mmol) in DMF (15 ml) were heated at 95° C. for 48 hours. The reaction was then partitioned between ethyl acetate and water. The organics were separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was triturated with diethyl ether and collected by filtration to give the title compound (0.79 g, 22%) as a white solid.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:20][OH:21]>ClCCl>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:21][CH3:20])=[O:9])(=[O:4])=[O:3]
Reactant: CO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution (20 mL) of 3-(chlorosulfonyl)benzoyl chloride (2.4 g) in dichloromethane was cooled to 0° C., and pyridine (791 mg) and methanol (320 mg) were added. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was filtrated, washed with a mixed solvent of ethyl acetate and isopropyl ether, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless oil (yield 2.17 g, 92%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[S:12][N:11]=1>O.C(O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[S:12][N:11]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2F)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2F)ns1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85.8 %

Procedure:
A solution of sodium hydroxide (0.17 g, 4.2 mmol) in water (4 mL) is added to a stirred solution of ethyl 3-(2-fluorophenyl)isothiazole-5-carboxylate (0.88 g, 3.5 mmol) in ethanol. The mixture is stirred for 6 h at 50° C. The ethanol is then removed by distillation and the resulting aqueous phase is washed with diethyl ether, acidified with 2N hydrochloric acid and filtered. The filtercake is dried in vacuo to give 3-(2-fluorophenyl)isothiazole-5-carboxylic acid (0.67 g, 86%) as beige crystals, mp 191°-192° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[SH:14].[CH3:19]I.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][N:6]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]1[S:14][CH3:19]
Reactant: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1ncc(C(=O)O)n1Cc1cc(F)cc(F)c1

Procedure:
Reaction of 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by standard techniques yields 1-(3,5-diflurobenzyl)-2-methylmercaptoimidazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[Cl:8][SiH:9]([Cl:11])[Cl:10].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:6][CH:5]([CH:4]([Si:9]([Cl:11])([Cl:10])[Cl:8])[CH:2]([CH3:3])[CH3:1])[CH3:7]
Reactant: CC(C)=CC(C)C
Reactant: Cl[SiH](Cl)Cl
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC(C)C(C(C)C)[Si](Cl)(Cl)Cl
Yield: 89.3 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 55 grams (0.56 mol) of 2,4-dimethyl-3-pentene, 148 grams (1.1 mol) of trichlorosilane and 17 grams (70 mmols) of 1,1'-azobis(cyclohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 4 days. The resulting reaction mixture was purified by distillation thereby obtaining 117 grams (0.50 mol) of 2,4-dimethyl-3-trichlorosilylpentane. The structure of the resulting product was identified by 1HNMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=[CH:5]2.C([Li])CCC.[CH:26]([C:28]1[N:29]=[CH:30][N:31]([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=1)=[O:27].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Si:14]([O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:26]([C:28]1[N:29]=[CH:30][N:31]([C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:32]=1)[OH:27])[CH:11]=[CH:10]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)ccc2cc(Br)ccc12
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(O[Si](C)(C)C(C)(C)C)ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxy-1-methylnaphthalene (35.1 g) was dissolved in THF (350 mL) and the solution was cooled to −70° C. A solution (1.6 M: 82 mL) of n-butyllithium in hexane was slowly added dropwise and the mixture was stirred for 1 hr. Then, a solution (300 mL) of 4-formyl-1-trityl-1H-imidazole (30.5 g) in THF was added dropwise. After stirring at −70° C. for 30 min., the reaction was stopped by adding 20% aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crude (6-tert-butyldimethylsilyloxy-5-methyl-2-naphthyl)(1-trityl-1H-imidazol-4-yl)methanol as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(OC)C=C2OC(C)(C)CC=12)=O.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)c2c(c1)OC(C)(C)C2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)cc2c1CC(C)(C)O2
Solvent: ClCCl
Product: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To the mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (3d) (1.74 g, 7.36 mmol) in CH2Cl2 (10 mL) at 0° C. was added BBr3 (22.0 mL, 22 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at 0° C. for 6 hr, quenched with H2O (100 mL), extracted with CH2Cl2 (2×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 10% EtOAc in hexanes to give an pale yellow solid (171 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1 H) 6.99 (s, 1 H) 5.87 (s, 1H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C12H14O4 m/z 223.0 (M+H)+.
Reaction SMILES: O.[ClH:2].[C:3](N1CCOC(C2C=CC(F)=C(F)C=2)(CCN2CCC(NC(N(C)C)=O)(C3C=CC=CC=3)CC2)C1)(=[O:10])[C:4]1C=CC=CC=1.[C:45]([N:53]1[CH2:58][CH2:57][O:56][C:55]([CH2:67][CH2:68][N:69]2[CH2:74][CH2:73][C:72]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)([NH:75][C:76]([N:78]([CH3:80])[CH3:79])=[O:77])[CH2:71][CH2:70]2)([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[C:61]([F:66])[CH:60]=2)[CH2:54]1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl.C1(S(O)(=O)=O)C=CC=CC=1.C1(C2(NC(N3CCCC3)=O)CCNCC2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH2:10].[ClH:2].[C:45]([N:53]1[CH2:58][CH2:57][O:56][C:55]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[C:61]([F:66])[CH:60]=2)([CH2:67][CH2:68][N:69]2[CH2:74][CH2:73][C:72]([C:81]3[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=3)([NH:75][C:76]([N:78]3[CH2:80][CH2:4][CH2:3][CH2:79]3)=[O:77])[CH2:71][CH2:70]2)[CH2:54]1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CN(C)C(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Agent: Cl
Agent: O=C(NC1(c2ccccc2)CCNCC1)N1CCCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1)N1CCCC1
Yield: 47.3 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 45 from 1.2 g of the compound obtained in step C of EXAMPLE 37, 1.4 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine benzenesulfonate, 1.2 g of K2CO3 and 2 ml of DMF to give 0.3 g of the expected product. M.p.=163-168° C.
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36]>>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36])=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: O=C1CCCCN1
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Product: COc1ccc2c(CN3CCCCC3=O)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in the example 369d was used, starting from Methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester and Piperidin-2-one to give 5 mg of 1-[6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylmethyl]-piperidin-2-one as a yellow solid. LC-MS m/e 366 (MH+).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11]>>[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1.[CH3:11][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:9]
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=C(C)CC(C)(C)C
Product: O=C1C=CC(=O)O1

Procedure:
Type A is the ammonium salt of a copolymer of maleic acid and 2,4,4-trimethylpent-1-ene obtained by ammoniacal hydrolysis of a copolymer of maleic anhydride and 2,4,4-trimethylpent-1-ene. Latter copolymer is obtainable in accordance with Example 3 of EP-A 9169. Instead of isolating the unhydrolyzed copolymer by spray drying as in Example 3 of EP-A 9169, 325 parts of water are added to the suspension and excess diisobutene is distilled off by steam distillation (bath temperature 80° C.). When an internal temperature of 98° C. is reached, steam is passed in for a further 1 h. Following the addition of a further 200 parts of water and 170 parts of 25% strength by weight ammonia, the mixture is stirred at 60° C. until a virtually clear aqueous solution is obtained (about 1 h). The solids content is then adjusted to 22% using water. The pH of the solution is 9. The K value of the copolymer (determined in accordance with Fikentscher as a 1% strength by weight solution in dimethylformamide) is in the range of 30–40.
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.O=S(Cl)Cl.[CH3:29]O>>[CH3:29][O:12][C:10](=[O:11])[C@@H:9]1[CH2:13][C@H:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:15][NH:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](SCc2ccc(Br)cc2)C[C@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(Br)cc2)CN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g) (0.0037 mol) (Preparation 9) was added and the mixture refluxed for 18 hrs. Upon cooling to RT, 40 mL of water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g). NMR (CDCl3, 200 MHz): 10.65 (1H, COOH), 7.4 (2H, d), 7.15 (2H, d), 4.15-4.35 (1H, m), 3.65 (2H, s), 2.95-3.35 (2H, m), 2.4-2.6 (1H, m), 1.85-2.2 (1H, m), 1.3-1.5 (9H). To a solution of cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added dropwise SOCl2 (0.2 mL), and the mixture was stirred for 72 hrs at RT. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with dilute aqueous NaHCO3, water, and dried over MgSO4. The solvent was evaporated in vacuo to afford cis-4-(4-bromo-benzylthio)-L-proline methyl ester (0.6 g).
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(O)C.O.OS(O)(=O)=O>CCCCCC>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 5 °C

Procedure:
A mixture of 120 g (0.238 mol) of 5, 3.0 liters of 95% ethanol, and 350 mL of water in a 5 liter round bottom flask is cooled to 5° C. in an ice bath for 30 minutes. Concentrated H2SO4 (650 mL) is added to this mixture over a period of 10 minutes in 50 mL portions. Any large chunks of suspended material are broken up mechanically. The mixture is heated under reflux for 20-24 hours. The brownish reaction mixture is cooled to 20° C. using an ice bath and then poured into 7 Kg of ice in a 12 liter carboy. The paste-like precipitate is collected on a Buchner funnel using either polypropylene filter cloth (Aldrich) or three layers of Whatman #1 filter paper, which is occasionally scratched to facilitate filtration. The pale-yellow cake is washed three times with 1 liter of cold water and dissolved in 1 liter of hot methanol, to which 1 liter of hexane and 50 mL of hot water are added. The resulting two-phase system is heated on a steam bath until all solid material is dissolved. This mixture is allowed to cool for 2-3 hours to 20° C.; at this point crystals begin to form at the solvent interface. The mixture is then cooled overnight at -15° C. to give a brown upper hexane phase, a lower light yellow aqueous phase, and white crystalline material. The crystals (roughly 90% pure by TLC) are collected by suction filtration and recrystallized again from methanol/hexane/water (2:2:1) as described above.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1.CC(C)([O-])C.[K+].O>COCCOC.C(O)C>[O:16]1[C:17]2([CH2:22][CH2:21][CH:20]([C:10]#[N:11])[CH2:19][CH2:18]2)[O:24][CH2:14][CH2:15]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
p-Toluenesulfonylmethylisocyanide (27.0 g) was added at room temperature to a solution of 1,4-cyclohexanedione monoethyleneketal (16.6 g) in 1,2-dimethoxyethane (133 ml) and ethanol (13 ml). Then, potassium tert-butoxide was added under ice cooling over an hour, and stirred at room temperature for three hours. After completion of the reaction, water was added and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1,4-dioxaspiro[4,5]decane-8-carbonitrile (12.8 g) as a colorless oil.