Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@@H:21]([O:23][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH2:20][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)N1CCCC1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O[C@H]2C[C@@H](C(=O)N3CCCC3)N(C(=O)OCc3ccccc3)C2)cc1

Procedure:
By repeating the process of Example 2(a) above but using N-(N-benzyloxycarbonyl-trans-4-hydroxy-L-prolyl)pyrrolidine in place of N-[N-(4-phenylbutanoyl)-trans-4-hydroxy-L-prolyl]pyrrolidine and 4-methoxyphenol in place of phenol, N-[N-benzyloxycarbonyl-cis-4-(4-methoxyphenoxy)-L-prolyl]pyrrolidine (SUAM 14491) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([NH2:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:32][CH2:31][O:30][C:28]([N:15]1[C:16]([NH2:17])=[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][C:11]2=[N:14]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(N)c2C1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 94.1 g of 3-amino-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 1.7 L of THF were added 135 mL of N,N-diisopropylethylamine. A solution of 37.6 mL of ethyl chloroformate in 300 mL of THF was added dropwise at 0° C. during 75 min. The mixture was stirred at 0° C. for 30 min. then evaporated under vacuum. The residue was taken-up with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with 500 mL brine, dried over sodium sulfate, and evaporated to dryness. The crude mixture of isomers was purified by silica gel flash-chromatography, using a starting 87:13 mixture of dichloromethane-ethyl acetate as eluant, and increasing gradually the percentage of ethyl acetate up to 50%. The fractions containing the same isomer were evaporated to give 61.6 g of 3-amino-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[CH:42]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][S:45]([CH:42]4[CH2:44][CH2:43]4)(=[O:47])=[O:46])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NS(=O)(=O)C3CC3)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of compound 9D (4.0 g, 7.02 mmol) in anhydrous CH2Cl2 (100 mL) were added cyclopropanesulfonyl chloride (16D, (1.97 g, 14.03 mmol) and triethylamine (3.91 mL, 28.07 mmol), successively. The reaction mixture was stirred at rt overnight. It was concentrated to small volume and purified with silica column chromatography eluting with dichloromethane/EtOAc to give the title compound (17D) which was recrystallized from hexanes/acetone to provide compound 17D as white powder in ˜60% yield. 1H NMR (CDCl3, 500 MHz) δ 10.66 (s, 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.67 (d, 2H, J=8.0 Hz), 7.62 (s, 1H), 7.54 (d, 2H, J=8.0 Hz), 7.43 (s, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.97 (d, 1H, J=9.0 Hz), 5.82 (d, 1H, J=8.0 Hz), 5.42 (d, 1H, J=9.0 Hz), 5.20 (s, 1H), 4.67 (d, 1H, J=11.5 Hz), 3.96 (s, 3H), 3.76 (d, 1H, J=11.5 Hz), 3.61 (br s, 2H), 3.44 (dd, 1H, J=12.0, 3.0 Hz), 2.93 (m, 1H), 2.41 (m, 1H), 1.15 (s, 2H), 0.94 (d, 2H, J=5.5 Hz). LCMS (ESI) m/z 696.19 (MNa+), 674.22 (MH+), 351.10 (100). HPLC: tR=4.95 min.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15]CS([O-])(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[ClH:22].[F:23][C:24]([F:57])([F:56])[C:25]1[CH:26]=[C:27]([CH2:35][O:36][C@@H:37]2[CH2:42][CH2:41][CH2:40][N:39](CC3C=[NH+]C=CC=3)[C@@H:38]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[ClH:22].[ClH:22].[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:27]([CH2:35][O:36][C@H:37]2[CH2:42][CH2:41][CH2:40][N:39]([CH2:15][C:11]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:14]=[CH:13][N:12]=3)[C@H:38]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:26]=[C:25]([C:24]([F:57])([F:23])[F:56])[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CCS(=O)(=O)[O-])cc1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccc[nH+]c3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccnc2CN2CCC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2c2ccccc2)cc1
Temperature: 100 °C

Procedure:
((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethanesulfonate (1.6 g) was added to a suspension of the compound of Description 3 (2.47 g) and potassium carbonate (800 mg) in dimethylformamide (10 ml) and the resulting mixture was heated at 100° C. for 2 h. The mixture was cooled, diluted with water (100 ml) and extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. This afforded a colourless oil which was purified by column chromatography on silica using 25-30% ethyl acetate in hexane. This afforded the product as a white crystalline solid which was recrystallised from dichloromethane/petrol: mp 125°-126° C. 1H NMR (360 MHz, DMSO-d6) d 1.4-1.5 (1H, m, NCH2CH2CHH), 1.5-1.67 (1H, m, NCH2CH2CHH), 1.8-2.0 (1H, m, NCH2CHH), 2.06-2.1 (1H, m, NCH2CHH), 2.35 (3H, s, CH3), 2.4 (1H, mc, NCHH), 2.7-2.86 (1H, m, NCHH), 3.50 (1H, d, J=14.0 Hz, CHH-imidazole), 3.56 (1H, brs, CHO), 3.76 (1H, d, J=1.5 Hz, CHPh), 4.08 (1H, d, J=14.0 Hz, CHH-imidazole), 4.09 (1H, d, J=12.0 Hz, OCHH), 4.48 (1H, d, J=12.0 Hz, OCHH), 6.96 (1H, d, J=1.0 Hz, imidazole-H), 7.12 (2H, d, J=8.5 Hz, ArH), 7.2-7.3 (3H, m, ArH), 7.34 (1H, d, J=1.0 Hz, imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H, s, ArH), 7.71 (1H, ArH), 7.79 (2H, d, J=8.5 Hz, ArH); MS (CI+) m/z 638 (M+ +1). Found: C, 58.48; H, 4.78; N, 6.72; S, 4.81. Calcd. for C31H29F6N3O3S: C, 58.39; H, 4.58; N, 6.59; S, 5.03%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32 M stock solution, 45.0 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting reaction solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The solution was then quenched by the slow addition of the reaction mixture to a 2 N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1×150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2(M+) 252.0917, found 252.0915.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](N2C=CN=C2)=[S:20])=[N:16][CH:17]=1>>[C:1]1([C@H:7]2[CH2:9][C@H:8]2[NH:10][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=2)=[S:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@@H]1c1ccccc1
Reactant: S=C(Nc1ccc(Cl)cn1)n1ccnc1
Product: S=C(Nc1ccc(Cl)cn1)N[C@@H]1C[C@@H]1c1ccccc1

Procedure:
(-)-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 mmol) from Example 423 was condensed with 1-(5-chloropyrid-2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according to the procedure of Example 372 to yield the titled product as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)=[C:4]([CH3:19])[CH:3]=1.[CH3:20]O>[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:14][C:13]([OH:15])=[CH:12][CH:11]=[C:10]3[N:16]=[CH:20]2)=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Nc1nc(O)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Ni]
Product: Cc1cc(Br)ccc1-n1cnc2ccc(O)nc21
Temperature: 50 °C
Reaction time: 45 h

Procedure:
To a solution of 6-(4-bromo-2-methylphenylamino)-5-nitropyridin-2-ol (4.50 g, 13.9 mmol) in MeOH (30 mL) was added Raney Ni (1.00 g). The mixture was stirred vigorously under H2 atmosphere overnight at which time additional Raney nickel (500 mg) was added. After stirring for an additional 45 h under H2 atmosphere, the mixture was filtered through Celite® and concentrated. The residue was dissolved in THF (20 mL) and trimethoxymethane (25 mL) and trifluoroacetic acid (100 μL) was added. The mixture was heated at 50° C. for 12 h followed by additional heating at 80° C. for 4 h. After cooling to room temperature, the solution was concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (442 mg). LCMS m/z=304.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.07 (s, 3H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.48 (dd, J1=8.3, J2=1.9 Hz, 1H), 7.55 (s, 1H), 7.82 (s, 1H), 8.04 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CO>[CH2:1]([N:8]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnc3c2c(C)nn3C)cc1
Temperature: 70 °C

Procedure:
A mixture of 0.48 g (0.97 mmol) of ethyl 4-[benzyl-(4-methoxybenzenesulfonyl) amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.29 ml of ION NaOH in 4 ml of tetrahydrofuran-methanol (1:1) was heated in an oil bath at 70° C. for 2 hours and the solvent removed under vacuum. The residue was dissolved in 20 ml of H2O and the solution extracted with 10 ml of diethyl ether. To the aqucous layer was added 2N citric acid (pH 4-5) and the precipitated solid filtered and washed with H2O to give a white solid which was dried under vacuum overnight to give crystals, mp 165-167° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.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[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: COc1cccc(F)c1B(O)O
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: O
Solvent: CC#N
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carb-aldehyde (1.07 g, 5.21 mmol), 2-fluoro-6-methoxyphenylboronic acid (0.9738 g, 5.73 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.3011 g, 5% mmol), and sodium carbonate (2.76 g, 26.1 mol, 5 eq) in MeCN (37.5 mL) and water (12.5 mL). After purification, 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde was obtained as white solid. 1H NMR (DMSO-d6) δ ppm 9.88 (1 H, s), 8.95 (1 H, s), 8.10 (1 H, d, J=8.1 Hz), 7.82 (1 H, d, J=7.1 Hz), 7.62-7.69 (1 H, m), 7.49-7.59 (1 H, m), 6.96-7.10 (2 H, m), 3.71 (3 H, s), 2.70 (3 H, s). Mass Spectrum (ESI) m/e=296.0 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: NCc1cccc(-c2ccc(Cl)cc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of (4′-chlorobiphenyl-3-yl)methanamine HCl salt (Chem-Impex International, Inc., 0.6 g, 2.36 mmol) in CH2Cl2 (6 mL) and 2-propanol (6.00 mL) was added 4-fluorobenzaldehyde (0.28 mL, 2.60 mmol). The resulting reaction mixture was stirred at rt for 1 h. and sodium triacetoxyborohydride (0.75 g, 3.54 mmol) was added under N2. After stirring at rt for 3 h, the reaction mixture was quenched with saturated aqueous NaHCO3, stirred for 10 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the filtrate solution was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with 0-10% ethyl acetate in CH2Cl2 to afford the desired compound (0.63 g, 73%) as a colorless oil. 1H NMR (CDCl3) δ 7.62-7.41 (m, 6H), 7.37-7.32 (m, 3H), 7.09-7.01 (m, 3H), 3.92 (s, 2H), 3.83 (s, 2H). MS (ESI): 326.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]/[CH:10]=[CH:11]\[CH:12]([OH:14])[CH3:13])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:14][CH:12]([CH3:13])/[CH:11]=[CH:10]\[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(S/C=C\C(C)O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S/C=C\C(C)OC(C)=O)cc1

Procedure:
1 g (4.76 mmol) of rac-(Z)-4-[(p-methoxyphenyl)thio]-3-buten-2-ol are dissolved in 50 ml of methylene chloride. whereupon the solution is treated with 0.77 ml (9.5 mmol) of pyridine and cooled to 0° . There is added dropwise thereto a solution of 0.5 ml (7.1 mmol) of acetyl chloride in 10 ml of methylene chloride and the mixture is stirred at 0° for 1 hour. The reaction mixture is washed successively with 50 ml of 1N hydrochloric acid, 50 ml of 5 percent sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (9:1) there is obtained pure rac-4-[[(Z)-3-acetoxy-1-butenyl]thio]anisole; IR: 1735 cm-1.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][O:17][CH3:18])=[C:10]([CH3:19])[CH:9]=1)(=O)C(C)(C)C.[OH-].[K+]>CO>[CH3:18][O:17][CH2:16][O:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([OH:7])=[CH:9][C:10]=1[CH3:19]
Reactant: COCOc1c(C)cc(OC(=O)C(C)(C)C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1c(C)cc(O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
8.09 g of crude 4-methoxymethoxy-3,5-dimethylphenyl pivaloate were dissolved in 30 ml of methanol. To the resulting solution, 30 ml of a solution of 3.40 g of potassium hydroxide in methanol were added dropwise, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated by evaporation. Water was added to the residue. The mixture was neutralized with 3N hydrochloric acid and sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=4/1), whereby 5.58 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([N+:12]([O-])=O)[C:5]=1Cl.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(N)c(C)c(F)c1
Temperature: 75 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester (Preparation 1d, 53 g), 5% Pd/C (9 g) and ammonium formate (80 g) were stirred together in ethanol (500 mL) at 75° C. for 32 h. The reaction was filtered through celite and filtrate evaporated to a solid. This solid residue was dissolved in dichloromethane, washed with water. The separated aqueous layer was further extracted with dichloromethane (3×100 mL) and the combined organics dried (MgSO4) and evaporated. Analysis showed significant unreacted starting material. The reaction was repeated by new 5% P/C (9 g) and ammonium formate (80 g) together in ethanol (500 mL) and heating at 75° C. for 20 h. Further 5% Pd/C (9 g) and ammonium formate (80 g) were added and heating continued for 10 h. The mixture was filtered through celite and the filter cake was washed with further ethanol. The combined filtrates were evaporated, the residue dissolved in dichloromethane, washed with water. The separated aqueous layer was further extracted with dichloromethane (3×100 mL) and the combined organics dried (MgSO4) and evaporated to afford the subtitle compound (34.7 g).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[C:25]([O:24][CH2:23][CH:12]1[NH:11][C:15](=[O:16])[C:14]([CH3:21])([CH3:20])[C:13]1=[O:22])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)C(=O)C(COC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OCC1NC(=O)C(C)(C)C1=O
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-5-tert-butoxy-2,2-dimethyl-3-oxopentanoate (8.7 g) in methanol (100 mL) was added 10% palladium carbon (containing 50% water, 4.0 g), and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as colorless crystals (yield: 3.81 g, 81%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[N:12]1[CH2:16][CH:15]([CH3:17])[CH2:14][C:13]1=[O:18])=[O:5])C.[OH-].[Li+].Cl>C1COCC1>[CH3:17][CH:15]1[CH2:16][N:12]([C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@H:6]2[C:4]([OH:5])=[O:3])[C:13](=[O:18])[CH2:14]1
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1N1CC(C)CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CC(=O)N([C@@H]2CCCC[C@H]2C(=O)O)C1
Temperature: 25 °C

Procedure:
trans-2-(4-Methyl-2-oxo-pyrrolidin-1-yl)-cyclohexanecarboxylic acid ethyl ester (395 mg) was dissolved in absolute THF (15 ml) and 1 N lithium hydroxide solution (5.12 ml) was added. The resulting mixture was refluxed over night. The reaction mixture was cooled to room temperature and then HCl conc. (1.80 ml) was added (pH=2). The mixture was evaporated and then diluted with toluene and evaporated to remove the water. The residue was purified by flash chromatography (AcOEt/MeOH 85/15) to give the product as a 1:1 mixture of epimers as light yellow foam (435 mg). MS (ESI): 224.3 (M+H+−).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1)#[N:2].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])(=[O:16])=[O:15]>N1C=CC=CC=1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:25])=[O:24])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#N)c2c1
Yield: 11.5 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 0.55 g of 3-cyano-5-amino-1H-indazole, 10 ml of pyridine and 0.88 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.15 g of N-(3-cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a yellow powder melting at 272° C. (analysis C15H12N4O4S2.0.85H2O, % calculated C, 47.87; H, 3.21; N, 14.88; S, 17.04. % found C, 47.88; H, 3.01; N, 14.75; S, 17.45).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26]Br)=[CH:23][CH:22]=1>ClCCl>[C:1]1([CH:7]2[N:12]([CH2:26][C:25]([C:24]3[CH:29]=[CH:30][C:21]([Cl:20])=[CH:22][CH:23]=3)=[O:28])[CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCNC1c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CN1CCNC(=O)C1c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A stirred mixture of 58.0 g (0.33 mol) of 3-phenyl-2-piperazinone, 85 g (0.62 mol) of blended potassium carbonate, and 76.9 g (0.33 mol) of 4-chlorophenacyl bromide in 400 ml of dichloromethane was heated at reflux for 12 hours. The mixture was cooled to ambient temperature, filtered, and the solid washed thoroughly with dichloromethane. The filtrate was concentrated to dryness, isopropanol added and stirred, the solid collected by filtration, washed thoroughly with isopropanol and dried in a vacuum oven at 50° C. to give 92.5 g (85 %) of 3-phenyl-4-(4-chlorophenacyl)-2-piperazinone. This material was used in Example 2 of the process. Pure material could be obtained by recrystallization from methanol to give a white solid (mp. 157°-158° C. dec.).