Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][N:28]=[C:27]1[CH3:35].C(N(CC)CC)C>>[CH3:25][N:26]1[C:30]([S:31]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:33])=[O:32])=[CH:29][N:28]=[C:27]1[CH3:35]
Reactant: Cc1ncc(S(=O)(=O)Cl)n1C
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1ncc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)n1C

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (72 mg, 0.22 mmol), 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (64.2 mg, 0.33 mmol) and triethylamine (0.13 mL, 0.66 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (48.3 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][OH:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(CO)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(CO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)methanol. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.29 (m, 2H), 8.11-8.07 (m, 1H), 7.98 (m, 1H), 7.74-7.67 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.41 (m, 1H), 7.36-7.29 (m, 2H), 3.40-3.32 (m, 4H), 2.46-2.36 (m, 2H), 1.59 (d, J=10.5, 2H), 1.48-1.36 (m, 1H), 1.01-0.89 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1.C(S)C>C(Cl)Cl>[OH:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2CN(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)CC1Cc2ccc(O)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.5 %

Procedure:
Anhydrous aluminum chloride (1.35 g, 10.15 mmole) was added all at once to a solution of methyl (±)-8-methoxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (562 mg, 2.03 mmole) and ethanethiol (0.75 mL, 10.15 mmole) in anhydrous CH2Cl2 (20 mL) at 0° C. under argon. The mixture was warmed to RT and stirred for 4.5 hr, then was recooled to 0° C. Ice cold H2O (20 mL) was added, and the mixture was stirred briskly for 5 min, then was extracted with CHCl3 (3×20 mL). The combined CHCl3 layers were dried (MgSO4) and concentrated to leave a residue. The aqueous layer was suction filtered to collect a solid precipitate. This precipitate and the residue from the CHCl3 layer were combined in 1:1 MeOH/CHCl3, and the solution was concentrated to leave an off-white solid. This was triturated with hot MeOH, and the mixture was allowed to cool to RT. The solid was collected by suction filtration and washed sequentially with cold MeOH and Et2O. Drying in high vacuum at 40° C. gave the title compound (467.9 mg, 88%) as a colorless solid: TLC (5% MeOH/CHCl3) Rf 0.17; 1H NMR (250, DMSO-d6) δ 9.29(s, 1 H), 6.89 (d, J=8.1 Hz, 1 H), 6.50-6.70 (m, 2 H), 5.16 (d, J=16.4 Hz, 1 H), 3.84 (d, J=16.4 Hz, 1 H), 3.60-3.85 (m, 1 H), 3.56 (s, 3 H), 2.30-3.00 (m, 4 H), 2.86 (s, 3 H); MS (ES) m/e 286 (M+Na)+, 264 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH2:24]CNC[CH:28]=2)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH2:24][CH2:3][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:1][CH:28]=2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(/C=C/C2=CCNCC2)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: Fc1ccc(/C=C/C2=CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 40 %

Procedure:
A mixture of 3-dimethylaminomethyl- 1H-pyrrolo[2,3-b]pyridine (1.57 g, 9 mmol) and (E)-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (2 g, 9 mmol) in toluene (50 ml) was refluxed overnight. The hot solution was filtered, and the product crystallised from toluene to give (E)-3-[4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridin-1-yl]methylpyrrolo[2,3-b]pyridine (1.2 g, 40%). M.p. 211°-213° C. (isopropanol). (Found: C, 75.05; H, 5.99; N,12.27; C21H20 FN3, 0.15H2O requires C, 75.04; H, 6.09; N, 12.50%); δH (DMSO-d6) 2.29 (2H, br s, tetrahydropyridinyl CH2), 2.61 (2H, t, J 5.6 Hz tetrahydropryridinyl CH2), 3.06 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, NCH2Ar), 5.87 (1H, br s, tetrahydropyridinyl 5-CH), 6.45 (1H, d, J 16.3 Hz, ArCHCHC), 6.83 (1H, d, J 16.3 Hz, ArCHCHC), 7.01-7.04 (1H, m, ArH), 7.14 (2H, t, J 8.9 Hz, ArH), 7.38 (1H, s, ArH), 7.47-7.51 (2H, m, ArH), 8.02 (1H, d, J 7.9 Hz, ArH), 8.18-8.20 (1H, m, ArH) and 11.45 (1H, br s, NH); m/z (CI+, NH3), 334 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=O)[CH3:18])=[O:14])=[CH:9][CH:8]=1)=[O:5].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:17]([CH3:18])=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(=O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(NC(=O)c3ccccc3Cl)cc2)nc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
a solution of 2-chloro-N-(4-(((2-oxo-1-phenylpropyl)amino)carbonyl)phenyl)benzamide (90 mg, 221 μmol) and phosphoryl trichloride (1.5 mL, 16093 μmol) in 2 mL pyridine was heated in a 70° C. oil bath. After 2 hours the reaction was poured into 10 mL saturated aqueous sodium bicarbonate solution and stirred vigorously for 30 minutes. The aqueous mixture was extracted with 25 mL ethyl acetate. The organic extract was washed with 10 mL each water then brine. The organic layer was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow-green oil. TLC indicated a very complex mixture of products. The crude product was purified by reversed-phase preparative HPLC to afford a colorless film (4 mg, 5%). ESI+ m/z=389.0 [MH]+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[C:17]([S:22][CH:23]([CH3:25])[CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([F:26])[CH:8]=1)C.[OH-].[Li+]>C1COCC1.CO.O>[F:26][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])[CH:12]=[C:11]([F:13])[C:10]=1[O:14][CH2:15][C:16]1[C:17]([S:22][CH:23]([CH3:25])[CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SC(C)C)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Sc1ncccc1COc1c(F)cc(CCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
After 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)phenyl]-propionic acid ethyl ester (66 mg, 0.167 mmol) obtained in Step A was dissolved in THF/MeOH/water (2:2:1, 5 mL), lithium hydroxide (12 mg, 0.50 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was added with diethyl ether, stirred, and then extracted. The aqueous layer was added with 1N HCl to adjust pH to 2˜3, and then extracted with EtOAc. The organic layer was dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (56 mg, 91%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.CO.BrBr.[NH2:13][C:14]([NH2:16])=[S:15]>O>[NH2:16][C:14]1[S:15][C:2]2[CH2:3][C:4](=[O:7])[CH2:5][CH2:6][C:1]=2[N:13]=1
Reactant: O=C1CCC(=O)CC1
Reactant: NC(N)=S
Agent: BrBr
Solvent: CO
Solvent: O
Product: Nc1nc2c(s1)CC(=O)CC2

Procedure:
8.8 g of 1,4-cyclohexanedione was dissolved with 40 mL of methanol. Solution was cooled to 10C and 4.2 mL of bromine was dropwise added at this temperature during 15 minutes. The temperature was kept at 10C for one hour and then allowed to rise to 20C. When bromine colour faded, 7.2 g of thiourea was added. The reaction mixture was then diluted with 20 mL of water and heated under reflux for 2 h. White precipitate was removed by filtration and filtrate was concentrated in vacuo and cooled. The crystals of product (6) were filtered off and washed with a cold water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Product: N#CCCOc1ccc(F)cc1
Yield: 70 %

Procedure:
A mixture of 11.2 g of 4-fluorophenol, 10.6 g of acrylonitrile and 2.02 g of triethylamine was refluxed for 16 hours with stirring and then acrylonitrile, triethylamine and 4-fluorophenol were removed under reduced pressure. The obtained residue was diluted with ether, washed successively with 10% aqueous solution of sodium hydroxide and 2N hydrochloric acid and dehydrated with anhydrous magnesium sulfate. Ether was distilled away to give 11.51 g of colorless liquid of 3-(4-fluorophenoxy)propionitrile (yield: 70%).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[NH:6][N:5]=[N:4]1)[CH3:2].[Br:9][CH2:10][CH2:11]Br.C1C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].O>[Br:9][CH2:10][CH2:11][O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[N:5][N:6]=1
Reactant: CCn1nn[nH]c1=O
Reactant: BrCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CCn1nnnc1OCCBr
Yield: 40 %

Procedure:
A mixture of 57 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5one, 69 parts of 1,2-dibromoethane, 564 parts of silver carbonate and 900 parts of benzene was stirred and refluxed over weekend using a water separator (in the darkness). The whole was filtered off over Hyflo while hot, washed with trichloromethane and the filtrate was evaporated to dry. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The second fraction was collected and the eluent was evaporated, yielding 22.3 parts (40%) of 5-(2-bromoethoxy)-1-ethyl-1H-tetrazole (200).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:10]([CH3:9])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(O)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(O)c1
Temperature: 10 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
2 g (18.33 mmol) of 3-aminophenol were dissolved in 6 ml of pyridine with magnetic stirring, the mixture was cooled to 10° C. and then 1.8 ml (23.26 mmol) of methanesulfonyl chloride were added. The cold bath was withdrawn and the mixture was stirred at r.t. for 18 h before being diluted with 100 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 100 ml of ethyl acetate. The organic phase was washed with 50 ml of a saturated NaHCO3 aqueous solution, extracted with 50 ml of an aqueous solution of NaOH (0.5 N). The basic aqueous phase was washed with 2×100 ml of ethyl acetate and then acidified down to pH 2-3 by adding a 1N HCl aqueous solution. The acidified aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 3.3 g (yield=80%) of N-(3-hydroxyphenyl)methanesulfonamide were obtained as an oil. LC-MS: m/z=186 (M-H+); UV purity at 254 nm=81%.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:5]=1[O:6]/[CH:7]=[CH:8]/[C:9]([O:11]CC)=[O:10])([CH3:3])[CH3:2].[OH-].[K+]>O.C(O)C>[CH:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:5]=1[O:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/Oc1c(C(C)C)cccc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1O/C=C/C(=O)O
Yield: 66.4 %

Procedure:
Ethyl (E)-3-(2,6-diisopropylphenoxy)acrylate (250 mg, 0.91 mmol) was combined with 0.5 g of solid KOH in 10 mL of a mixture of water/ethanol (20:80), and the mixture was refluxed overnight. The solvent was removed under reduced pressure. The residue was acidified with 5% HCl solution and then extracted with three 25 mL portions of ethyl acetate. The ethyl acetate solution was extracted with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 150 mg (60%) of (E)-3-(2,6-diisopropylphenoxy)acrylic acid 30b. 1H NMR (400 MHz, CDCl3) 1.17-1.19 (d, 12H), 2.98-3.05 (m, 2H), 5.05-5.08 (d, 1H, J=12.4 Hz), 7.14-7.22 (m, 3H), 7.81-7.85 (d, 1H, J=12.4 Hz). MS (ESI): 271 [M+Na].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH:26]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2[CH:33]=O)[CH2:28][CH2:27]1.[O-]CC.[Na+]>C(O)C>[CH2:27]1[CH2:28][CH:26]1[CH2:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1/[CH:33]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC1CC1
Yield: 42.3 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-Cyclopropylmethoxy-3-methoxybenzaldehyde (200 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 160 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.28-0.30 (m, 2H), 0.51-0.53 (m, 2H), 0.90-1.01 (m, 1H), 3.69 (d, J=7.5 Hz, 2H), 3.77 (s, 3H), 6.92 (d, J=15.6 Hz, 2H), 6.98-7.00 (m, 2H), 7.56-7.64 (m, 4H), 7.84-7.86 (m, 2H), 8.06-8.08 (m, 1H), 8.22 (d, J=15.6 Hz, 1H), 8.84-8.86 (m, 1H); ESI-MS (m/z) 549.36 (M+H)+.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:47]=[CH:46][C:31]([C:32]([NH:34][CH2:35][C@H:36]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:37](O)=[O:38])=[O:33])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].[Si](ON)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:47]=[CH:46][C:31]([C:32]([NH:34][CH2:35][C@@H:36]([C:37](=[O:38])[NH:2][OH:1])[N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:33])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCCCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)NO)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
270 mg (2.0 mmol) of 1-hydroxybenzotriazole and 390 mg (2.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride are added successively to a solution of 580 mg (1.7 mmol) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-piperidin-1-ylpropanoic acid in 15 ml of dimethylformamide. The reaction medium is stirred for 30 min at ambient temperature then 300 mg (2.0 mmol) of O-tert-butyldimethylsilylhydroxylamine in 5 ml of dimethylformamide are added. After stirring at ambient temperature for 18 h then hydrolysis with 2 ml of an aqueous solution of 5% citric acid, the reaction medium is stirred at ambient temperature for a further 30 min, then extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The residue obtained is purified by chromatography over silica gel eluted with a 98/2 dichloromethane/methanol mixture. 80 mg (13%) of 4-but-2-ynyloxy-N—((S)-2-hydroxycarbamoyl-2-piperidin-1-ylethyl)benzamide are obtained in the form of a white solid having a melting point of 144° C.
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].FC(F)(F)S(O[C:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH3:30])(=O)=O.C(OCC)C>CC(N(C)C)=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>[CH3:30][C:23]1[CH2:24][CH2:25][CH2:26][C:27]([CH3:29])([CH3:28])[C:22]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCCCCC[Zn]Br
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)C(C)(C)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCCCCCCC1=C(C)CCCC1(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To freshly prepared ethyl 9-(bromozincio)nonanoate (37.7 mmol) in dimethylacetamide under nitrogen in a reaction tube was added 2,6,6-trimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (10.8 g, 39.6 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (872 mg, 0.754 mmol). The tube was sealed and the mixture was stirred at 95° C. for 2 h. The reaction mixture was allowed to cool and was then poured into diethyl ether (100 mL). The upper layer was decanted and the lower layer was washed twice with diethyl ether (2×25 mL). The combined ether layers were washed with sat NH4Cl and brine, dried (MgSO4) and concentrated to give crude material (˜12 g). The material was purified by flash chromatography (silica, 0 to 1.5% EtOAc in hexane). The obtained oil was stirred under vacuum for 8 h in order to remove most of the side-product, ethyl nonanoate, and was then purified by a second flash chromatography (silica, 0 to 15% toluene in hexane). The fractions were analyzed by LCMS and GCMS. The purest fractions were collected and concentrated at a temperature below 25° C. to give ethyl 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoate as a colorless oil (6.16 g, 53% yield over two steps). LCMS ESI+m/z 309 [M+H]+; GCMS m/z 308 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][C:8]2[S:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[C:9]=2[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)C(Sc2ccc(C)cc2)C1
Solvent: O
Product: CCOC(=O)C1CCc2c(sc3ccc(C)cc23)C1

Procedure:
To 130 g. of polyphosphoric acid contained in a 500 ml. three-necked flask provided with a stirrer and condenser, was added 13 g. of 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester. The mixture was heated on a steam bath for 90 minutes and then poured onto a mixture of 200 g. of ice and 200 ml. of water. The mixture was stirred until the dark oily complex was decomposed, and a light yellow color appeared. The product was extracted with ether, and the solution then washed with water until it was neutral. After drying over anhydrous potassium carbonate, the ether was distilled off on the steam bath, and the residue was crystallized from methanol. The yield of 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 68°-69°, was 6 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[O:33]=[C:34]1[NH:38][C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][O:35]1>>[C:41]([O:40][CH2:39][C@@H:37]1[CH2:36][O:35][C:34](=[O:33])[N:38]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1)(=[O:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2N2CCCS2(=O)=O)CC1
Yield: 87.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (3.12 g) described in Preparation Example 179 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.33 g), the title compound (3.47 g) was obtained.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:15]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of isatin (4.41 g, 30 mmol) in DMF (60 mL) at 0° C. was added 60% NaH (1.50 g, 37.5 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C. and 1-bromo-3-methylbutane (4.7 mL, 37.5 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 1 h at 0° C. followed by 6 h at rt. The reaction was cooled to 0° C., quenched with sat. NH4Cl, ice, H2O, extracted with EtOAc (200 mL×2), dried over Na2SO4 and concentrated to give crude 1-isopentylisatin as a dark orange red liquid which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H, partially overlapping with the peak at 7.12 ppm), 7.12 (t, J=7.6 Hz, 1H, partially overlapping with the peak at 7.15 ppm), 3.66 (t, J=7.6 Hz, 2H), 1.67-1.57 (m, 1H), 1.48 (q, J=7.2 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H); MS ESI 217.9[M+H]+, calcd for [C13H15NO2+H]+ 218.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CO>[ClH:21].[O:20]=[C:16]1[NH:17][CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC(=O)C2)CC1
Agent: Cl
Solvent: CO
Product: O=C1CN(C2CCNCC2)CCN1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-(3-Oxo-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (660 mg) was dissolved in methanol (5 mL) and 1 N hydrochloric acid (10 mL) was added. The mixture was stirred at 50° C. for 2 h. After removal of all solvents, acetonitrile (2×10 mL) was added and removed twice. The residue was then lyophilized to give 4-(3-oxo-piperazin-1-yl)-piperidine hydrochloride (665.8 mg).