Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]12[CH2:36][CH2:35][C@@:34]3([CH3:37])[C:29](=[C:30]([CH3:38])[CH2:31][CH2:32][CH2:33]3)[C@H:4]1[O:5][C:6](=[O:28])[CH:7]2[CH2:8][NH:9][CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@H:13]2[C:17]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(#N)C>[OH:2][C:3]12[CH2:36][CH2:35][C@:34]3([CH3:37])[C:29](=[C:30]([CH3:38])[CH2:31][CH2:32][CH2:33]3)[C@@H:4]1[O:5][C:6](=[O:28])[CH:7]2[CH2:8][N:9]([CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@@H:13]2[C:17]3[C@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26])[C:39](=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C2[C@H]3OC(=O)C(CNCC4C(=O)O[C@H]5C6=C(C)CCC[C@]6(C)CCC45O)C3(O)CC[C@]2(C)CCC1
Agent: Cl
Solvent: CC#N
Product: CC(=O)N(CC1C(=O)O[C@@H]2C3=C(C)CCC[C@@]3(C)CCC12O)CC1C(=O)O[C@H]2C3=C(C)CCC[C@]3(C)CCC12O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in step 1 of example 55 (200 mg, 0.389 mmole) was dissolved in dry acetonitrile (4 mL) and to it acetic anhydride (43.78 mg, 0.426 mmole) and TEA (59.04 mg, 0.58 mmole) were added. The reaction mixture was stirred at room temperature (25° C.) for 2 hours. Reaction mixture was concentrated and crude product was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[S:6].Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:7][C:5](=[S:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:14]#[N:15]
Reactant: Cc1cccc(C(O)=S)c1
Reactant: N#CSCCl
Product: Cc1cccc(C(=S)OCSC#N)c1
Yield: 79 %

Procedure:
10 g (0.052 mol) of the K salt of 3-methyl-thiobenzoic acid and 5.6 g (0.05 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 9.9 g of an oily liquid having a density of 1.27 (this corresponds to a yield of 79% of the theoretical conversion).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[C:14]1([C:20]2[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][C:23]=3[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:27][CH2:28][C:23]4[O:22][N:21]=[C:20]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:24]=4[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1ccc(-c2noc3c2CNCC3)cc1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2onc(-c3ccccc3)c2C1
Yield: 69 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Phenyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][C@H:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:19][C:16]1([CH3:20])[O:15][C@@H:14]([CH2:13][C:12]2[CH:21]=[CH:22][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:18][O:17]1
Reactant: CC1(C)OC[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cc2ccc(O)cc2)O1
Yield: 99.8 %

Procedure:
A solution of (S)-4-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.00 g, 3.35 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on carbon (0.360 g, 0.34 mmol) and the resulting mixture hydrogenated under 1 atm of hydrogen pressure. The resulting mixture was filtered through a pad of Celite® and the pad of Celite washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenol (696 mg, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[ClH:22]>>[ClH:22].[CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: CCCOc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of HCl (2M in dioxane, 40 ml) was added tert-butyl 7-propoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.2 g). The resulting mixture was stirred at RT for 4 hours. The solvent was removed under reduced pressure to afford the title compound as a solid (1.7 g, 97%). TLC—Chloroform/methanol (9/1): Rf=0.15. 1H-NMR (DMSO-d6, 400 MHz) δ 0.96 (3H, t), 1.71 (2H, m), 2.90 (2H, m), 3.32 (2H, m), 3.89 (2H, m), 4.17 (2H, s), 6.81 (2H, m), 7.10 (1H, d), 9.63 (2H, br. s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (884 mg, 4.8 mmol) in DMF (11 ml) was added NaH (60% dispersion in mineral oil, 190 mg, 4.8 mmol) at 0° C. After 5 min the reaction mixture was added to a solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (1 g, 4.4 mmol) at 0° C. and the resultant mixture was allowed to warm to room temperature. After one hour the LCMS analysis showed the presence of the desired product and the complete consumption of the bromo-ketone stating material was confirmed by TLC (EtOAc/Hexanes 1:1). An aqueous solution of HCl (1 M) was then added until a white precipitate appeared. Water was added and the white solid filtrated, rinsed with water and dried in vacuo to give ethyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-nitro-1H-pyrrole-2-carboxylate as a white solid (1.32 g, yield 83%). 1H-NMR (400 MHz, CDCl3): δ 1.29 (t, 3H, J 7.1 Hz), 3.90 (s, 3H), 4.22 (q, 2H, J 7.2 Hz), 5.77 (s, 2H), 6.98-7.20 (m, 2H), 7.50 (d, 1H, J 1.8 Hz), 7.63 (d, 1H, J 1.8 Hz), 7.95-8.00 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=[N:35][O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2c(Cl)nc(-c3ccccc3)nc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(C=NOCc2ccccc2)cc2c(Cl)nc(-c3ccccc3)nc21
Yield: 47.9 %

Procedure:
A solution of the aldehyde 20 (50 mg, 0.14 mmol), O-benzylhydroxylamine hydrochloride (26 mg, 0.16 mmol), and pyridine (12 mg, 0.15 mmol) in CH2Cl2 (2 mL) is stirred at ambient temp. for 5 h, then sat. NH4Cl solution is added, and the mixture is extracted with EtOAc (3×5 mL). The combined extracts are washed with brine and dried over MgSO4. Crystallization of the crude solid from hexanes gives 31 mg (0.067 mmol, 48%) of the title compound as colorless solid, single oxime isomer. MS (ES): m/z 463.0/465.0 (90/48) [MH+], 363.1/365.2 (100/32) [MH+-Boc].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C.Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C@H:2]([CH3:4])[OH:3]
Reactant: C[C@H](O)C(=O)O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.1 %

Procedure:
(S)-Lactic acid (60 g) and 75 g of benzyl bromide were dissolved in 500 ml of dimethylformamide, to which 72.5 g of potassium iodide and 150 g of potassium carbonate were added with ice cooling. After the mixture was stirred at room temperature for 6 hours, 500 ml of ethyl acetate and 500 ml of diisopropyl ether were added thereto. The supernatant layer was obtained by decantation and the precipitate was washed with 100 ml of diisopropyl ether. The organic solutions thus obtained were combined and poured into 200 ml of 5N-hydrochloric acid under ice-cooling. The separated organic layer was washed with 250 ml of 2N-hydrochloric acid, 100 ml of an aqueous solution of sodium thiosulfate and 100 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to give 29.3 g of (S)-benzyl lactate (yield: 37%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.[F:13][C:14]([F:41])([F:40])[C:15]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:29]Br)[CH2:25][O:26]2)=[C:21]([F:31])[CH:20]=1>CN(C=O)C>[F:41][C:14]([F:13])([F:40])[C:15]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:29][N:3]3[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]3)[CH2:25][O:26]2)=[C:21]([F:31])[CH:20]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Fc1cc(OCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc2c1C=C(CBr)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 mL) was added triphenylphosphine dibromide (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added EtOAc and IPE, the resulting solid was removed by filtration, and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium hydride (24 mg) was added to a DMF solution (5 mL) at 0° C., and subsequently, ethyl 1H-pyrazole-4-carboxylate (76 mg) was added thereto. The mixture was stirred at room temperature for 0.5 hours, and a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (220 mg) in DMF (5 mL) was added thereto at 0° C. The reaction liquid was stirred at room temperature for 13 hours, quenched with a saturated NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH2:38][O:39][CH:40]([CH3:42])[CH3:41])[O:11][C:12]1[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=2[F:27])[N:15]=[C:14]([NH:28][S:29]([C:32]2[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=2)(=[O:31])=[O:30])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:18][C:16]1[N:15]=[C:14]([NH:28][S:29]([C:32]2[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=2)(=[O:31])=[O:30])[CH:13]=[C:12]([O:11][C@H:10]([CH2:38][O:39][CH:40]([CH3:41])[CH3:42])[CH2:9][OH:8])[N:17]=1
Reactant: CC(C)OC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)OC[C@H](CO)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 34 using N-{6-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(isopropoxymethyl)ethoxy]-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}-1-methyl-1H-imidazole-4-sulfonamide (the product from step (v) (90 mg) in THF (5 mL) and 1M solution of tetrabutylammoniumfluoride in THF (0.28 mL) to give the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([I:17])[C:3]=12.[OH-:19].[Na+]>CS(C)=O.O1CCOCC1>[I:17][C:16]1[C:3]2[C:2]([OH:19])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=[N:5][C:4]=2[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cn1nc(I)c2c(O)c(-c3ccccc3)nnc21
Temperature: 50 °C

Procedure:
A mixture of 4-chloro-3-iodo-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (1.5 g, 4.05 mmol) and NaOH aqueous solution (4 M, 2 mL) in DMSO (6 mL) and dioxane (6 mL) was heated to 50° C. for 2.5 h. The mixture was left to cool to rt, then neutralised to pH 2-3, when a precipitate formed. The solid was filtered, washed with water and dried, to give 1.33 g of the intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:15][CH2:14][CH:13]([O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[CH3:16])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Product: CC(CNCc1ccc(Cl)o1)Oc1ccc2ccccc2c1Cl
Yield: 77 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-chlorofuran-2-carbaldehyde in 77% yield as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([NH:10]C(=O)C)[CH:9]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH:9]=1)[NH2:10])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1N1CCCC1
Temperature: 0 °C

Procedure:
0.58 g (2.3 mmol) of N-(5-nitro-2-pyrrolidin-1-ylphenyl)acetamide was admixed with 12 ml of conc. hydrochloric acid and heated to reflux for 1.5 hours. The solution was added to 100 ml of ice/water, neutralized with 2 N sodium hydroxide solution and admixed three times with ethyl acetate. After the mixture had been dried, the solvent was distilled off under reduced pressure to obtain the product quantitatively as a red solid which was used for the reactions a-d described in Example 1 without further purification (reaction with the acyl isocyanate, reduction with SnCl2 and acylation with Ac2O).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH2:10]([C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:13])[NH:14][C:15](=[O:25])[C:16]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:3]2[OH:2])[CH:11]=[CH2:12]
Reactant: C=CCc1cc(C(=O)OC)c(NC(=O)Cc2cc(C)cc(C)c2)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCc1cc2c(O)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 5-allyl-4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-benzoic acid methyl ester (1.4 g in 40 mL dry tetrahydrofuran) at 0° C. was added dropwise a solution of sodium bis(trimethylsilyl)amide (9.8 mL of a 1.0M solution in tetrahydrofuran) and the mixture warmed to room temperature. After 4 hours, the reaction was cooled to 0° C. and quenched by the addition of of 200 mL iced 6N hydrochloric acid. The slurry was stirred for 15 minutes then filtered and washed sequentially with ice water (500 mL), cold hexane (200 mL) and cold toluene (100 mL). The residue was dried in vacuo to give the title compound (960 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([SH:17])=[N:15][N:14]=[N:13]2)=[CH:8][CH:7]=1>O.O1CCCC1.[Cl-].[Na+].O>[CH3:3][S:17][C:16]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[N:13]=[N:14][N:15]=1
Reactant: Oc1ccc(-n2nnnc2S)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nnnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (2.06 g) in water (120 ml) followed by methyl iodide (3.5 ml) was added to a solution of 1-(4-hydroxyphenyl)-1H-tetrazole-5-thiol (10 g) in tetrahydrofuran (30 ml) and stirred at room temperature for 5 h. The mixture was poured into brine (120 ml), extracted with ethyl acetate (3×60 ml), dried (Na2 SO4) and evaporated to give the title compound as a brown solid (10.64 g). T.l.c. (Dichloromethane/methanol (990:10)), Rf=0.42
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:15]=1.C(N(C(C)C)C(C)C)C>O.CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][N:22]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:15]=1
Reactant: BrCCCOC1CCCCO1
Reactant: c1cncc(CCNCc2ccncc2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: c1cncc(CCN(CCCOC2CCCCO2)Cc2ccncc2)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
Sodium iodide(1.5 g) was added to a DMF solution (20 ml) of 2-(3-bromopropoxy)tetrahydropyran(0.85 ml). The mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature. (2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (1.28 g), and N-ethyldiisopropylamine(1.3 ml) were added thereto. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound(236 mg) as a colorless oily matter.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[N:10]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:9][CH2:8][N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6]1)=O.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[C:27]([O:26][C:24]([N:7]1[CH2:8][CH2:9][N:10]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C@H:5]([CH2:3][OH:2])[CH2:6]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2ccc(C(F)(F)F)cc2s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(C(F)(F)F)cc3s2)[C@H](CO)C1
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of (S)-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1,3-dicarboxylic acid-1-t-butyl ester-3-methyl ester (1.18 g) in tetrahydrofuran (10 mL) was added lithium borohydride (65.7 mg). The mixture was stirred for 20 hours. To the reaction solution was added aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (840 mg). Yield: 76%.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)C.O1CCCC1.O.[OH-].[Li+].Cl>O>[CH:12]1([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:16])=[O:3])[CH2:11][CH2:10]2)[CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)CC1CCN(C2CCC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 130.7 %

Procedure:
To a stirred mixture of (1-cyclobutyl piperidin-4-yl) acetic acid ethyl ester (652.9 mg, 2.90 mmol, obtained in above step), tetrahydrofuran (6 mL) and water (6.0 mL) cooled at 0° C. lithium hydroxide monohydrate (133 mg, 3.19 mmol) was added in a single lot. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled again to 0° C. and acidified with 2N hydrochloric acid to pH: 2-3. The volatiles were removed under reduced pressure and the traces of water were removed by azeotropic distillation with toluene to obtain (1-cyclobutyl piperidin-4-yl) acetic acid (747.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2cc(Cl)ccc21
Product: O=C1CCc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
86.0 g (0.51 mole) of 5-chloro-1-indanone are introduced in portions into 540 ml of fuming nitric acid (d=1.54), cooled to -20° C., so that the temperature of the reaction mixture remains between -10° and -15° C. After the addition has ended, the mixture is subsequently stirred for 45 minutes at -15° to -20° C., the reaction solution is poured onto ice and the precipitate which has separated out is filtered off and washed with water. The crude product of melting point 110°-113° is recrystallized from ethanol, whereby the melting point of the pure 5-chloro-6-nitro-1-indanone rises to 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(Cl)cc(Cl)c1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 10% Pd/C (1.5 g) in THF (200 mL) was added 3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). The reaction was hydrogenated on a Parr shaker at 50 psi for 3 h. The catalyst was removed by filtration through celite and the organic solution was concentrated in vacuo to afford 3-(3,5-dichlorophenyl)-propionic acid (11.3 g). 1H NMR (400 MHz, CDCl3) δ 7.00–7.35 (m, 3H), 2.89 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C(C(OO)=[O:22])=CC=CC=1>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]2[O:22][CH:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.29 g of N-BOC-1,2,5,6-tetrahydropyridine in 25 ml of CH2Cl2, a suspension of 6.2 g of chloroperbenzoic acid in 50 ml of CH2Cl2 are added and the mixture obtained is stirred for ca. 12 hours at RT. The mixture obtained is extracted with saturated aqueous NaHCO3-solution and 0.5 m aqueous Na2S5O3-solution and the organic phase obtained is washed, dried and the solvent is evaporated. N-BOC-3,4-epoxy-piperidine is obtained.