Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[CH:3][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.2 %

Procedure:
4-Aminopyridine (0.141 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.023 g, 0.0460 mmol, 9%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>CO>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Methyl α-bromo-α-[p-(phenoxy)phenyl]acetate (6.42 g) is reacted with 3.61 g of 4-chlorothiophenol in methanol as in Example 16 to afford a yellow oil which solidifies on standing. Recrystallization from 50 ml of petroleum ether affords the product as white crystals, mp 66°-67.5° C.
Reaction SMILES: NCC[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].C([O-])(=O)C.[Na+].C(N1C=CC=C(C(Cl)=O)C1=O)C1C=CC=CC=1>CC(C)=O>[C:7]([OH:9])(=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:4][CH:5]=1
Reactant: NCCc1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: O=C(Cl)c1cccn(Cc2ccccc2)c1=O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 1 h

Procedure:
20 ml of acetone are added to 16 ml of an about 1 molar solution of 3-(2-aminoethyl)-benzoic acid containing the corresponding amount of sodium acetate, and 3.7 g of 1-benzyl-1,2-dihydro-2-oxo-nicotinic acid chloride (prepared from 1-benzyl-1,2-dihydro-2-oxo-nicotinic acid and thionyl chloride) are added with agitation and cooling. Agitation is then continued for 1 hour at room temperature, the acetone is removed under reduced pressure, and dilute hydrochloric acid is added to the residue. The precipitated product is suction-filtered, reprecipitated from dilute ammonia, and recrystallized from dilute methanol. The 4-(2-<1-benzyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzoic acid so obtained has a melting point of 150°-152° C. and of 171°-173° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[OH:31].C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:22]2[CH:23]=[CH:24][C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 5,6,7,8-tetrahydro-naphthalen-2-ol via the same procedure used for the: preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3), to produce a white solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#[N:11].[OH-].[Na+]>O>[ClH:1].[ClH:1].[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([NH:2][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])=[CH:4][CH:5]=1
Reactant: N#CNC(=N)N
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)cc1

Procedure:
A stirred mixture of 4.3 g. (.03 mole) of p-toluidine hydrochloride and 2.5 g. (0.03 mole) of cyanoguanidine is immersed in a a 210° C. oil bath for fifteen minutes. The resulting amber glass-like reaction product is dissolved in 100 ml of water, alkalized with 40% sodium hydroxide solution, and extracted with 250 ml of ether. The ether layer is backwashed twice with 10 ml of water, dried over sodium carbonate, filtered, and the ether solution made strongly acidic with a saturated etheral hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried in vacuo at 25°C to obtain 1-(p-tolyl)biguanide dihydrochloride.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[CH3:36]N(C=O)C.[H-].[Na+].CI>O>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH3:36])[C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(C)C(=O)Nc2ccc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)C(C)(C)c2cc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)ccc21
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a mixture of 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (300 mg, 0.62 mmol) and DMF (3 ml), sodium hydride (27 mg, 0.68 mmol) was added followed by stirring for 30 minutes with cooling on ice-bath. To the reaction mixture, methyl iodide (97 mg, 0.68 mmol) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (140 mg, 45%) as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CN1CCOCC1.[CH2:25]([O:27][C:28](=[O:32])[C:29](Cl)=[O:30])[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][C:28](=[O:32])[C:29]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)=[O:30])[CH3:26]
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.235 g, 0.99 mmol), N-methyl morpholine on polystyrene (0.538 g, 1.24 mmol), and CH2Cl2 (5 mL) was added chloro-oxo-acetic acid ethyl ester (0.135 g, 0.99 mmol) and the resulting mixture was agitated on an orbital shaker for 16 h. The reaction contents were filtered onto an acidic SPE cartridge and eluted with CH2Cl2. The CH2Cl2 filtrate was evaporated to give 0.165 g (50%) of N-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]oxalamic acid ethyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 9.21 (bs, 1H), 8.38 (d, J=2.3 Hz, 1H), 7.48 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H); HPLC-MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10].C(O)C.[C-:15]#[N:16].[Na+].[OH-].[Na+]>O.CCOCC>[C:15]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])#[N:16]
Reactant: [C-]#N
Reactant: CC(=O)CCC#CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)CCC#CCCCC#N

Procedure:
To a solution consisting of 2.77 parts of 9-chloro-5-nonyn-2-one in 8 parts by volume of ethanol is added a solution containing 2.77 parts of sodium cyanide dissolved in 4 parts of water. The resulting reaction mixture is heated at 80° - 100° C. for about 24 hours, then is cooled and diluted with ether, and then 20 parts by volume of dilute aqueous sodium hydroxide is added with stirring. The layers are separated and the alkaline layer is extracted with ether. The ether extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 9-cyano-5-nonyn-2-one. This compound exhibits an infrared adsorption maximum at 2250 reciprocal centimeters and nuclear magnetic resonance peaks at δ2.15 and δ2.50.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)([CH2:11]2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]23[CH2:15][CH:12]([CH2:11]2)[C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]3=[O:25])=[CH:17][CH:18]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1ccc(C23CC(C2)C(=O)N(Cc2ccccc2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 2.46 g of 3-benzyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.3 g of 5% palladium-on-carbon and worked up. Melting point 164°-165.5° (from ether/ethyl acetate).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Reaction time: 64 h
Yield: 88.8 %

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.6 g) in ethanol/THF (10/10 ml) was added at room temperature 1N sodium hydroxide solution (2 ml), and the mixture was stirred for 64 hours. To the mixture was added 1N hydrochloric acid (3 ml), and the mixture was concentrated, The resulting solid was collected by filtration, which was washed with water, 2-propanol and diisopropylether to give pale yellow powder of 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic acid (510.6 mg).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.Cl.[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)N)=[CH:15][CH:14]=1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[C:20]3[C:21](=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:3]([C:4]3([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]3)=[C:2]2[CH3:10])=[CH:15][CH:14]=1
Reactant: CC(=O)CC1(CC#N)CC1
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C1(CC#N)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a 0° C. mixture of the ketone from Step 4 (920 mg, 6.71 mmol) and the hydrazine from Step 5 (2.15 g, 7.0 mmol) in 35 mL toluene was added acetic acid (0.97 mL, 17 mmol). The mixture was warmed to room temperature and stirred 1 h, then concentrated to dryness. The residue was dissolved in toluene and heptane and concentrated again and the process repeated until there was no more acetic acid remaining. The residue was then dissolved in 30 mL dioxane and treated with HCl (4M solution in dioxane, 4 mL, 16 mmol). The mixture was heated to 60° C. for 1.5 h, then cooled and partitioned between water and ethyl acetate. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. Purification by flash chromatography (15% ethyl acetate/hexanes) provided 2.32 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=O)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1.N1CCCCC1>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[C:15]([O:18][CH3:19])=[N:16][CH:17]=1
Reactant: COc1ncc(Br)cc1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ncc(Br)cc1C=C1C(=O)Nc2ccccc21
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a solution of indolinone (130 mg, 0.98 mmol) in ethanol (5 mL) was added 5-bromo-2-methoxypyridine-3-carbaldehyde (J. Het. Chem, 1985, (22), 1583-1592) (200 mg, 0.98 mmol, 1 eq), followed by piperidine (0.194 mL, 1.9 mmol, 2 eq). The reaction mixture was heated at 80° C. for 2 hours and then allowed to cool to room temperature. The precipitate that formed was collected by filtration and washed with ethanol to give the title compound (180 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11]#[N:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.Cl.[OH-].[Na+]>COCCOC>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][CH2:10][CH2:11][NH2:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CCSc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: NCCSc1cc(Cl)cc(Cl)c1
Yield: 81.8 %

Procedure:
To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2 g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10M borne dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5N sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.0 g of a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH2:22][Cl:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCl)cc1
Yield: 82.2 %

Procedure:
A mixture of 4-nitrophenol (139 g, 1 mole), 2-(benzenesulphonyloxy)ethyl chloride (220.5 g, 1 mole--see Ber. (1920), 53, 1836) and anhydrous potassium carbonate (138 g, 1 mole) in methyl ethyl ketone ("MEK"--1000 ml) was stirred at reflux for 16 hours. After cooling, the mixture was poured onto water and the organic layer was separated. Following two further extractions with methyl ethyl ketone, the combined organic fractions were dried (MgSO4), filtered and evaporated. The resultant solid was crystallised from ethanol to give the title compound, (165.8 g), m.p. 60°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([F:12])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:5]1[CH2:10][CH2:9][C:8]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=3)[NH:31][C:7]=2[CH2:6]1)[F:12]
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)C(F)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 68.8 %

Procedure:
To 1.70 g (5.2 mmol) (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester in glacial acetic acid (20 mL), 1.05 g (5.72 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. over night. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 2:1 followed by a trituration from Et2O yielded 1.56 g (70%) of (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 436 (MH+).
Reaction SMILES: C[C@H]1P(C2C(P3[C@H](C)CC[C@H]3C)=CC=CC=2)[C@H](C)CC1.[O:21]=[C:22]1[CH2:26][CH2:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]1[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[H+].[B-](F)(F)(F)F>C(Cl)Cl>[CH3:36][CH2:35][CH2:34][CH2:33][CH2:32][CH:23]1[C:22](=[O:21])[CH2:26][CH2:25][CH:24]1[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Agent: C[C@@H]1CC[C@@H](C)P1c1ccccc1P1[C@H](C)CC[C@H]1C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 1.5 h
Yield: 99 %

Procedure:
In a glovebox, into a 10 ml glass vial were placed 15.5 mg (0.0485 mmole) of [(COD)Ru(methylallyl)2], 14.9 mg (0.0485 mmole) of (R,R)-Me-DuPHOS and 250 μl of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate (1.08 mmole). To this suspension was added 0.630 ml of a 0.081 M solution of titrated HBF4.etherate (0.049 mmole) in CH2Cl2 with stirring. This concentrated solution was stirred for 1.5 hours, after which 21.5 g (95.9 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate and 11.5 ml of CH2Cl2 were added. The resulting yellow solution was placed in a 75 ml autoclave, purged with hydrogen and pressurized to 90 bar of hydrogen. After 8 hours, the solution was exposed to air and passed through a column of silica gel to separate the catalyst. This gave a 99% yield of the desired Hedione® product with the following ratios of isomers: cis/trans=98/2; (+)-cis/(−)-cis=82.4/17.6, 64.8% ee.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].Cl.[OH2:5]>[Pd]>[CH2:2]([OH:5])[C@@H:1]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:3])[OH:5])[OH:3])[OH:5])[OH:3]
Reactant: CCO
Reactant: O
Agent: [Pd]
Agent: Cl
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
0.18 g (0.3 mmol) of 1,5-dideoxy-2,3,6-Tri-O-benzyl-1,5-{[6-(trimethylsilyl)hexyl]imino}-D-glucitol 20 ml of a 4:1 mixture of ethanol and water and 0.1N hydrochloric acid (3 ml, 0.3 mmol) are hydrogenated at atmospheric pressure in presence of 60 mg of palladium 10% on charcoal to afford 0.065 g (66%) of expected 1,5-dideoxy-1,5-{5-(trimethylsilyl)hexyl]imino}-D-glucitol as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6](O)=[CH:7][CH:8]=1)#[N:2].[Na].[ClH:12].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:22].C(N(CC)CC)C>CCOCC.C(Cl)Cl>[Cl:12][C:4]1[N:5]=[C:6]([Cl:22])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cl
Reactant: N#Cc1ccc(O)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cl)nc1Cl
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A dry mixture of powdered 3-cyano-6-hydroxy-pyridin-2-ol anion, sodium salt (102.34 g, 0.648 mol), as prepared in the previous step, and triethylamine hydrochloride (89.20 g, 0.648 mol) was swirled until the two components appeared completely mixed. This dry mixture was then cooled on an ice bath while POCl3 (150 mL, 1.62 mol) was slowly poured in under air with intermittent swirling. Triethylamine (90.3 mL, 0.648 mol) was then added rapidly in 2 mL portions with frequent manual swirling while cooling on an ice bath. The flask containing the resulting warm dark semi-solid was then fitted with a reflux condenser and CaSO4 drying tube and stirred under air at 140° C. for 20 h. The easily stirred dark brown thick “solution” was then allowed to cool to rt, chilled on an ice bath, diluted with ether (800 mL), and washed with ice (800 mL). The very dark organic layer was washed with ice water (1×1 L), and the aqueous layers were combined and extracted with ether (3×1 L). The combined ether extracts were concentrated under reduced pressure to give a wet orange-brown solid. This was dissolved in DCM (1 L), dried (2×Na2SO4), and concentrated under reduced pressure at 60° C. to afford the title compound as a brown solid (80.7 g, 466 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=[O:26])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH3:27])=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and o-tolyl isocyanate (31 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as colorless solid.
Reaction SMILES: ClC1C=CC([C@@H]2[C@@H]([C@@H](OC3C=CC(Cl)=C(Cl)C=3)C)CCN(C(C3CCN([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)CC3)=O)C2)=CC=1.N1CCCCC1.C([N:54]1[CH2:59][CH2:58][C@H:57]([C@H:60]([OH:62])[CH3:61])[C@@H:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH2:55]1)C1C=CC=CC=1.C(C1C=NC(O)=CC=1)#N.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[F:70][C:65]1[CH:64]=[C:63]([C@@H:56]2[C@@H:57]([C@@H:60]([O:62][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=3)[CH3:61])[CH2:58][CH2:59][NH:54][CH2:55]2)[CH:68]=[CH:67][C:66]=1[F:69]
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Agent: N#Cc1ccc(O)nc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol and 3-cyano-6-hydroxy-pyridine via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol to yield 6-{(S)-1-[(3S,4S)-3-(3,4-Difluoro-phenyl)-piperidin-4-yl]-ethoxy}-nicotinonitrile. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as off-white solid. MS (m/e): 557.3 [(M+H)+].