Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cc1cc(N2CCOCC2)nc(Cl)n1)c1ccccc1
Temperature: -5 °C
Yield: 57.1 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (6 g, 19.8 mmol) was dissolved in DCM (50 mL) and stirred (under nitrogen) at −5° C. Triethylamine (3.06 mL, 21.8 mmol) was added to give a clear brown solution. Morpholine (1.65 mL, 19.8 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9]([Cl:13])=[N:10]2)=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)C>[N:21]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9]([Cl:13])=[N:10]2)=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: Fc1ccc(-c2cc(Cl)nc3cc(CBr)ccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1

Procedure:
A solution of 7-(bromomethyl)-2-chloro-4-(4-fluorophenyl)quinoline (1.0 g, 2.9 mmol) and sodium azide (204 mg, 3.1 mmol) in ethanol (40 mL) was refluxed for 16 h. The solution was concentrated and dichloromethane was added. The mixture was filtered, and concentrated to give the title compound. MS (+ESI): 313 (M+H)+.
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])[CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]1([O:5][C:4]([CH2:3][CH:2]([C:7]([O:9][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])[CH2:1][C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)CC(CC(=O)O)C(=O)O
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(CC(CC(=O)OC1CCCCC1)C(=O)OC1CCCCC1)OC1CCCCC1
Yield: 83.4 %

Procedure:
A mixture of 1,2,3-propanetricarboxylic acid (25 g), cyclohexanol (55 g), and p-toluenesulfonic acid (100 mg) in toluene (500 mL) was refluxed for 2 days and water removed from the reaction mixture. After reaction was complete, solvent was removed in vacuuo to yield a viscous oil. The crude material was redissolved in heptane and passed through a pad of silica gel to obtain 1,2,3-propanetricarboxylic acid tricyclohexyl ester (50 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: CCOC(=O)Cc1ccc(-n2c(C)nc3cnccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cnccc2n1-c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A solution of ethyl 4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenylacetate (750 mg, 2.54 mmol) and sodium hydroxide 160 mg, 4.0 mmol) in a mixture of ethanol (5 ml) and water (5 ml) was stirred at room temperature for 16 hours and evaporated. The residue was taken up in water, acidified with 2M hydrochloric acid to pH 4-5 and extracted into 1-butanol. The combined 1-butanol extracts were evaporated and the residue triturated with diethyl ether. The resulting solid was collected, washed with hexane and dried to give the title compound (267 mg, 39%) as a buff solid, m.p. 226°-230° C., which was characterised by its 1H-NMR spectrum. 1H-NMR (d6 -DMSO) δ=8.86(1H,s), 8.23(1H,d,J=8 Hz), 7.48(4H,s), 7.15(1H,d,J=8 Hz), 3.70(2H,s), 2.42(3H,s).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:15]([C:13]3[NH:12][C:7]4=[CH:8][C:9]5[O:10][CH2:11][C:2](=[O:1])[NH:3][C:4]=5[CH:5]=[C:6]4[CH:14]=3)=[O:17])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C1COc2cc3[nH]c(C(=O)O)cc3cc2N1
Solvent: CCOCC
Product: O=C1COc2cc3[nH]c(C(=O)N4CCC(Cc5ccc(F)cc5)CC4)cc3cc2N1

Procedure:
The title compound is prepared from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylic acid and 4-(4-fluorobenzyl)piperidine according to the method described in Example 1/c. Mp.: 219-226° C. (diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.05 g, 20 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) in DMF (50 mL) at −40° C. under N2, was added NaH (60% in mineral oil, 880 mg, 22 mmol). The mixture was stirred at rt for 15 min, then cooled to −40° C. To this solution was added (2-(chloromethoxy)ethyl)trimethylsilane (3.67 g, 22 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed twice with 10% LiCl, and dried over MgSO4. The title compound was purified by flash column chromatography (silica gel, eluding with hexane, followed by Et2O) to give the desired product (5.6 g, quantitiatve yield) as an oil. LC/MS(ESI+) m/z 283 (M+H)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][O:53][Si](C(C)C)(C(C)C)C(C)C)[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1.C(O)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][OH:53])[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])[C:31]=2[CH:30]=[N:29]1
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 22 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
1M TBAF in THF (5.11 mL, 5.11 mmol) was added to (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ1) (3.4 g, 5.11 mmol) and acetic acid (0.307 g, 5.11 mmol) in THF (35 mL). The resulting solution was stirred at 22° C. for 20 hours. It was quenched with NH4Cl solution (sat., 25 mL) and diluted with EtOAc (50 mL). The organic phase was washed with saturated sodium bicarbonate (25 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with EtOAc to afford the product (2.23 g, 85%). This was crystallised from EtOAc (10 mL) and iso-hexane (6 mL) to give the desired product as a white crystalline powder (1.9 g, 73%) confirmed to be of the same crystalline form as that described previously.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][C:44](Cl)=O>ClCCl>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:44]([CH2:43][CH2:42][O:41][CH3:40])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.62 g, 65.5 mmol) in dichloromethane (1 L) was cooled to ˜0° C.; triethylamine (10.0 mL, 72.1 mmol) was added. Methoxypropionyl chloride (8.57 mL, 78.6 mmol) was added dropwise, and the reaction was stirred at ambient temperature for two hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (840 mL). Triethylamine (33 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 30.77 g of tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a brown oil, which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid (4 g) is dissolved in 20 mL of methanol. To the solution, 3 mL of concentrated sulfuric acid is added. The reaction mixture is brought to gentle reflux over 24 hours. Methanol is removed and the residue is diluted with water. The compound of interest is extracted into ethyl acetate. The organic layer is extracted with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. Solvent is removed and the product is in the form of off-white powders.
Reaction SMILES: [Cl:1][C:2]1[S:20][C:5]2[N:6]=[C:7]([NH:18][NH2:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]1[S:20][C:5]2[N:6]3[C:23]([CH2:22][Cl:21])=[N:19][N:18]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2sc(Cl)cc2C(c2ccccc2Cl)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 7-chloro-5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are introduced, with cooling at 15° C., into 15 ml of glacial acetic acid and a solution of 0.25 g of chloroacetyl chloride in 5 ml of glacial acetic acid is slowly added dropwise thereto. The mixture is then stirred for a further 2 hours, treated with 0.3 g of sodium acetate and stirred for 1 hour. The solution is poured on to ice-water, neutralized and shaken out with methylene chloride. After evaporation of the solvent, the residue is refluxed with 30 ml of absolute xylene for 1 hour. After evaporation of solvent, the residue is recrystallized from ethyl acetate containing active carbon to yield 2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 101°-103° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(Cl)Cl.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 91.2 %

Procedure:
Diethyl aminomalonate hydrochloride (20.5 g) was suspended into 180 ml of methylene chloride, and 29.4 g of triethylamine was added while cooling with ice-cold water. After 30-minute-stirring, 15 g of p-toluoyl chloride was added dropwise, and the mixture was stirred for 24 hours at room temperature. The reaction solution was washed with water, dilute hydrochloric acid, and water, dried over anhydrous magnesium sulfate and concentrated. To the residue was added isopropyl ether, and the resultant crystals were collected by filtration and dried to provide 25.9 g of the objective compound as white crystal. M.p. 101-102° C.
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\Br)/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>O.O.CC(C)=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C(Br)=C/c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C#Cc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Potassium hydroxide (3.48 mmol), dissolved in water (0.87 M (4.0 ml)), is added over about 30 minutes to a refluxing solution of the alpha-bromochalcone (3.48 mmol) in 0.35 M of 1:1 water/acetone (5 ml each). After 20 minutes of further refluxing, the solution is cooled and diluted with water. The water is extracted with ether, which is dried with MgSO4 and evaporated. Chromatography on silica gel yielded 1,3-diphenylpropynone and its derivatives. VI. alpha-Tetralonylideneacetophenone Derivatives
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][C:5]1=[O:20])=[N+:2]=[N-:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O>C1COCC1>[N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(=O)CO1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57.6 %

Procedure:
To a solution of 4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-one (Intermediate 55) (1 g, 3.57 mmol) in dry THF (25 mL) under nitrogen cooled to −78° C. was added L-selectride (1 M in THF, 4.3 mL, 4.3 mmol) and the mixture was stirred at −78° C. for 45 min. The mixture was allowed to warm to room temperature and water (10 mL) was added. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave racemic 4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol (relative stereochemistry as shown above) as a yellow oil (580 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.63 (dd, J=10.6, 3.5 Hz, 1H), 4.21-4.14 (m, 3H), 4.01 (s, 3H), 3.69-3.58 (m, 1H), 2.45-2.33 (m, 1H), 2.27-2.08 (m, 2H), 2.01-1.84 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:13][CH2:12][N+:11]([O-:22])([CH3:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1(c2ccc(F)c(F)c2)CCN(C)C1
Solvent: ClCCl
Product: COC1(c2ccc(F)c(F)c2)CC[N+](C)([O-])C1

Procedure:
Preparation according to Example 32: Enantiomer 1 of 3-(3,4-difluorophenyl)-3-methoxy-1-methylpyrrolidine (0.009 g, 0.039 mmol), dichloromethane (2 ml), 3-chloroperoxybenzoic acid (77%) (0.018 g, 0.08 mmol). The crude product was analyzed by LCMS (Qtrap, Applied Biosystems, Q1 MS), analysis showed <95% conversion: MS (m+1)/z; 244 (M+1, bp), 243 (8), 214 (4), 197 (4), 142 (4).
Reaction SMILES: Cl[CH:2]([N:9]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:16]([S-:24])([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[S:17].[K+].C1C=CC=CC=1>CC(C)=O>[P:16]([S:24][CH:2]([N:9]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:17])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: Cc1cc(=O)n(C(Cl)c2ccccc2)o1
Reactant: CCOP(=S)([S-])OCC
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCOP(=S)(OCC)SC(c1ccccc1)n1oc(C)cc1=O
Yield: 62.2 %

Procedure:
To a solution of 1.12 g of 2-(α-chlorobenzyl)-5-methyl-4-isoxazolin-3-one in 15 ml of acetone were added 1.12 g of potassium O,O-diethyl dithiophosphate, and the mixture was then shaken for several minutes. After this, 20 ml of benzene were added to the reaction mixture and then most of the acetone was distilled off. After filtering the solution, the solvent was distilled from the filtrate and the remaining yellowish-brown oil was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. There were obtained 1.16 g (62.0% of theory) of O,O-diethyl S-[α-(5-methyl-3-oxo-4-isoxazolin-2-yl)benzyl] phosphorodithioate, in the form of a pale yellow oil, n23D =1.5697.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:38])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:35])[F:37])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.36 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.047 g, 0.091 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.031 g, 68%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.57 (d, J=7.83 Hz, 1 H) 7.98-8.13 (m, 6 H) 7.90 (s, 1 H) 7.53 (d, J=8.31 Hz, 2 H) 7.38 (td, J=8.80, 2.40 Hz, 1 H) 6.61 (dd, J=11.00, 2.50 Hz, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C26H17F4O4S [(M−H)−] 501, obsd. 501.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COc1ccc(CN)cc1
Solvent: COCCOC
Product: COc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-phenoxybenzoic acid (500 mg, 2.33 mmol) and DMF (1 drop) in CH2Cl2 (10 mL) under argon was added oxalyl chloride (1.3 mL, 2.0M in CH2Cl2, 2.6 mmol) dropwise. Bubbling of escaping gasses continued for 5 min after addition. The reaction was stirred at room temperature for 1 h, then concentrated in vacuo to give the title compound as a crude pale yellow oil.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([CH3:15])[CH2:9][CH2:10][P+](C)(C)C.[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])[CH:20]=O.CN(C)C=O>CCOCC>[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])/[CH:20]=[CH:10]\[CH2:9][CH:8]([CH3:15])[CH3:7]
Reactant: C[C@H](C=O)CCCl
Reactant: CC(C)CC[P+](C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C/C=C\[C@@H](C)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
23.5 ml of n-butyllithium (about 2-M in n-hexane) are added dropwise under argon to a suspension of 20.4 g of 3-methylbutyl-trimethylphosphonium bromide in 80 ml of dry ether, a reaction temperature of about 20° being adhered to by slight cooling. Thereafter, the mixture is stirred at room temperature for a further 2 hours. The mixture is cooled to -10° and a solution of 5.4 g of (S)-4-chloro-2-methylbutyraldehyde in 5 ml of dry ether is added thereto. The separated precipitate is stirred for one hour without cooling bath, whereupon 100 ml of dimethylformamide are added dropwise at room temperature. The mixture is stirred at room temperature for 16 hours, hydrolysed on ice and extracted with ether. The ether phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silicagel as well as on neutral aluminium oxide of the activities III and II (elution agent: n-hexane). After distillation under reduced pressure (13 mm Torr/90°), there are obtained 4.13 g (53%) of (S)-cis-1-chloro-3,7--dimethyl-4-octene. [α]D20 =+32.6° (2.15% in chloroform).