Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2].CN(C)C=O.[H-].[Na+].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=1>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[N:17]([CH2:52][C:51]3[CH:54]=[CH:55][C:48]([F:47])=[CH:49][CH:50]=3)[CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4ncc[nH]4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4nccn4Cc4ccc(F)cc4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To the solution of N-{4-[3-cyano-4-(2,4-dichlorophenyl)-5-(1H-imidazol-2-yl)-2-thienyl]pyridin-2-yl}-N-(4-methoxybenzyl)acetamide (60.0 mg, 0.104 mmol) in dry N,N-Dimethylformamide (5.0 mL, 64 mmol) was added Sodium hydride (3.96 mg, 0.157 mmol). The resulted red-brown solution was stirred at r.t. for 10 min. 4-Fluorobenzylbromide (32.6 mg, 0.172 mmol) was added and the mixture was stirred at r.t. for 2 hours. The mixture was quenched with aqueous saturated NaHCO3 (10 mL), diluted with water, extracted with DCM (4×25 mL), washed with water, brine, dried over Na2SO4, filtered, rotovaped to give a crude residue. Chromatograph in silica column using DCM/EtOAc (30/70 to 0/100) afforded a solid product (0.055 g, yield 77.1%). LCMS: (AA) ES+, 682, 684. 1H NMR (400 MHz, d1-chloroform) δ: 8.60-8.62 (d, J=5.02 Hz, 1H), 7.63 (s, br, 1H), 7.51-7.53 (m, 1H), 7.34 (m, 1H), 7.14-7.26 (m, 5H), 6.92-6.97 (m, 2H), 6.80-6.86 (m, 3H), 6.70-6.73 (m, 2H), 5.14 (m, 2H), 4.71-4.84 (m, 2H), 3.76 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [ClH:1].Cl.C[O:4][C:5](=[O:13])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.CO>[OH-].[Na+]>[ClH:1].[ClH:1].[NH2:7][C@H:6]([C:5]([OH:13])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COC(=O)C(N)CCCCN
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na+]
Solvent: CO
Product: NCCCC[C@H](N)C(=O)O
Temperature: 4 °C
Reaction time: 5 h

Procedure:
In 1N NaOH, 2 g of Sephadex G-25 (dextranepichlorohydrin copolymer made by Pharmacia Co.) was immersed. Then the copolymer was separated by filtration. It was allowed to react with cyanuric chloride for 15 seconds in dioxane. The reaction mixture was washed with cold acetone and ice water and then 200 mg of the enzyme Pronase E was dissolved therein. In a borate buffer solution, the s-triazine derivative of Sephadex G-25 obtained as described above was immersed and gently agitated for 5 hours at pH 8.0 and 4° C to have the enzyme Pronase immobilized. The amount of the enzyme immobilized was 67 mg per g of carrier and the specific activity of the immobilized enzyme at 40° C and pH 6.0 was found to be 2.53 μ.moles/mg.min. The optimum pH of this immobilized enzyme on DL-lysine methyl ester dihydrochloride as the substrate was found to be around 6.1. The immobilized enzyme was packed in a jacketed column. With the column temperature kept at 40° C, 50 ml of a DL-lysine methyl ester dihydrochloride solution having a concentration of 10% and kept at pH 6.8 was fed downflow from the column head at space velocity of 13 hr-1. pH of the effluent was lowered to 5.75 as the reaction proceeded. When the effluent from the column was tested for conversion by the ninhydrin process under conditions selected so as to permit coloration with amino acids and no coloration with amino acid esters, it was revealed that 40% of the DL-form had undergone the reaction. The effluent was mixed with a volume of methanol about four times as large, and the salt consequently precipitated therein was removed. Thereafter, the mixture was concentrated to about 20 ml by evaporation of the solvent. To the concentrate was added about 100 ml of acetone to produce 2.02 g of L-lysine dihydrochloride in the form of precipitate. This salt was found to have specific optical rotation, [α]54620°C, of +15.8 (C = 2, 6N-HCl). When it was recrystallized from watermethanol, the purified product showed a specific optical rotation of +19.2. This operation of the resolution by use of the column described above was performed a total of ten cycles over a period of 15 days with the same space velocity. During the period, the specific optical rotation of the precipitate remained unchanged, although the conversion tested by the ninhydrin process fell to eventually 30% of the DL-form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]#[N:22])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](=[O:24])[NH2:22])([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(Nc2ccccc2)C1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2)(C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-cyano-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.65 mmol) in DMSO (10 ml) was added potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol). The reaction mixture was stirred at RT overnight. Further portions of potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol) were added and stirring continued for 24 hrs. The mixture was diluted with EtOAc (10 ml) and washed with brine (30 ml). The organics were separated and the aqueous was extracted with EtOAc (10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[I:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH3:23])=[C:17](/[CH:19]=[CH:20]/[C:21]#[N:22])[N:18]=2)[CH:15]=1>CN(C=O)C>[I:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([CH3:23])=[C:17]([CH:19]3[CH2:4][CH:20]3[C:21]#[N:22])[N:18]=2)[CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: Cc1c(/C=C/C#N)nc2ccc(I)cn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C2CC2C#N)nc2ccc(I)cn12
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To a stirred suspension of NaH (60% in oil, 270 mg) in DMF (5 ml) was added trimethylsulfoxonium iodide (1.37 g) at room temperature, and the mixture was stirred for 3 h. A solution of (2E)-3-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)prop-2-enenitrile (600 mg) in DMF (1 ml) was added, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) followed by preparative HPLC to afford the title compound (40 mg) as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1ccc(Cl)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)ccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichloro-4-fluorobenzene and isolated as white solid. MS(m/e): 459.2 (MH+).
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.C([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][CH3:31])=[CH:21]1)(=O)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:30]([CH2:29][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][CH:21]=2)[CH3:31])=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(C(C)=O)c2ccccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CN(Cc1c[nH]c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 59.3 %

Procedure:
EDC (1.03 g, 5.40 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.89 g, 5.40 mmole), 1-acetyl-3-(methylaminomethyl)indole (1.00 g, 4.95 mmole), HOBt.H2O (0.73 g., 5.40 mmole) and diisopropylethylamine (1.72 mL, 9.90 mmole) in DMF (50 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (0.90 g, 52%) as a light yellow solid after drying in vacuo: MS (ES) m/e 307 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CS(C)=O>[CH3:3][C:4]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.7 g sodium hydride (60% in mineral oil) are suspended in 10 ml dimethylsulfoxide at 0° C. The a solution of 6.4 ml diethyl 2-methylmalonate in 10 ml dimethylsulfoxide is added dropwise. The mixture is stirred for 30 minutes and then diluted with 20 ml dimethylsulfoxide. After stirring for further 2 hours a solution of 5 g 4-fluoronitrobenzene is added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then it is partitioned between icewater and ethylacetate. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed with brine. After drying with magnesium sulphate the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18].[C:21](OC(=O)C)(=[O:23])[CH3:22].C1C=CC=CC=1>N1C=CC=CC=1>[C:21]([O:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COCOCCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCOCCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1

Procedure:
100 mg of 5-hydroxy-2-(3-methoxymethoxypropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 83) were dissolved in 1 ml of pyridine, and 50 mg of acetic anhydride were added. The reaction mixture was allowed to react for 20 hours at room temperature. Benzene was then added to the reaction mixture, and the benzene solution was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 20:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:32]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH3:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:3]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](O)C2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of methyl 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate (865 mg, 2.44 mmol) in DMF (10 ml) was added imidazole (1.54 g, 24.4 mmol) and tert-butyidimethylsilylchloride (1.83 g, 12.2 mmol) at 0° C. After 3 hr stirring, saturated NaHCO3 aqueous solution was added to the reaction mixture and extracted with CH2Cl2. The extract was washed with water and brine. dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 40 g, CH2Cl2/MeOH: 100/1-50/1) to give 760 mg (66%) of title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 417.04 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18](OCC)=[O:19])=[C:7]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])=[C:7]2[OH:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Temperature: 90 °C
Yield: 83.7 %

Procedure:
In a sealed flask was combined ethyl 8-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.8 g, 5.6 mmol), dioxane (75 mL), tert-butyl 2-aminoacetate hydrochloride (3.8 g, 22 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.9 mL, 22 mmol). The flask was sealed and heated at 90° C. for 10 hours. After cooling to room temperature, the reaction was concentrated to give a solid that was purified by flash chromatography (20% EtOAc/hexane) to afford a white solid (1.9 g). MS m/e=406.1 (M+H)+.
Reaction SMILES: B(F)(F)F.[C:5]([OH:22])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=1[OH:26].C([O-])(=O)C.[Na+]>O.C(Cl)Cl>[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[C:28]([C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][C:25]=1[OH:26]
Reactant: Cc1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Reaction time: 8 h

Procedure:
Boron trifluoride was introduced with vigorous refluxing until saturation into a mixture of 27.2 g of palmitic acid, 13.7 g of 2-methylhydroquinone and 45 ml of methylene chloride. After standing overnight the mixture was refluxed for another hour and then decomposed with stirring in a solution of 25 g of sodium acetate in 220 ml of water. After 45 min the solution in methylene chloride was separated and evaporated. The residue was stirred with methanol, filtered with suction and recrystallized from n-chlorobutane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[S:35](Cl)(=[O:37])=[O:36]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:35]([C:27]3[N:26]([CH3:25])[C:34]4[C:29]([CH:28]=3)=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:36])=[O:37])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Reactant: Cn1c(S(=O)(=O)Cl)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2ccccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (cf. Example 20e, 0.050 g) in dichloromethane (2.0 ml) was added 1-methyl-1H-indole-2-sulfonyl chloride (0.036 g; cf. Chan, Ming Fai; Wu, Chengde; Raju, Bore Gowda; Kogan, Timothy; Kois, Adam; Verner, Erik Joel; Castillo, Rosario Silvestre; Yalamorri, Venkatachalapathi; Balaji, Vitukudi Narayanaiyengar, U.S. Pat. No. 5,962,490) and DMAP (0.021 g). The reaction mixture was stirred at 80° C. for 18 h, cooled and directly chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.048 g) as a yellowish foam. MS (ISN): 546.5 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][O:10]C1CCCCO1)=[O:5])[CH3:2]>CO>[CH2:1]([O:3][C:4]([CH:6]([P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][OH:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCCOC1CCCCO1)P(=O)(OCC)OCC
Solvent: CO
Product: CCOC(=O)C(CCCO)P(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
The diethyl 1-ethoxycarbonyl-4-(tetrahydropyran-2-yloxy)butylphosphonate prepared in the step (a) was dissolved in 500 ml of methanol, followed by the addition of 20 g of a cation-exchange resin (Dowex 50w-8, H type). The obtained mixture was mildly refluxed for 7 hours, cooled to room temperature, and filtered to remove the resin. The filtrate was distilled to remove the solvent, giving 68.8 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13]
Reactant: COC[C@@H]1CCCN1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a cold suspension of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride (5.28 g, 21.5 mmol) in a 1:1 mixture of THF:CHCl3 (254 mL) was added drop-wise via syringe pump a solution of (S)-(+)-2-(methoxymethyl)-pyrrolidine (3.45 mL, 28.0 mmol, 1.3 eq) (Aldrich) and N,N-diisopropylethylamine (7.49 mL, 43 mmol, 2 eq) in CHCl3 (42 mL) over a period of 70 minutes under a dry N2 atmosphere with cooling in an ice bath. After stirring an additional 20 minutes the mixture was concentrated. The residue was flash chromatographed (Biotage KP silica gel, 98/2 CH2Cl2/CH3OH) to give the title compound as a dark greenish-yellow foam (6.48 g. 93% yield). NMR (400 MHz, DMSO-d6): consistent MS: (API-ES−) m/z 323 [M−H].
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].[CH2:15]([SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:15]([S:27][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C/C=C/C(=O)C1C(C)C=CCC1(C)C
Reactant: CCCCCCCCCCCCS
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of δ-damascone (10.0 g; 52.1 mmol) and 1-dodecanthiol (8.42 g, 41.7 mmol) in THF (150 ml) was treated with DBU (7.92 g; 52.1 mmol) and stirred at 45° C. for 90 min. The reaction solution was treated with 5% aqueous HCl, extracted twice with ether, washed with H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated at 70° C./0.01 mbar. Yield of crude product: 16.2 g (99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]Cl)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4].[I-:27].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][I:27])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4]
Reactant: [I-]
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1

Procedure:
A solution of 51.6 g (0.132 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 29.8 g (0.198 mole) of sodium iodide in 1000 ml of acetone is refluxed for 45 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed once with diluted aqueous sodium bisulphate solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product crystallises out. After filtration under suction and drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 139°-142°.