Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>O>[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: C#Cc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 6 ml of a DMF solution containing 512 mg of {2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (45b)), 1.3 g of potassium carbonate and 0.64 ml of 2-(2-bromoethoxy)tetrahydropyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give [2-{3-ethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (491 mg, isomer mixture) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[CH2:21](I)[CH:22]=[CH2:23].O>C1COCC1>[CH2:23]([O:10][C@H:8]1[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C@H:5]([C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[CH2:9]1)[CH:22]=[CH2:21]
Reactant: C=CCI
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of 9.6 g of tert-butyl (2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate in THF (100 ml) was added 937 mg of NaH and the reaction mixture was stirred at 60° C. for one hour. After returning to room temperature, 12.5 g of allyl iodide was added to the reaction solution, and the reaction mixture was refluxed for one hour. To the reaction solution was added water and the resulting mixture was extracted with EtOAc, then was washed with saturated brine. The organic layer was dried over Na2SO4, then the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=18/1 to 9/1; v/v) to obtain 6.70 g of the title compound (light brown oil).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[NH4+].O[N:36]1C(=O)CCC1=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:36][C:1]([CH2:4][N:5]([C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(CC(N)=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, N-hydroxysuccinimide-ammonium salt, TBTU and triethylamine in DMF.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)[C:9]([CH3:23])([CH3:22])[CH2:8]2)(=[O:4])=[O:3].[CH3:24][O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:31])[C:27]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:10]2[C:9]([CH3:23])([CH3:22])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)[NH:11]2)[CH:16]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 7.7 %

Procedure:
A mixture of 3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1 g, 3 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.65 g, 9 mmol) and potassium carbonate (2.07 g, 15 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 10 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (100 mg, 7%) as a brown oil: LC/MS m/e calcd for C23H30N2O4S (M+H)+: 431.57, observed: 431.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[C:9]([O:10][CH3:12])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Dissolve 2,6-dichloro-3-hydroxy-benzaldehyde (10.7 g, 56 mmol) in N,N-dimethylformamide (80 ml), add potassium carbonate (15 g, 112 mmol), cesium carbonate(18.3 g, 56 mmol), iodomethane (7 ml, 112 mmol) and stir over night at room temperature. Filter reaction mixture into water washing solids with DMF, extract filtrate with ethyl acetate wash with water, brine, dry over sodium sulfate, filter and concentrate to yield 10 g (87%) of 2,6-dichloro-3-methoxy-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (0.35 g, 0.09 mmol) in anhydrous THF (2 mL), triphenyl phosphine (70.8 mg, 0.27 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.032 mL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (0.052 mL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to purification by preparative HPLC. The proper fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. The solution was evaporated under reduced pressure to afford Compound 13 as an off-white solid in 52.8% yield. LCMS m/z (%)=476 (M+H 35Cl, 100), 478 (M+H 37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.55 (s, 1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.97 and 2.72 Hz, 1H), 7.47 (d, J=2.70 Hz, 1H), 743-7.36 (m, 1H), 7.26 (d, J=9.04 Hz, 1H), 7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, 3H), 2.58-2.45 (m, 2H), 2.45-2.29 (m, 4H), 1.75-1.69 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=O)=[CH:30][CH:29]=1>>[CH2:10]([N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:35]([CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[N:1][C:2]=2[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(Cc2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1
Yield: 18 %

Procedure:
An amidation reaction was carried out under the same conditions as in Example 1 using 6.48 g (30 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide obtained in Reference Example 2 and using, instead of benzoyl chloride, 4-methoxyphenylacetyl chloride which was separately prepared according to a conventional method. A crude amide product was obtained after the post-treatment. The crude amide was subjected to a cyclization reaction for 13 hours under the same conditions as in Example 1. 1.92 g of 7-benzyl-2-(4-methoxybenzyl)hypoxanthine was obtained after the post-treatment. Yield 18% (2 steps).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:14]Cl>O>[N:1]([CH2:14][C:13]1[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=[C:11]([C:10]([F:9])([F:23])[F:24])[CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (74.3 g, 1.14 mol) is suspended in water (125 mL), then DMSO (625 mL) is added. After stirring for 30 minutes, a solution consisting of 3,5-Bis(trifluoromethyl)benzyl chloride (255.3 g, 0.97 moles) and DMSO (500 mL) is added over 30 minutes. (The 3,5-Bis(trifluoromethyl)benzyl chloride is heated to 35° C. to liquefy prior to dispensing (MP=30-32° C.)). The benzyl chloride feed vessel is rinsed with DMSO (50 mL) into the sodium azide solution, the mixture is heated to 40° C., and then maintained for an hour at 40° C., then cooled to 23° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1C=C([CH:10]=[CH:11][CH:12]=1)N)=[O:4].C(I)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=O)[CH3:26])[CH3:23]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[C:25]([CH:10]=[CH:11][CH:12]=1)[N:24]([CH2:22][CH3:23])[CH2:28][CH3:29])=[O:4]
Reactant: CCN(CC)C(C)=O
Reactant: COC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN(CC)c1cccc(NC(=O)OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 4.5 g of 3-(methoxycarbonylamino)-aniline, 21.6 g of ethyl iodide, 14.4 g of sodium carbonate, and 90 ml of N,N-diethylacetamide was stirred for 1 hour at 110° C. The reaction mixture obtained was poured into 300 ml of water followed by stirring well and extracted with ethyl acetate. The extract was washed with water, dried by Glauber's salt, and the solvent was distilled off using a rotary evaporator to provide 6.0 g (yield: 100%) of an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.[ClH:19].[NH2:20][OH:21].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=[N:20]\[OH:21]
Reactant: NO
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C2CCC1CC(/C(=N/O)c1ccccc1F)C2

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanone (29.5 g), hydroxylamine hydrochloride (16.5 g) and ammonium acetate (27.5 g) were heated in 80 ml of refluxing ethanol-water (3:1 mixture) for 19 hours. The mixture was cooled and the precipitated product was collected (25.2 g).
Reaction SMILES: N1CCCCC1.C(NC(N1C2C(=CC(OC3C=CN=C(NC(=O)OC4C=CC=CC=4)C=3)=CC=2)C=C1)=O)C.[CH2:38]([NH:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([NH:59][C:60]([N:62]4[CH2:67][CH2:66][CH:65](N5CCCC5)[CH2:64][CH2:63]4)=[O:61])[CH:54]=3)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1)=[O:42])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([NH:59][C:60]([N:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)=[O:61])[CH:54]=3)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1)=[O:42])[CH3:39]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Agent: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCCCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (4 ml) and piperidine (0.31 ml, 3.13 mmol) were added to a mixture (0.336 g) of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as crystals (182 mg, 0.45 mmol).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[C:15]3[N:16]([N:20]=[N:21][N:22]=3)[CH:17]=[CH:18][N:19]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:17]1[N:16]2[N:20]=[N:21][N:22]=[C:15]2[C:14]([N:12]2[CH2:13][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2nccn3nnnc23)C1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl methyl(1-(tetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)carbamate (200 g, 0.66 mol) and DMF (1 L). To the above was added N-bromosuccinimide (117 g, 0.66 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (500 mL), and dried to afford 200 g (79%) of the product as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2([OH:21])[CH2:19][OH:20])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]2([OH:21])[CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)COS(C)(=O)=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2.76 g (1.05 equivalents) methylsulphonyl chloride were added to a solution of 6.42 g (24 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane prepared as described in Example 1 (i) and 2.55 g (1.1 equivalents) triethylamine in 50 ml dichloromethane at 10°-15° C. The reaction mixture was kept at 10°-15° C. for further 2 hours and then washed with 20 ml water, then 20 ml aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and flashed. Trituration with 60/80 petroleum gave 6.64 g 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-methylsulphonyloxymethylcyclopentane (Isomer A) as a white solid, m.pt. 113°-114° C. Yield: 80%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:14]([S:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([S:18][C:19](=[O:24])[CH:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[C:21](=[O:23])[CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)SC(C)(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-ethanesulfonylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:19][C:20]1[C:25]([C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1
Reactant: OB(O)c1ccc(F)nc1F
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(F)nc3F)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0,05 M of 4-(trans-4-pentylcyclohexyl)bromobenzene, 0,06 M of 2,6-difluoropyridine-3-boronic acid, 1,25 g of Pd(PPh3)4, 100 ml of toluene, 40 ml of ethanol and 50 ml of 2 M Na2CO3 -solution is heated at 60 ° C under stirring for 2 hours. Customary work-up and recrystallisation from ethanol gives 2,6-difluoro-3-[4-(trans-4-pentylcyclohexyl)phenyl]-pyridine with C 58° N 107° I.
Reaction SMILES: N[C@H](C=O)CCSC.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[C:22]([O-:27])(=O)[C:23]([CH3:25])=[O:24].[Na+].C(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[C:30]1([CH2:25][C:23]([CH2:22][OH:27])=[O:24])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CSCC[C@H](N)C=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CO)Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
9.5 ml of 0.1 M citric acid and 40.5 ml of 0.1 M tri-sodium citrate were diluted to 100 ml to give a pH 6 citrate buffer solution. (Ref.: Buffers for pH and Metal Ion Control, D. D. Perrin and B. Dempsey, Publ. John Wiley and Sons, pg 103). Petroleum spirit (40 ml), ethanol (0.5 ml), the pH 6 citrate buffer (5 ml) and sodium pyruvate (2.5 g, 23 mmol) were stirred at room temperature for 1 h. Benzaldehyde (127 mg, 1.2 mmol) and baker's yeast (5 g) were then added and the reaction stirred at 5° C. for 24 h. The mixture was then filtered and yeast washed with diethyl ether. After removal of the solvent in vacuo the product was purified by flash distillation (200° C./1 mm) to give phenylacetylcarbinol (44 mg, 24%). The GC of the product showed pure PAC (11.88 min.). Chiral GC showed a ratio of 97.5:2.5, 95% ee.
Reaction SMILES: C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35]O)([CH3:30])([CH3:29])[CH3:28].[C:38]1(=[O:44])[NH:42][C:41](=[O:43])[CH:40]=[CH:39]1>O1CCCC1>[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][N:42]1[C:38](=[O:44])[CH:39]=[CH:40][C:41]1=[O:43])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=CC(=O)N1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCN1C(=O)C=CC1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A toluene solution of Mitsunobu reagent (diethyl azodicarboxylate) (1.106 g/ml, 8.2 mmol, 1.29 ml) was gradually added to a tetrahydrofuran solution (25 ml) of triphenylphosphine (2.15 g, 8.2 mmol) at −78° C. To the thus obtained solution, a tetrahydrofuran solution (5 ml) of (2-hydroxyethyl)carbamic acid tert-butyl ester (1.32 g, 8.2 mmol) and maleimide (794 mg, 8.2 mmol) was added, followed by stirring at −78° C. for 5 minutes and further stirring at room temperature for 36 hours. The thus obtained reaction solution was concentrated, ether was added thereto, and the formed precipitate was removed by filtration. The thus obtained filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2-(maleimido)ethylcarbamic acid tert-butyl ester (531 mg, 2.53 mmol, yield 31%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](N)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].N(OCCC(C)C)=O.C[Si](C)(C)[Br:29].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:29])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N)c(-c2ccc(F)cc2)n1
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.26 g 5-amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester in 25.0 ml dibromomethane was added 0.85 ml isoamyl nitrite. To the resulting suspension was added during 30 minutes a solution of 0.82 ml trimethyl bromosilane in 5 ml dibromomethane at room temperature. The mixture was stirred at room temperature for 2 hours. To the resulting turbid solution was added 10% aqueous sodium bicarbonate, the phases were separated and the organic layer was dried over magnesium sulfate, evaporated and purified by chromatography on silica gel using a gradient of heptane to 10% ethyl acetate in heptane to yield 0.81 g of the title compound as white crystals. MS (ISP) (M+H+)=311.1 and 313.0.
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[K]>C(Cl)(Cl)(Cl)Cl>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: [K]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 94 %

Procedure:
To 100 ml. of carbon tetrachloride saturated with chlorine at 0° C. to 5° C. were added 5 grams (27 mmoles) of potassium phthalimide. The resulting yellow-green suspension was allowed to warm to room temperature and then was stirred for 60-90 minutes. The solvent then was removed in vacuo, and about 100 ml. of water were added to the resulting white solid. The mixture was filtered, and the collected solid was washed with water and vacuum dried to obtain 4.6 grams (94% yield) of N-chlorophthalimide.