Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:20][OH:21])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:29]([CH3:31])[CH3:30].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:20][O:21][CH:29]([CH3:31])[CH3:30])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)I
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=NO)c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(c1ncc(Cl)cc1Cl)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To 655 mg of tert-butyl (S)—N-[2-(3,5-dichloropyridin-2-yl)-2-hydroxyimino-1-methylethyl]carbamate in 1.6 ml of N,N-dimethylformamide, 445 mg of potassium carbonate and 789 mg of 2-iodopropane were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, washed with water (10 ml×2) and dried over saturated aqueous sodium chloride and then aqueous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 411 mg of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][O:3]1.[Br:10]N1C(=O)CCC1=O.C([O-])(=O)C.[NH4+]>CCOCC.C(OCC)(=O)C>[Br:10][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[CH2:7][C:6]1=[O:8]
Reactant: CC1(C)CC(=O)CCO1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)C(Br)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
Into around-bottom flask, was placed a solution of 2,2-dimethyloxan-4-one (1.00 g, 7.80 mmol, 1.00 equiv) in ether (20 mL). N-Bromosuccinimide (1.50 g, 25.5 mmol, 3.26 equiv) was added in portions, followed by the addition of ammonium acetate (60.0 mg, 0.78 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 25° C., then diluted with ethyl acetate (20 mL). The resulting mixture was washed brine (2×40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:30) as the eluent to obtain the title compound as a yellow oil (508 mg, 31%).
Reaction SMILES: Cl[CH2:2][Cl:3].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:16])=[C:12](CO)[N:13]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[Cl:3][CH2:2][C:12]1[N:13]=[C:9]([C:5]2[O:4][CH:8]=[CH:7][CH:6]=2)[O:10][C:11]=1[CH3:16]
Reactant: ClCCl
Reactant: Cc1oc(-c2ccco2)nc1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1CCl
Yield: 31 %

Procedure:
The dichloromethane (1 mL) solution of {2-(furan-2-yl)-5-methyloxazol-4-yl}methanol (36 mg, 0.2 mmol), N,N-dimethylaminopyridine (37 mg, 0.3 mmol) and p-toluene sulfonyl chloride (57 mg, 0.3 mmol) was stirred at 60° C. for 2 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 4-(chloromethyl)-2-(furan-2-yl)-5-methyloxazole (13 mg, 31%) as a transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]2[C:11]([C:12]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:14]=[CH:15]2)=[N:10]1
Reactant: Fc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: Fc1ccc(CBr)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(F)cc2Cl)cc1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-7-trifluoromethyl-1H-indazole (6.43 g, 23 mmol) in 20 mL DMF was added 2-chloro-4-fluoro benzyl bromide (7.0 g, 31 mmol). The reaction mixture was heated overnight at 120° C. After cooling to room temperature, ethyl acetate was added and the solution was washed three times with brine. The organic layer was dried over NaSO4 and concentrated. Flash chromatography (hexane/CH2Cl2, 1:1, as eluent) afforded 4.1 g of pure product. Three grams (3 g) of product were recrystallized from 10 mL of isopropanol to recover 1.98 g of crystalline product, mp 78° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[O:11][C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([Si:2]([CH3:14])([CH3:13])[CH3:1])[O:11][C:10]=12
Reactant: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Reactant: O=P(Cl)(Cl)Cl
Product: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Temperature: 100 °C

Procedure:
2-(Trimethylsilyl)furo[3,2-b]pyridine N-oxide (10.51 g, 50.7 mmol) dissolved in POCl3 (47.3 ml, 507 mmol) in a sealed flask and heated at 100° C. for one hour. The reaction was cooled to RT, poured into a beaker washing with minimal DCM, and cooled in a brine bath. Saturated sodium bicarbonate solution was added very slowly and then solid sodium bicarbonate was added portion wise until the solution was at about pH=8. The solution was extracted twice with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 5-40% EtOAc:Hex) to afford 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine as a pale yellow oil. MS: M+H+=226.2
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>ClCCl.CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:14](=[O:15])[N:3]([CH3:4])[CH3:2])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.0 mmol) and (S)-N-t-butoxycarbonyl-2-amino-4-phenylbutyric acid (0.84 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 3:1 dichloromethane/DMF reaction solvent) giving the product which was used without further purification. Yield 238 mg, 93%; HPLC (60/40) 5.98 minutes (97%).
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([C:4]1[C:16]([O:17][CH3:21])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCc1cc(C(C)=O)c(OC)cc1OCCCCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture of 1.365 g of 5-(4-acetyl-5-hydroxy-2-allylphenoxy)pentanenitrile, 0.966 g of potassium carbonate, and 1.42 g of methyl iodide in 50 ml of dimethylformamide was stirred together at room temperature for 5 hours. The mixture was partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide 1.2 g of the desired title product, m.p.=40°-42° C. NMR, MS.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(C(C)C)CC)(C)C.[CH2:36]([O:38][CH2:39]Cl)[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:37]
Reactant: CCOCCl
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (500 mg, 2.06 mmol) in dry dichloromethane (20 ml) at room temperature was added diisopropylethylamine (1.33 g, 10.3 mmol) and, after 3 minutes, ethoxymethyl chloride (831 mg, 10.3 mmol) in dichloromethane (5 ml). The reaction was stirred for 1 h before diluting with dichloromethane (30 ml), washing with water (2×20 ml), dilute hydrochloric acid (20 ml), saturated sodium chloride solution (20 ml) and drying (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-ethoxymethoxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (567 mg), nD 1.5182. NMR peaks at: 185.3, 181.6, 155.5, 137.1, 133.8, 133.2, 132.0, 131.4, 126.3, 126.2, 33.6, 30.1, 29.5, 29.4, 29.3, 28.9, 24.1, 23.9, 16.7, -1.6; 96.9, 65.8, 15.0 (O--CH2 --O--CH2CH3).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1CN
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.29 g) and DBU (0.33 g) was refluxed for an hour and then stirred at room temperature for 2 hours and allowed to stand overnight. The resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.45 g) as colorless prisms, mp 249°-252.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound. ES-MS m/e (%): 517.4 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35](C(Cl)(Cl)Cl)[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1.O>CN(C=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35]([N:2]([CH3:3])[CH3:1])[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(N(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dimethylamine (40% aqueous, 0.51 mL, 4.1 mmol) was dissolved in DMF (2 mL) under nitrogen, and N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.151 g, 0.23 mmol) was added. The reaction mixture was stirred for 40 minutes at ambient temperature, then poured into water (40 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×25 mL), brine (25 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel, eluting with 75% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6) 10.9 (br, 1), 9.4 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 3.9 (s, 3), 3.8 (s, 2), 3.0 (s, 6) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1)=[O:27]>C(Cl)Cl.CO>[CH3:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:5]3[N:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)=[CH:11][CH:12]=2)[CH2:20][CH2:21]1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1
Reactant: O=Cc1ccc(OB(O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(C=O)cc4)cn3)cc2)CC1

Procedure:
The product was obtained analogously to Example 1.1e starting from 5-bromo-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine and 4-formylphenylboric acid. Yield: 0.20 g (47% of theoretical); C28H28N2O2 (M=424.534); calc.: molpeak (M+H)+425; found: molpeak (M+H)+: 425; Rf value: 0.40 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A28 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), propane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 1.09 (t, 3H), 1.90 (m, 2H), 2.07 (m, 4H), 2.95 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.57 (m, 2H), 5.67 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C19H25N5O7S2 499.12, found 500.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1Cl
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-3-methylbenzoic acid (6.75 g, 39.39 mmol) [prepared as described above] in EtOAc were added a few drops of DMF and oxalyl chloride (5.1 ml, 1.5 eq.). After stirring the reaction mixture for 1.5 h, the solvent was removed in vacuo to give 2-chloro-3-methylbenzoyl chloride, which was used in the next step without further purification.
Reaction SMILES: [Na].N.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](OCC)=[O:31]>>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:15][CH2:16]1)=[O:22])=[O:31]
Reactant: CCOC(=O)c1ccccn1
Reactant: NC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1
Agent: N
Agent: [Na]
Product: O=C(NC(=O)c1ccccn1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.5 %

Procedure:
Sodium (0.1 g, 4.35 mmol) in liquid ammonia (100-150 cm3) was stirred until the blue colour was discharged. A bomb was charged with [1-(naphth-2-yl-methyl)piperid-4-yl]urea (0.83 g, 2.93 mmol) and the liquid ammonia solution was added. The mixture was stirred at room temperature for 2 days then the bomb was cooled to -78° C., and ethyl picolinate (0.6 g, 3.97 mmol) was added. Stirring was continued for 3 hours at room temperature then the ammonia was allowed to evaporate and the gummy residue triturated with water then ethyl acetate. The ethyl acetate suspension was filtered to give recovered [1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.33 g). The filtrate was evaporated and the residue chromatographed on silica eluting with chloroform then chloroform:ethyl acetate 4:1 to give the title compound (0.37 g).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([OH:20])[C@@H:12]2[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@@H:11]2[CH2:10]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[C@@H:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C@@H:11]2[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@]1(O)C[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@]1(O)C[C@H]2OC(C)(C)O[C@H]2[C@H](OS(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
Triethylamine (5.0 mL, 35.9 mmol) was added dropwise to a 0° C. solution of Example 13B (4.4 g, 17.9 mmol) and methanesulfonyl chloride (1.38 mL, 17.9 mmol) in dichloromethane (60 mL). After stirring overnight, the reaction mixture was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated to afford the crude desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:5]=1[O:12][CH3:13].[C:16](O[K])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:17]/[C:16]2[CH:19]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:5][CH:18]=2)=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: CC(C)(C)O[K]
Reactant: COc1cc(C=O)ccc1C(OC)OC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc(C(OC)OC)c(OC)c2)cc1

Procedure:
The compound was prepared according to the general Horner-Wittig methodology, from 4-formyl-2-methoxybenzaldehyde dimethylacetal (630 mg, 3 mmol), dimethyl-4-carbomethoxylbenzyl phosphonate (775 mg, 1 eq.) using tBuOK (404 mg, 1.2 eq.) as base in anhydrous THF (15 ml); the mixture was heated at 70 C for 90 minutes then worked up as described previously and purified by MPLC with hexanes/ethyl acetate 0-30% gradient. Yield: 795 mg (76%). MS, m/e: 342 (M+) 15%; 311 (M+-MeO, 100%); 294 (5%); 234 (4%); 164 (12%); 139 (10%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=C)/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H](C(C)C)C.[BH4-].[Na+].[CH3:32][OH:33]>N1C=CC=CC=1>[CH3:4][CH2:3][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3[CH2:26][C@@H:32]([OH:33])[C:24](=[CH2:25])[C@H:23]([OH:28])[CH2:22]3)/[C@@H:13]2[CH2:12][CH2:11]1)[CH3:1]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C1[C@H](O)CC(=C/C=C2\CCC[C@]3(C)[C@@H]([C@@H](C)CC)CC[C@@H]23)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A solution of vitamin D2 (5 g, 12.7 mmol) in methanol (400 mL) and pyridine (5 mL) was cooled to −78° C. while purging with argon. The argon stream was stopped and a stream of ozone was passed until a blue color appeared. The solution was purged with oxygen until the blue color disappeared and treated with NaBH4 (1.2 g, 32 mmol). After 20 minutes, the second portion of NaBH4 (1.2 g, 32 mmol) was added and reaction was allowed to warm to room temperature. The third portion of NaBH4 (1.2 g, 32 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 70 mL of water and concentrated under vacuum. The residue was extracted with methylene chloride (3×100 mL). The organic phase was washed with 1M aqueous solution of HCl (2×100 mL), saturated aqueous solution of NaHCO3 (100 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (25% ethyl acetate/hexane) to yield 2.05 g (9.69 mmol, 76% yield) of diol 1 as white crystals. [α]D+56.0 (c 0.95, CHCl3); mp 110-111° C.; 1H NMR (400 MHz, CDCl3) δ 0.96 (3H, s), 1.03 (3H, d, J=6.6 Hz), 3.38 (1H, dd, J=10.5 Hz, J=6.8 Hz), 3.64 (1H, dd, J=10.5 Hz, J=3.2 Hz), 4.09 (1H, d, J=2.3 Hz); 13C NMR (100 MHz, CDCl3) δ 13.6, 16.6, 17.4, 22.6, 26.6, 33.5, 38.2, 40.2, 41.3, 52.3, 52.9, 67.8, 69.2; MS (EI) m/z 212 (2, M+), 194 (17), 179 (18), 163 (10), 135 (19), 125 (34), 111 (100); exact mass calculated for C13H22O ([M−H2O]+) 194.1671, found 194.1665.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>O1CCCC1>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=4[CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: CC(C)n1c(=O)oc2cc(N3C[C@H](CN)OC3=O)ccc21
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture is stirred at room temperature overnight and then concentrated. The product is isolated by column chromatography (silica gel, methylene chloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([F:10])=[CH:6][C:7]=1[C:8]([NH2:9])=[O:13]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
A suspension of 25 g (130.90 mmol) of 2,6-dichloro-5-fluoro-3-cyanopyridine in conc. sulphuric acid (125 ml) was stirred at 60-65° C. for 1 h. After cooling to RT, the contents of the flask were poured into ice-water and extracted three times with ethyl acetate (100 ml each time). The combined organic phases were washed with water (100 ml) and then with saturated aqueous sodium hydrogen carbonate solution (100 ml), dried and concentrated on a rotary evaporator. The material obtained was dried under high vacuum.