Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:4]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=S(=O)(CCCCl)c1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(F)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To mmol 4-(3-chloro-propane-1-sulfonyl)-1,2-difluoro-benzene (300 mg, 1.18 mmol) in 10 ml THF at −78° C. was added dropwise a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF (3.65 ml, 3.32 mmol). The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was quenched by addition of 1 M aq HCl (2 ml) and water (10 ml), and then extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/heptane 1:10) to afford the title compound (90 mg, 37%) as an off-white amorphous solid. MS (ISP): 219.2 MH+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CCCO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CCCO)c1
Yield: 95.9 %

Procedure:
To a solution of 3-(3-nitrophenyl)propan-1-ol (2.70 g, 14.9 mmol) in methanol (50.0 mL) was added 10% palladium on carbon (0.54 g, 0.46 mmol). The resultant mixture was hydrogenated at 50 psi overnight. The reaction mixture was then filtered and concentrated to give the desired product as a light brown thick oil (2.16 g, 96%). LCMS for C9H14NO (M+H)+: m/z=152.1.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][N:9]1[CH2:10][CH2:11][C:6]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
1(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester (14.0 g, 26.5 mmol) dissoved in THF:Methanol (100: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.87 (60%); off white solid; mp 239° C.; MS: 501.9 (M+H)+
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=O)=O)=[CH:7][C:6]=1[N+:15]([O-])=O.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl.CCCCCC>Cl.O>[NH2:15][C:6]1[CH:7]=[C:8]([SH:11])[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Nc1cc(S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a cooled solution (0° C.) of tin(II) chloride (11.260 g, 59.40 mmol) in 10 ml concentrated hydrochloric acid was slowly added 4-chloro-3-nitro-benzenesulfonyl chloride (1.690 g, 6.60 mmol) portionwise. The resulting suspension was kept cool and stirred for 15 minutes before the mixture was heated to reflux for 1 hour. After cooling to room temperature the mixture was diluted with water (100 ml) and carefully neutralised using NaHCO3. The aqueous phase was extracted with chloroform (4×50 ml) and the organic phase separated and dried over Na2SO4. Removal of solvent under vacuum afforded a bright yellow solid. Column chromatography on silica gel using 1:1 chloroform/hexane as the mobile phase afforded 3-amino-4-chlorobenzene thiol as a white solid (0.632 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:4]=1.Br[C:23]1[CH:24]=[C:25]([C:30]2([C:41]3[CH:42]=[N:43][CH:44]=[N:45][CH:46]=3)[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:40])=[N:31]2)[CH:26]=[CH:27][C:28]=1[F:29]>CN(C=O)C.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>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[C:32]([NH2:40])=[N:31][C:30]2([C:25]1[CH:26]=[CH:27][C:28]([F:29])=[C:23]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:24]=1)[C:41]1[CH:46]=[N:45][CH:44]=[N:43][CH:42]=1
Reactant: NC1=NC(c2cncnc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccnc(-c2cc(C3(c4cncnc4)N=C(N)c4c(F)cccc43)ccc2F)c1
Temperature: 110 °C
Yield: 14.9 %

Procedure:
4-Methoxy-2-(tributylstannyl)pyridine (265 mg, 0.67 mmol), 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine (178.3 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium(0) (138 mg, 0.11 mmol) were mixed in dry DMF (2.00 mL) and heated in a microwave reactor at 110° C. for 305 min. The resulting product mixture was filtered and purified by preparative-HPLC to give the title compound (28.2 mg, 12% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:7]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=[CH:5][N:4](C(OCC)=O)[N:3]=1>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: CCOC(=O)N1C=CC(c2c(-c3ccccc3)nn3ccccc23)C(Cl)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Clc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Yield: 76.9 %

Procedure:
A mixture of 3-(3-chloro-1-ethoxycarbonyl-1,4-dihydropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.26 g), manganese (IV) oxide (12.6 g) and chloroform (12.6 ml) was refluxed for 10 hours. After filtration, organic layer was dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel 12.6 g) with a mixture of hexane and ethyl acetate as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-chloropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.78 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[N:11][C:10]=1[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)ccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1nc(C=O)ccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 19.4 g. (0.0846 mol) of 3-benzyloxy-6-hydroxymethyl-2-methylpyridine (liberated from the hydrochloride salt) and 100 g. of manganese dioxide in 800 ml. of chloroform is refluxed with vigorous stirring for three hours. The mixture is filtered and the chloroform is evaporated to give a yellow oil which is chromatographed on alumina, eluting with chloroform. The recovered material is purified through its hydrochloride salt and reconverted to the base, 5-benzyloxy-6-methyl-2-pyridinecarboxaldehyde, m.p. 62°-63°C.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.[H-].[Na+].CN(C)C=[O:17]>>[NH:7]1[C:6](=[O:17])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 100 °C

Procedure:
6-Chloroguanine (0.75 g) and sodium hydride (60% in oil, 0.18 g) in dry dimethylformamide were stirred at room temperature for one hour. DL-erythro-2,2-Dimethyl-4-p-toluenesulfonyloxymethyl-5-hydroxymethyl-1,3-dioxolane [0.70 g, prepared according to A. Holy, Coll. Czech. Chem. Commun Vol 44, pages 593-612 (1979)] was added and the reaction mixture was heated at 100° C. for 17 hours, after which it was filtered through a Celite pad, and the solution was evaporated in vacuo. The residue was refluxed with acetic acid (25 ml) for 2 hours. The solvent was evaporated and the residue was coevaporated with water (3×5 ml). The residue was dissolved in a small volume of 1N hydrochloric acid, and added to a column of Dowex 50×8 (H+, 70 ml)which was eluted with water (1 liter) followed by aqueous ammonia (diluted 1/10). The elution was monitored by a UV detector. The appropriate fractions were evaporated in vacuo, and the residue was coevaporated with water several times, finally dissolved in boiling water (230 ml) and filtered to give 9-(DL-erythro-2,3,4-trihydroxybutyl) guanine (0.20 g). NMR (DMSO-d6)δ: 7,8 (s,8C-H); 6.4 (NH2); 4.22 (N-CH2).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:10]([CH2:29][O:30]CC2C=CC(Cl)=CC=2)[O:9][C@H:6]1[O:7][CH3:8])(=[O:3])[CH3:2].N1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[Sn](Cl)(Cl)Cl>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:10]([CH2:29][OH:30])[O:9][C@H:6]1[O:7][CH3:8])(=[O:3])[CH3:2]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1COCCN1
Product: CO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Yield: 87.2 %

Procedure:
The general procedure C using 20 (73.1 mg, 0.135 mmol), morpholine (14.1 μL, 0.162 mmol), Pd(OAc)2 (1.2 mg, 0.0054 mmol), 1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino) biphenyl (5.4 mg, 0.0054 mmol) and K3PO4 (40.0 mg, 0.189 mmol) for 12 h at 100° C. afforded a yellow oil. Cleavage of the aminated intermediate with SnCl4 (162 μL 1.0 M in CH2Cl2, 0.162 mmol) using general procedure D gave 49.0 mg (87%) of 26 as a white solid after purification by flash column chromatography on silica gel (50% EtOAc/Hexanes). [α]24D: −23.5° (c 3.24, CH2Cl2); IR (thin film) 3474, 2879, 1747, 1234, 1082 cm−1; 1H-NMR (CDCl3) δ 7.37-7.26 (m, 10H), 5.00-4.92 (m, 1H), 4.85 (d, J=11.0 Hz, 1H), 4.83 (d, J=11.9 Hz, 1H), 4.69 (d, J=11.0 Hz, 1H), 4.67 (d, J=11.0 Hz, 1H), 4.34 (d, J==7.9 Hz, 1H), 3.92-3.88 (m, 1H), 3.77-3.69 (m, 3H), 3.49 (s, 3H), 3.42-3.40 (m, 1H), 1.98 (s,3H), 13C-NMR (CDCl3) δ 169.8, 138.2, 137.9, 128.7, 128.6, 128.2, 128.1, 128.0, 1:27.9, 102.1, 82.7, 77.7, 75.4, 75.3, 75.2, 73.2, 61.9, 57.1, 21.1; FAB MS m/z (M+Na)+: calcd 439.1733, obsd 439.1730.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[F:38]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[F:38]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccncc3F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1cnccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 38.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-fluoropyridine (89 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-2-trifluoromethyl[1,8]naphthyridine (33 mg, 40%). δH (360 MHz, CDCl3) 7.43-7.49 (2H, m), 7.58-7.61 (3H, m), 7.86 (1H, d, J 8.8), 8.55 (2H, dd, J 6.0 and 2.1), 8.63 (1H, d, J 1.8), 9.30 (1H, d, J 4.2). m/z (ES+) 388 [MH]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][CH2:10][CH2:9][C@H:8]([NH2:7])[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-3-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (546 mg, 1.1 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Colourless oil (355 mg, 86%). LCMS (Method B): RT 1.89 min [M+H]+ 377.3.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:13][CH3:14])[C:8](=[O:12])[CH:9]([OH:11])[CH3:10])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:11][CH:9]([CH3:10])[C:8]([N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1)[CH2:13][CH3:14])=[O:12]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(C(=O)C(C)O)c1cn(-c2cccnc2)nc1Cl
Solvent: ClCCl
Product: CCN(C(=O)C(C)OC(=O)N(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-hydroxypropanamide (0.10 g, 0.34 mmol) in CH2Cl2 (1.1 mL) was added dimethylcarbamic chloride (0.073 g, 0.68 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with CH2Cl2, washed with water. The phases were separated, dried and concentrated. The residue was purified by basic alumina gel chromatography eluting with 0%-70% acetone/hexanes to afford the title compound F93 as a light yellow oil (0.11 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([N:35]2[CH2:39][C@H:38]([CH2:40][N:41]3[CH:45]=[CH:44][N:43]=[N:42]3)[O:37][C:36]2=[O:46])[CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH2:32][C@@H:31]([CH2:33]O)[O:30][N:29]=2)=[CH:26][CH:27]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:33][C@H:31]1[O:30][N:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[CH:20]=[CH:19][C:18]([N:35]4[CH2:39][C@H:38]([CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[N:42]5)[O:37][C:36]4=[O:46])=[CH:17][C:16]=3[F:15])=[CH:23][N:24]=2)[CH2:32]1)=[O:12])=[O:4]
Reactant: COC(=O)N(C)CCCCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N(C)CCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The carbamate prepared as above (0.37 g, 1.82 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.2 g, 0.46 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 3.5 hours at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white powder (0.225 g), melting point: 103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>C(OCC)(=O)C.O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with methyl 2-(4-chlorophenyl)benzoxazole-4-carboxylate (0.50 g, 1.74 mmol), THF (10 mL), methanol (10 mL), lithium hydroxide (0.08 g, 3.48 mmol) and water (10 mL). The reaction was stirred at room temperature for 18 hours. After this time, the reaction was diluted with ethyl acetate (50 mL) then acidified to pH 4 with 2 N HCl. The aqueous layer was extracted with ethyl acetate (2×25 mL). The organic layers were then combined and washed with brine (1×25 mL), dried with sodium sulfate, filtered and concentrated to dryness in vacuo to yield 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.43 g, 90% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 11.53 (bs, 1H), 8.26 (d, J=8.5 Hz, 2H), 8.18 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.55 (t, J=8.0 Hz, 1H); MS (ESI) m/z 274 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO>O1CCCC1.[C].[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([OH:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
To a solution of 2-hydroxy-4-nitrobenzonitrile (3.98 g, 24.25 mmol) in tetrahydrofuran (17 mL) were added methanol (70 mL) and 10% palladium-carbon (460 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (2.5 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.16 g, 97%) as a brown oil. This was used for the next reaction without further purification.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:16](=[O:18])=[O:17].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[C:12]=1[C:16]([OH:18])=[O:17]
Reactant: COc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.0M in hexane; 25.0 ml, 0.25 mol) was added dropwise to a stirred, cooled (-78° C.) solution of 3,5-difluoroanisole (35.9 g, 0.25 mol) in dry THF (200 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured into a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide (twice), the combined basic extracts were acidified with 36% hydrochloric acid, and the product was extracted into ether (twice), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[CH:28]1([CH2:31][NH:32][C:33](=[O:49])[C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])O.[Na+]>CC(O)C.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:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([C:33]([NH:32][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[O:49])=[CH:35][CH:36]=3)[C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(C)c(Br)c2)cc1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
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: CC(C)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)cc1
Temperature: 85 °C

Procedure:
3-Bromo-N-[3-t-butyl-1-(4-methylphenyl)-pyrazol-5-yl]-4-methylbenzamide (Intermediate 2 2, 43 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (33 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0;5 ml) were mixed in propan-2-ol (2 ml) and heated at 85° C. under nitrogen for 96 hrs. The cooled reaction was absorbed onto silica and applied to a SPE cartridge (Si, 5 g) and eluted with an ethyl acetate/cylohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum to give N3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N4′-(cyclopropylmethyl)-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>ClCCl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:13]([NH:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])=[O:15])[C@@H:10]([CH3:12])[OH:11]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Yield: 85.4 %

Procedure:
Boc-threonine (produced by Wako Pure Chemical Industries Ltd.) (11.0 g, 50 mmol) and glycine ethyl ester hydrochloride (produced by Wako Pure Chemical Industries Ltd.) (8.4 g, 60 mmol) were dissolved in dichloromethane (250 mL). After triethylamine (8.4 mL, 60 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 12.4 g, 60 mmol) and hydroxybenzotriazole (9.2 g, 60 mmol) were further added thereto, the mixture was reacted at room temperature for overnight with stirring. After completion of the reaction, reaction mixture was filtered, and then the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the product was crystallized from hexane, to obtain Boc-Thr-Gly-OEt (1) (13.0 g) (yield; 85.1%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\[CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)/[CH2:3][CH2:4][CH:5]=[O:6]>C1CCCCC1.[Pd]>[CH3:1][CH:2]([CH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)[CH2:3][CH2:4][CH:5]=[O:6]
Reactant: C/C(=C\C1CCC(C)CC1)CCC=O
Agent: [Pd]
Solvent: C1CCCCC1
Product: CC1CCC(CC(C)CCC=O)CC1

Procedure:
(E)-4-Methyl-5-(4-methylcyclohexyl)pent-4-enal (2.94 g; 15.13 mmol) was hydrogenated in cyclohexane (20 ml) at 20 bar and room temperature in the presence of 5% w/w palladium on charcoal (0.15 g). The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 15:1) followed by bulb-to-bulb distillation (60° C./0.01 mbar).