Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:18])[CH:11]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (9.2 g, 37.4 mmol) in CH2Cl2 (150 mL) and TBDMS-Cl (5.6 g, 37.4 mmol), was added Et3N (5.2 mmol, 37.4 mmol) portionwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours at the same temperature. The reaction was washed with H2O (150 mL). The CH2Cl2 was dried over MgSO4 and concentrated under vacuum. To a solution of the residue in MeOH (100 mL), was Pd/C (150 mg) added. The reaction was stirred under H2 (1 atm) for 5 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (8.9 g, 88.3%) as a grayish solid. The crude compound was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 6.99˜6.96 (m, 1H), 6.83˜6.81 (m, 2H), 3.70 (t, 2H), 2.63 (t, 2H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[O:16])(=[O:10])=[O:9].F[C:31]1C=CC=C[C:32]=1S(Cl)(=O)=O>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:32]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3F)c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3F)c2)cc1

Procedure:
4-[3-(2-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=413.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 2-fluoro-benzensulfonyl chloride and yielded 4-[3-(2-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=[C:14](Cl)[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:23]1([CH3:22])[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH:29][C:14]2[C:13](=[O:21])[N:12]([CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: Cc1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (656 mg, 2.00 mmol), as prepared in the preceding step, 4-methylphenethylamine (380 mg, 2.81 mmol), triethylamine (405 mg, 4.01 mmol), and ethyl acetate (20 mL) was refluxed overnight. After cooling to room temperature, the solution was washed with 10% citric acid (×2). The aqueous solutions were back extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and contracted to give the title compound as a yellow solid (854 mg, 100%). 1H NMR (CDCl3) δ 7.38-7.32 (m, 5H), 7.12 (s, 4H), 6.09 (s, 1H), 5.21 (s, 2H), 4.79 (s, 2H), 3.65 (dd, 2H, J=7.0, 13.0 Hz), 2.88 (t, 2H, J=7.1 Hz), 2.32 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:24])[C@H:17]([CH3:23])[CH2:18][C:19]([F:22])([F:21])[F:20])C1C=CC=CC=1.O>C(OCC)C>[F:20][C:19]([F:22])([F:21])[CH2:18][C@@H:17]([CH3:23])[CH2:16][OH:24]
Reactant: C[C@H](CC(F)(F)F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H](CO)CC(F)(F)F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of lithium borohydride (23 mL, 2.0 M in THF, 45 mmol) was added dropwise to a solution of (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-methylbutanoyl]-1,3-oxazolidin-2-one (12.9 g, 40.9 mmol) and water (810 μL, 45.0 mmol) in diethyl ether (200 nL) at 0° C. The reaction mixture was allowed to warm to 25° C. and, after 1 h, was cooled to 0° C. and quenched with aqueous 1 N NaOH (124 mL). The mixture was warmed to 25° C. and stirred until both layers were homogeneous. The layers were separated and the organic extract was washed with brine, dried using MgSO4 and concentrated. Flash chromatography (eluent: 3:7 ether-petether) provided (2R)-4,4,4-trifluoro-2-methylbutan-1-ol (5.05 g, 87%) as a colorless oil. 1H NMR was identical to that which was found in the literature (J. Med. Chem. 37: 1282–1297 (1994)).
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10, 2.5 g (5.74 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in the presence of 3.22 mg of [Ru(OAc)2((S)-6-MeO-2-naphthyl)-MeOBIPHEP)] (S/C molar ratio 2000) at 40° C. under 15 bar of hydrogen for 24 h to reach 99.6% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 75.8% ee with 98.5% purity (HPLC area). To a solution of 6.50 g (15.8 mmol) of crude product in 33 ml of tetrahydrofuran was added dropwise at reflux (63-65%° C.) under stirring a solution of 1.91 g (15.6 mmol) of (S)-phenyl ethylamine (commercially available from Fluka) in 3 ml of tetrahydrofuran. Addition of seed crystals and turning off the bath heating brought about the start of the crystallization. The crystallization was completed over night at room temperature, the white crystals were filtered off, washed with 20 ml of cold (−20° C.) tetrahydrofuran and dried to constant weight (50° C./10 mbar/6h) to afford 6.57 g (79.2%) of (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as (S)-phenyl ethylamine salt of 96.3% ee with 99.9% purity (HPLC area), with a mp. of 157-159.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCOC(C)=O.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 29 %

Procedure:
To a suspension of 5-tert-butyl-2-methoxy-1,3-dinitrobenzene (10.2 g, 0.04 mol) in EtOAc (150 mL) was added in a single portion a solution of sodium sulfide nonahydrate (19.2 g, 0.08 mol) in water (200 mL). Aliquate® 336 (0.8 g, 5 mole %) was added in a single portion, and the two-phase mixture was brought to a reflux. All solids dissolved, and the mixture became red/brown. After about 3 h, TLC (3:1 hexanes:EtOAc) revealed almost complete loss of starting material. The mixture was filtered warm through a pad of diatomaceous earth to remove insolubles, and the filter cake was washed with fresh EtOAc. The clarified two-phase mixture was separated, and the organic layer was washed with sodium carbonate solution, followed by water and then saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated under reduced pressure to a thick, dark oil. This oil was extracted three times with refluxing hexanes, leaving behind a dark residue. The orange extract deposited some more dark oil, from which the warm supernatant was decanted. The resulting orange solution was heated back to reflux, and treated with both activated charcoal and diatomaceous earth. The solution was filtered hot, and the filter cake washed with hot hexanes. Re-heating the orange filtrate resulted in a clear solution. Quickly cooling the solution in an ice/acetone bath and scratching the flask with a glass rod resulted in the deposition of an orange/yellow precipitate. The suspension was allowed to cool for 1 h, and then filtered. The filter cake was washed with a small portion of cold hexanes, and then dried on the filter, providing the title compound as a yellow/orange powder (2.6 g, 30%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][OH:23])[C:16]=1[CH3:24]>O.O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([OH:23])[C:3]([NH:2][CH3:1])=[O:4])[C:16]=1[CH3:24]
Reactant: CN=C=O
Reactant: COC(=O)c1ccccc1Nc1cccc(CNO)c1C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)N(O)Cc1cccc(Nc2ccccc2C(=O)OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Methyl isocyanate (0.33 g, 5.8 mmol) is added dropwise to 2-[[3-(N-hydroxyamino)methyl-2-methylphenyl]amino]benzoic acid methyl ester (1.5 g, 5.2 mmol) in 33% water/dioxane (60 mL) with ice bath cooling. The reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (50 mL) and dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by recrystallization first from ether and then from ethyl acetate to give 2-[[3-[[hydroxy[(methylamino)carbonyl]amino]methyl]2-methylphenyl]amino]benzoic acid methyl ester (0.68 g, 38%). mp=173-175° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Br-].[CH2:31]([Zn+])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cc2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), 0.5M benzyl zinc(II) bromide in THF (1.32 mL) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (18 mg) in THF (2 mL) was stirred at 60° C. for 16 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine and dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-8% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccnc(Cl)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 2-chloro-3-pyridinol (11.3 g, 87.2 mmol) in concentrated sulfuric acid (25 mL) was cooled in an ice-bath and a 1:1 mixture of nitric acid and sulfuric acid (25 mL) was added slowly. After everything was added, solution was stirred at 0° C. for 1 hour and then at room temperature for another hour. Mixture was diluted with water and extracted with methylene chloride. Organic phases were dried over magnesium sulfate, filtered, and concentrated. Residue was purified by column chromatography on silica gel (ethyl acetate/hexane 2:1→3:1) to give 2-chloro-4-nitro-pyridin-3-ol as a tanned solid (3.58 g, 24%). 1HNMR (CDCl3, 400 MHz) δ 10.5 (s, 2H), 8.14-8.13 (d, J=5.5 Hz, 1H), 7.88-7.87 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[C:9]([CH3:10])=[CH:14][N:15]([CH3:16])[CH3:17])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Product: CC(=CN(C)C)C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 50.0 g of p-chloropropiophenone and 200 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 28 hours. The reaction mixture was evaporated in vacuo to give a yellow oil. The oil was then subjected to Kugelrohr distillation. The residual oil from the distillation was collected and triturated with hexane to provide crystals. The solid was collected by filtration and gave 21.5 g of 4'-chloro-3-dimethylamino-2-methylacrylophenone as yellow crystals, m.p. 45°-47° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]2[C:24]([C:25]3[N:30]=[C:29](S(C)=O)[C:28]([F:34])=[CH:27][N:26]=3)=[CH:23][N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]2=[N:20][CH:21]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:34][C:28]1[C:29]([NH:1][CH:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:30][C:25]([C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([F:15])[CH:17]=3)[N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:23]=2)=[N:26][CH:27]=1
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Temperature: 80 °C

Procedure:
A suspension of ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.20 g, 1.00 mmol), 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 25a (0.54 g, 1.20 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol) in THF (14.4 mL) was refluxed at 80° C. overnight. After removing the solvent in vacuo, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 300 mg of the desired product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.99 (d, J=3.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 5.23 (d, J=8.9 Hz, 1H), 4.80 (td, J=9.7, 3.6 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H), 3.91 (q, J=7.1 Hz, 2H), 2.73-2.58 (m, 1H), 2.44 (dd, J=14.7, 9.6 Hz, 1H), 2.33-2.21 (m, 3H), 1.72-1.46 (m, 7H), 1.42-1.31 (m, 1H), 1.28 (t, J=6.1 Hz, 1H), 1.17 (dd, J=13.4, 6.2 Hz, 2H), 0.98 (t, J=7.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.25 minutes (M+H) 584.29.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[N:24]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:11]3[N:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH:18]1([NH:17][C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[N:3][CH:4]=4)[N:24]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(Cl)nc1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(NCCCO)nc1
Yield: 30.2 %

Procedure:
To a biotage initiator microwave vial (0.2-0.5 mL) containing 6-chloro-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-nicotinamide ((B11), 0.27 mmol, 100 mg, 1 eq.), 3-aminopropan-1-ol (0.54 mmol, 0.028 mL, 2 eq.) and N,N-diisopropylethylamine (0.54 mmol, 0.094 mL, 2 eq.) in butanol (2 mL), was capped and heated in a biotage initiator 60 microwave for 30 minutes at 180° C., and a further 10 minutes at 210° C. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (33.4 mg, 30%). HPLC, Rt: 2.37 min (purity: 92%). LC/MS M+(ESI): 410.2, M−(ESI) 408.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N+]([O-])=O)=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1.[CH3:24][S-:25].[Na+]>CN1CCN(C)C1=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:25][CH3:24])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: C[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc(C)c2)c1
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OCCc2cccc(C)c2)c1
Yield: 66.5 %

Procedure:
The compound of step 1 (900 mg, 2.85 mmol) was dissolved in 1,3-dimethyl-2-imidazolidinone (6 ml), and sodium methanethiolate (0.23 g, 3.29 mmol) was added. The mixture was reacted at room temperature for 60 h, then partitioned between a saturated sodium chloride solution and EA, and the aqueous phase extracted with EA. The organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 600 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[C:15]#[N:16])[CH:7]=[C:8]([Cl:13])[C:9]=1[N:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CN(C)c1c(Cl)cc(CC#N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1c(Cl)cc(C(C#N)C(=O)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.41 g (35.3 mmol) of sodium hydride are initially charged in absolute THF (50 ml), and 4.05 g (17.6 mmol) of [3,5-dichloro-4-(dimethylamino)phenyl]acetonitrile in 20 ml of absolute THF are added dropwise at 0° C. The mixture is stirred at 0° C. for 20 minutes, and 5.02 g (35.3 mmol) of ethyl trifluoroacetate are then added dropwise at 0° C. The reaction mixture is warmed to room temperature and then carefully added to water. After washing with n-hexane, the aqueous phase is acidified with 1 N HCl. A colourless solid precipitates out and is, after filtration with suction and air-drying, used without further purification for the next step.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:19][CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O.[H-].[Na+].CI.[CH2:26]1COCC1.O>C1COCC1>[CH3:1][O:3][CH2:4][CH:5]([N:19]([CH3:26])[CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=CNC(CCOc1cccc2ccccc12)COC=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC(CCOc1cccc2ccccc12)N(C)C=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)-1-butanol formate, described in Example 3, in THF (30 ml) is added dropwise to a suspension of 51% sodium hydride (600 mg) in THF (30 ml). The mixture is heated at 40° C. for one and a half hours and then cooled to room temperature. A solution of methyl iodide (2.4 g) in THF (10 ml) is added and the mixture stirred at room temperature for 18 hours. Excess sodium hydride is decomposed by the addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated to dryness. The oily residue is subjected to chromatography on silica gel. Elution with methanol-chloroform (1:30) gives the title compound, nmr (CDCl3) δ 2.05 (m, 2H), 2.85 (s, 3H), 3.35 (s, 3H), 3.6 (m, 1H), 4.15 (m, 4H), 6.75-8.35 (7H), 8.15 (s, 1H).
Reaction SMILES: [CH2:1]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[C:11]([O:13]C)=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].CO>O>[CH2:1]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ocnc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCc1ocnc1C(=O)O
Yield: 79.9 %

Procedure:
40 g of 5-n-pentyl-4-methoxycarbonyloxazole, 27 g of potassium hydroxide, 1000 ml of methanol and 50 ml of water are treated in the same manner as described in Preparation 1-(2). 29.7 g of 5-n-pentyl-4-oxazolecarboxylic acid are thereby obtained. Yield: 80%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.[C-:19]#[N:20].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu](I)I.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:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[CH:7][C:8]=1[C:19]#[N:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)c1cccc(Cc2ccccc2C#N)c1
Yield: 151.3 %

Procedure:
To a solution of 3-tert-butylphenyl trifluoromethanesulfonate (6.17 g, 21.9 mmol) in acetonitrile (80 ml) were added sodium cyanide (2.15 g, 43.8 mmol) and copper iodide (0.42 g, 2.19 mmol). To the mixture was added tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) under nitrogen stream and the mixture was heated under reflux for 5 hrs. The mixture was diluted with ethyl acetate, and insoluble material was filtered off with celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ether=1:0, 20:1) to give 3-tert-butylbenzylbenzonitrile (4.13 g) as a colorless transparent oil. The compound included impurities, but was directly used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Reactant: Clc1ccc(CCCCCBr)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)C(C#N)CCCCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.5 g (17.2 mmol) of 5-(4-chlorophenyl)pentyl bromide, 3.36 g (17.2 mmol) of (4-methylphenyl)sulfonylacetonitrile, 2.26 g (17.2 mmol) of 1,8-diazabicyclo(5,4,0)undec-7-ene and 30 ml of benzene is stirred at room temperature for 6 hours. Then the reaction mixture is washed with water; the organic phase is dried, and concentrated. The concentrate is chromatographed with a mixture of toluene and dioxane (10:1) on silica gel. Yield: 4.2 g (65% of theory) of the title compound, a colorless oil.