Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.[N:9]1([CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>ClCCl>[N:9]1([CH2:15][CH2:16][CH2:17][S:18]([NH2:1])(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: N
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: NS(=O)(=O)CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dichloromethane (40 ml) was saturated with ammonia gas with cooling (dry ice/acetone), and then 3-morpholin-4-yl-propane-1-sulphonyl chloride (279 mg, 1.23 mmoles) was added. The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate evaporated and the residue was dried at 40° C. in vacuo to afford compound 58 (210 mg) as a gum. LC/MS System A; Rt=0.28 mins, m/z (ES+)=209 (M+H for C7H16N2O3S).
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][C@@H:7]2[C@@H:4]([CH2:5][C:6]2=[O:9])[CH2:3]1.[BH4-].[Na+]>CO>[C@@H:4]12[CH2:5][C@H:6]([OH:9])[C@@H:7]1[CH2:8][C@H:2]([OH:1])[CH2:3]2
Reactant: O=C1C[C@H]2C[C@@H](O)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1C[C@@H]2C[C@H](O)[C@@H]2C1
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 19.33 g (153 mmol) of (1R,3R,5R)-3-hydroxybicyclo[3.2.0]heptan-6-one in 560 mL of dry methanol was added at -78° C. 7.52 g (199 mmol) of sodium borohydride in portions. The reaction mixture was stirred for 2 h and then quenched with 20 mL of saturated ammonium chloride. The mixture was concentrated in vacuo, diluted with 600 mL of ethyl acetate and washed twice with 100 mL of water and 100 mL of brine. The organic layers were dried (MgSO4) and the solvent concentrated in vacuo. The crude product was purified by chromatography on silica gel with petroleum ether (40/60)--ethyl acetate (1:1 v:v). The crude product was recrystallised from hexane to yield 13.70 g (70%) of a colourless solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[O:5][C:4](=[O:15])[C@@H:3]1[O:16][CH3:17].[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[NH:21][C:20]1=[O:36].C(C(CCCC)C([O-])=O)C.[Na+].C(Cl)Cl>C1COCC1>[O:36]=[C:20]1[CH:19]([NH:18][C:4](=[O:15])[C@H:3]([O:16][CH3:17])[C@H:2]([OH:1])[C@@H:6]([OH:5])[C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[NH:21]1
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C(C)(C)C)[C@H]1O
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Temperature: 60 °C
Yield: 125.8 %

Procedure:
235 mg of 2 (818 μmol), 400 mg of 14 (1.59 mmol), 340 mg of sodium 2-ethylhexanoate (2.04 mmol) in 3.5 mL of THF are successively introduced into a 30 mL round-bottomed flask, with stirring and under an argon atmosphere. The mixture is heated at 60° C. for 5 h and the stirring is maintained at RT for 24 h. 15 mL of CH2Cl2 are added to the reaction medium. The mixture is washed with twice 10 mL of HCl (1N) and then 10 mL of a saturated aqueous NaCl solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. 510 mg of crude product are obtained, which product is chromatographed on a silica cartridge (30 g, eluent CH2Cl2/MeOH 97/3). 73 mg of expected product Ex6 are recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:45]=[CH:44][C:33]([C:34]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:35])=[CH:32][CH:31]=2)=[N:22][CH:21]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:20]2[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[C:23]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:36][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[O:35])=[CH:44][CH:45]=3)=[N:22][CH:21]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cnc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3nccn23)ccn1
Temperature: 85 °C

Procedure:
A mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (85 mg, 0.34 mmol), 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl benzamide (150 mg, 0.35 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) and NaOtBu (109 mg, 1.1 mmol) in DMF:water (3:1, 9 mL) is heated at 85° C. for 18 hours. After this time the reaction mixture is cooled to room temperature and the solvents removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title ethoxypyridine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:42]2[CH2:41][CH2:40][N:39]([C:45]3[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=3)[CH2:44][CH2:43]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 77.2 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (542 mg, 1.42 mmol, 77%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)[CH:6]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[C:9]([CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[NH2:17])[CH:6]=1
Reactant: Cc1cnn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cnn(-c2cc(N)cc(C(F)(F)F)c2)c1
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To a solution of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (560 mg, 2.065 mmol) in MeOH (10 mL) was added Pd/C (21.98 mg, 0.206 mmol) in one portion. Then the mixture was stirred under H2 for 12 h. LCMS analysis showed the starting material disappeared. The suspension was filtered through a pad of Celite® and the filter cake was washed with MeOH (2 mL). The combined filtrates were concentrated to dryness to give crude product, which was purified by preparative TLC (PE/EA=5/1, Rf=0.25) to afford pure product 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (280 mg, 1.158 mmol, 56.1% yield). 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.52 (s, 1H), 7.15 (s, 2H), 6.82 (s, 1H), 2.15 (s, 3H). ES-LCMS: m/z 242.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCO>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)[C:3]=2[CH:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1

Procedure:
A solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (900 mg, 3.17 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (709 mg, 3.80 mmol) and DIPEA (618 mg, 4.75 mmol) in EtOH (20 mL) was stirred at refluxed temperature for 3 hours. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the tile compound. MS (m/z): 434 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCl.C[OH:12]>>[C:1]1([S:7]([CH3:8])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: CO
Agent: ClBr
Product: CS(=O)c1ccccc1
Yield: 87 %

Procedure:
A solution of thioanisole (2.48 g, 20 mmol) in methanol (100 mL) in a 250-mL flask was cooled in an ice bath. Stabilized BrCl solution (15 wt. % solution, 18 mL, ~28 mmol) was then added dropwise, with stirring. After the addition, the ice bath was removed, the reaction mixture was allowed to stand at room temperature and the progress of the reaction was monitored by gas chromatography (GC). In less than one hour, the starting material was totally converted to product and the orange-reddish solution turned light yellow. The reaction mixture was quenched with a few drops of sodium sulfite solution, diluted with ethylene dichloride (EDC, 100 mL), and washed with water (100 mL). After phase separation, the colorless organic layer was dried (Na2SO4) and concentrated under reduced pressure to furnish 2.44 g (~87% yield) of methyl phenyl sulfoxide as a colorless oil. GC analysis indicated the presence of ~2% of the corresponding sulfone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([OH:14])[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9][CH:8]=1)=[CH2:5]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C(=O)OC)C(OC(C)=O)c1cnc(C)nc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 61.1 %

Procedure:
2-[Hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]-acrylic acid methyl ester (1.58 g, 7.58 mmol, 1 eq) and 4-DMAP (0.4 eq, 370 mg) were dissolved in 30 ml of dry DCM under argon atmosphere. To the mixture, cooled at 0° C., was added acetic anhydride (1.5 eq, 1.07 ml) dropwise, during 2 minutes. The mixture was warmed-up to room temperature and was stirred overnight (16 hours). The mixture was then poured into 150 ml of NaHCO3 saturated water solution and organic substances were extracted with DCM (3 times, 150 ml of DCM was used in total). The gathered DCM layers were dried, the solvent was evaporated and obtained was 2-[acetoxy-(2-methyl-pyrimidin-5-yl)-methyl]-acrylic acid methyl ester (1.16 g, yield=61.1%, purity=90%) in form of orange transparent oil. MS: [M+H]+=251.25 1H NMR (300 MHz; CDCl3) δ/ppm 2.73 (s, 3H), 3.72 (s, 2H), 6.05 (s, 1H), 6.49 (s, 1H), 6.61 (s, 1H) 8.65 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][C@H:14]([OH:31])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](O)=[O:45].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(=O)([O-])O.[Na+]>[CH2:32]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:44]([C:40]2[NH:39][CH:43]=[CH:42][CH:41]=2)=[O:45])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:31])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=C(O)c1ccc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a stirred suspension of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-1-propanol (51.3 mg), 1H-pyrrole-2-carboxylic acid (11.9 mg) and 1-hydroxybenzotriazole hydrate (13.5 mg) in 1,2-dichloromethane (1.0 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.5 mg) under ice-cooling and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The extracts were combined, washed twice with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (eluent: toluen/ethyl acetate=5/5) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-amino]-3-hydroxypropyl]phenyl]-1H-pyrrole-2-carboxamide (43 mg) as a gum.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>CN1C(=O)CCC1.CCOC(C)=O.O>[NH2:15][C:14]1[O:22][C:21]([C:20]2[C:19]([F:18])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1nc(-c2c(F)cccc2F)oc1N
Temperature: 120 °C
Yield: 70 %

Procedure:
To a solution of aminomalononitrile p-toluenesulfonate (0.050 g, 0.2 mmol) in NMP (0.5 mL) was added 2,6-difluorobenzoyl chloride (27 ul, 0.21 mmol) and the resulting solution heated in the microwave at 120° C. for 5 minutes. The solution was diluted with EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-amino-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.030 g, 0.14 mmol, 69%) as an off-white solid. 1H NMR (DMSO) δ 7.30 (2H, t), 7.61 (1H, m), 8.14 (2H, br. s). LCMS (1) Rt: 1.59 min; m/z (ES+) 222.
Reaction SMILES: C[O:2][C:3](=[O:18])/[C:4](/[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[CH:5]/[CH2:6][CH3:7].[OH-].[Na+]>C(O)C>[CH3:17][S:14]([C:11]1[CH:10]=[CH:9][C:8](/[C:4](=[CH:5]\[CH2:6][CH3:7])/[C:3]([OH:18])=[O:2])=[CH:13][CH:12]=1)(=[O:15])=[O:16]
Reactant: CC/C=C(/C(=O)OC)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC/C=C(/C(=O)O)c1ccc(S(C)(=O)=O)cc1
Temperature: 47.5 °C
Yield: 82.5 %

Procedure:
A solution of (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid methyl ester (1.83 g, 6.82 mmol) in ethanol (30 mL) was treated with a 1N aqueous sodium hydroxide solution (15 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×70 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid (1.43 g, 82%) as a black solid: EI-HRMS m/e calcd for C12H14O4S (M+H)+ 254.0621, found 254.0623.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]([CH3:30])[CH3:29])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH:28]([C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:31])[CH:18]3[CH3:32])=[CH:15][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:29])[CH3:30]
Reactant: CC(C)c1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1C1CCNCC1)N1C(=NNC(=O)C1C)CO2
Yield: 89 %

Procedure:
A solution of 4-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 0.036 mmol) in DCM (6 mL) and trifluoroacetic acid (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 7-isopropyl-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as pale yellow solid (0.033 g, 89%). LC/MS (Table 1, Method 5) Rt=2.217 min.; MS m/z: 343 [M+H]+.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8]CC2C=CC([N+]([O-])=O)=CC=2)[CH2:6][CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1.[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl trans-3-fluoro-4-[(4-nitrobenzyl)oxy]piperidine-1-carboxylate (180 g, 0.45 mol) in THF/H2O (1500 mL) was added LiOH (39 g, 0.9 mol) in portions at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc:petroleum ether=1:2) showed the starting material was consumed completely. The reaction mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SO4 and concentrated to a crude residue. The residue was purified by column chromatography (EtOAc:petroleum ether=1:20) to afford benzyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=S)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:18]([NH:21][NH2:22])([CH3:20])[CH3:19].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: CC(C)C(=O)CC(=S)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc(OCc2ccccc2)nn1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a suspension of 4-methyl-3-oxothiopentanoic acid O-benzyl ester (0.84 g) and isopropylhydrazine hydrochloride (0.52 g) in acetonitrile (4 mL) was added triethylamine (1.4 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The solvent of the organic layer was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/dichloromethane=1/1-2/3) to give the title compound (0.44 g).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH:15][C:14]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][S:36]([CH2:39][C:40]([F:43])([F:42])[F:41])(=[O:38])=[O:37])([CH3:34])[CH3:33])[CH:29]=[CH:30][CH:31]=2)=[N:13]1)[CH3:11].C(=O)([O-])O.[Na+]>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][F:7])=[CH:22][CH:23]=2)=[CH:15][C:14]([C:26]2[CH:27]=[C:28]([C:32]([NH:35][S:36]([CH2:39][C:40]([F:41])([F:43])[F:42])(=[O:38])=[O:37])([CH3:34])[CH3:33])[CH:29]=[CH:30][CH:31]=2)=[N:13]1)[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CF)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (DAST, 0,021 mL, 0.16 mmol, 1.3 equiv) was added to a solution of N-[1-(3-{1-ethyl-5-[4-(hydroxymethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (62 mg, 0.13 mmol, 1 equiv) in dichloromethane (1.2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then saturated sodium hydrogencarbonate was added. The crude mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(fluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (22 mg, 35%). Calcd (M+1)+: 500.2. Found: 500.1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: N#C[O-]
Reactant: COc1ccc(Cl)c(N)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A solution of 2-chloro-5-methoxyaniline (5 g, 25.76 mmol) and potassium cyanate (5.22 g, 64.41 mmol) in a mixture of acetic acid (125 mL) and water (12.5 mL) was stirred at room temperature overnight. The solvent was evaporated, and the residue taken into a mixture of CH2Cl2 and an aqueous saturated solution of NaHCO3. The layers were separated, the aqueous one being extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography on silica gel (cyclohexane/EtOAc/MeOH:80/20/2) to give 2.06 g (40%) of intermediate 5.