Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([C:25]([NH:27][NH2:28])=N)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:7])[CH3:6]>C(O)C.C(OC(C)C)(C)C>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([C:25]2[S:2][C:1](=[S:3])[NH:28][N:27]=2)[CH:11]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])[CH3:6]
Reactant: S=C=S
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(-c2n[nH]c(=S)s2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
Carbon disulfide (1.6 g, 0.021 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1- dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (3.0 g, 0.085 mole) in absolute ethanol (36 ml). The mixture is allowed to warm to room temperature and stir three hours. The mixture is stripped of volatiles under reduced pressure and the residue is dissolved in isopropyl ether and the solvent removed under reduced pressure. The resulting solid is recrystallized from isopropyl ether/hexane to give 2.8 g of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione (3.5 g theor., 80%); mp 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([N:21]=[C:22]=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[NH:1][C:22]([NH:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:23]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccccc2[nH]1)Nc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution was prepared containing 5.32 g. of 2-aminobenzimidazole in 150 ml. of tetrahydrofuran (THF). A second solution containing 6.76 g. of naphthyl isocyanate in 100 ml. of THF was added with stirring over a 30 minute period. The reaction mixture was heated at refluxing temperature for 6 hours and then cooled N-(2-benzimidazolyl)-N'-naphthylurea precipitated and was separated by filtration. Recrystallization of the filter cake from acetone yielded purified N-(2-benzimidazolyl)-N'-naphthylurea melting at 327°-328° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:4][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][CH:7]=1.N#N>CCO.[Pd]>[NH2:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2=CCC3(CC2)OCCO3)ccc1N
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CCOC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Reaction time: 24 h

Procedure:
10% Pd/C (345 mg, 0.0812 mmol) was added to a solution of ethyl 3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate (Compound 232F, 247 mg, 0.812 mmol) in EtOH (5.0 mL). The flask containing this mixture was subjected to 3 cycles of evacuation and N2 purging. After the 4th evacuation the flask was purged with H2 and allowed to stir for 24 hours. The reaction mixture was filtered through celite, the filter cake was washed with MeOH and DCM. The combined filtrate was concentrated to 228 mg of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.07 Hz, 3H), 1.59 (dd, J=12.51, 5.43 Hz, 2H), 1.63-1.70 (m, 2H), 1.70-1.79 (m, 4H), 2.59 (tt, J=11.15, 3.51 Hz, 1H), 3.87 (s, 4H), 4.28 (q, J=7.07 Hz, 2H), 6.50 (s, 2H), 7.17 (s, 2H). MS (ES+): m/z=306.91 (100) [M+1]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.Cl>C(O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:33])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 787.2 %

Procedure:
N-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (135 mg, 0.26 mmol) was dissolved in ethanol (5 mL) and concentrated aqueous hydrochloric acid (100 μL) was added. The reaction stirred at 25° C. for 90 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo to give a beige foam. The foam was dissolved in methylene chloride (4 mL) and hexanes (4 mL) were added to crystallize the desired product. Collection by filtration followed by rinsing with excess hexanes afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (830 mg, 78%) as colorless crystals: ESI-LRMS m/e calcd for C20H27N3O4S [M+] 405.17, found 406.35 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.21 (m, 2H, CH2), 1.38-1.82 (m, 8H, 4×CH2), 2.01-2.23 (m, 1H, CH), 3.17 (s, 3H, SO2CH3), 3.66 (q, J=5.5 Hz, 2H, OCH2), 3.89-3.95 (m, 1H, CH), 3.98 (t, J=5.5 Hz, 2H, NCH2), 4.80 (t, J=5.5 Hz, 1H, OH), 6.40 (d, Jo=2.2 Hz, 1H, Ar), 7.51 (d, Jo=2.2 Hz, 1H, Ar), 7.62 (d, Jo=8.5 Hz, 2H, Ar), 7.85 (d, Jo=8.5 Hz, 2H, Ar), 10.70 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][CH:21]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:27]=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:25][CH:24]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1ncc(Br)cc1/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a 15 mL round bottom flask was added 5-bromo-2-fluoropyridin-3-ylboronic acid (400 mg, 1.820 mmol), SODIUM CARBONATE (386 mg, 3.64 mmol) and 1-(trifluoromethyl)-4-vinylbenzene (407 mg, 2.366 mmol) in dimethylformamide (6 mL). The solution was stirred at room temperature and the flask was purged with oxygen for 3 min. To the purged flask was quickly added palladium(II) acetate (40.9 mg, 0.182 mmol) and the reaction flask was again sealed and purged with oxygen for 15 min. The reaction mixture was then stirred at room temperature overnight and monitored by TLC to determine when the reaction was complete. The next day the reaction was complete by LC/MS. There was no boronic acid left so the reaction was quenched with water and diluted with ethylacetate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was puried by silica gel chromatography eluting with 0% EtOAc/100% hexanes to 15% EtOAc/85% hexanes affording (E)-5-bromo-2-fluoro-3-(4-(trifluoromethyl)styryl)pyridine (177 mg, 0.511 mmol, 28.1% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 8.12 (dd, J=8.0, 4.0, 1H), 7.66 (m, 4H), 7.29 (d, J=16.0, 1H), 7.17 (d, J=16.0, 1H).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:22])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: OC1(c2ccccn2)CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C1(O)CCOCC1

Procedure:
To a stirred solution of 2-(4-hydroxytetrahydropyran-4-yl)pyridine (2.08 g, 11.6 mmol) in dichloromethane (100 mL) was added, with stirring, m-CPBA (77%, 2.86 g, 12.76 mmol) and the mixture stirred at ambient temperature overnight. After this time, potassium carbonate (1.62 g, 11.60 mmol) was added, the reaction stirred for two hours and the mixture filtered. A further aliquot of potassium carbonate (1.62 g, 11.60 mmol) was added to the filtrate and the mixture again stirred for two hours. After filtration and concentration in vacuo, the N-oxide was obtained as a pale brown solid (2.28 g, quant.) and used without further purification; NMR δH (400 MHz, DMSO) 8.33 (1H, dd, J 6.3 Hz, 1.1 Hz), 7.65 (1H, dd, J 8.0 Hz, 2.0 Hz), 7.52 (1H, td, J 7.9 Hz, 1.3 Hz), 7.44 (1H, td, J 7.6 Hz, 2.0 Hz), 7.32 (1H, br s), 3.78 (4H, m), 2.23 (2H, td, J 12.5 Hz, 5.1 Hz), 1.80 (1H, d, J 11.4 Hz); LC-MS Retention time 0.99 min, (M+H)+ 196.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[CH:9][CH:8]=1)=[O:4]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)COc1ccc(C(=O)O)cc1

Procedure:
5 g of benzyl 4-(methoxycarbonylmethyloxy)benzoate were dissolved in methanol/ethyl acetate and hydrogenated in the presence of 600 mg of catalyst (Pd/C, 10% strength). After flushing with inert gas, the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether/heptane (9/1) and filtered off with suction. Yield: 3.3 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8]C)=O.[F:16][C:17]([F:30])([F:29])[C:18]1[N:22]2[N:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]2=[N:20][N:19]=1.C(N(CC)CC)C.ClCCl>ClC(Cl)C.COCCOC>[C:10]1([CH:4]2[CH2:3][N:2]([CH2:27][C:25]3[CH:24]=[N:23][N:22]4[C:18]([C:17]([F:30])([F:16])[F:29])=[N:19][N:20]=[C:21]4[CH:26]=3)[C:6](=[O:8])[CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cnn2c(C(F)(F)F)nnc2c1
Reactant: COC(=O)CC(CN)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1CC(c2ccccc2)CN1Cc1cnn2c(C(F)(F)F)nnc2c1
Temperature: 11 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Methyl 4-amino-3-phenylbutanoate hydrochloride x11 (0.19 g, 0.83 mmol, 1.05 eq) is added to a solution of aldehyde x235 (0.17 g, 0.79 mmol) in dry dichloroethane (DCE) (7.8 ml). The mixture is kept at room temperature for 30 min, cooled to 10-12° C., and a solution of triethylamine (0.15 ml, 0.83 mmol, 1.05 eq) in dry DME (2.5 ml) is added dropwise. The mixture is additionally stirred at the same temperature for 1 h and cooled to 0-5° C. Then STAB (0.23 g, 1.10 mmol, 1.4 eq) is added in portions under vigorous stirring. The mixture is additionally stirred at 0-5° C. for 30 min and kept at room temperature overnight. Then the mixture is heated to 60° C. for 2 h and cooled to room temperature. An equal volume of dichloromethane is added, and the mixture is washed with 10% K2CO3 (2×10 ml). The mixture is dried over anhydrous Na2SO4 and evaporated. The oily residue is triturated with ether, and the formed crystals are separated by filtration, washed twice with ether, and vacuum-dried to give white fine-crystalline 4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one 255.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)CC.C([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[N:31]([CH2:38][CH3:39])[N:32]=[C:33]([C:36]#[N:37])[C:34]=1Br)(=O)C>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:37][C:36]1[C:33]2=[N:32][N:31]([CH2:38][CH3:39])[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][OH:25])=[C:34]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CCn1nc(C#N)c(Br)c1CCCCOC(C)=O
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCCO
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCO
Temperature: 100 °C
Yield: 32.6 %

Procedure:
Triphenylphosphine (21 mg, 0.082 mmol), 2-aminophenylboronic acid hydrochloride (710 mg, 4.1 mmol), 2 M aqueous sodium carbonate (4.1 mL), n-propanol (4.8 mL), and water (1 mL) were added to 4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate (0.86 mg, 2.7 mmol), and the flask was evacuated and backfilled with nitrogen five times before the addition of palladium (II) acetate (6.0 g, 0.027 mmol). The reaction was evacuated and backfilled with nitrogen three more times and then heated overnight at 100° C. An analysis by HPLC indicated that the reaction was incomplete. Additional triphenylphosphine (10 mg, 0.038 mmol), 2-aminophenylboronic acid hydrochloride (300 mg, 1.73 mmol), solid sodium carbonate (500 mg), and palladium (H) acetate (3.0 g, 0.013 mmol) were added at ambient temperature, and the reaction was heated at reflux for three hours and allowed to cool to ambient temperature. The reaction was diluted with brine and extracted with chloroform. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (10 mL) and sodium methoxide (2.2 mL of a 47% solution in methanol) were added to the resulting dark oil. The reaction was heated at reflux for three hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with chloroform/CMA in a gradient from 100:0 to 75:25) to provide an oil. The oil was crystallized from acetonitrile and recrystallized from acetonitrile to provide 250 mg of 4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol as gold-colored crystals, mp 159-160° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:24][CH2:25][OH:26]>CC#N.O.C([O-])(O)=O.[Na+]>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: Ic1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: OCCN1CCN(c2ccc(I)cc2)CC1
Temperature: 91 °C
Yield: 51.7 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (2.25 g, 7.8 mmol) and iPr2NEt (3.4 mL, 19.5 mmol, 2.5 equiv.) in CH3CN was added 2-chloroethanol (995 mg, 11.7 mmol, 1.5 equiv.). The resulting mixture was refluxed 7 h (oil temp. 91° C.), then O/N (15 h, oil temp. 83° C.) and 6 h (oil temp. 90° C.) before cooling to rt. After diluting with H2O (30 mL) and sat. NaHCO3 (30 mL), it was extracted with EtOAc (60 mL×2) and washed with H2O and brine. Removal of solvents followed by trituration with MeOH (15 mL) afforded the title compound as a beige solid (1.340 g, 81%). A second trituration of the concentrated mother liquor gave additional 602 mg of crude product as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.43 (t, J=5.0 Hz, 1H), 3.51 (q, J=5.6 Hz, 2H), 3.12-3.07 (m, 4H), 2.55-2.49 (m, 4H, partially overlapping with DMSO signal), 2.41 (t, J=6.0 Hz, 2H); MS ESI 332.9[M+H]+, calcd. for [C12H17IN2O+H]+ 333.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[O:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:8]1=[O:9].Cl>O>[OH:7][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:12]=1[CH2:11][CH2:10][C:8]2=[O:9]
Reactant: O=C1CCc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C1CCc2c(O)cccc21
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
Anhydrous aluminum chloride (550 g, 4.135 mol, 4 eq) and sodium chloride (105 g, 1.795 mol, 2.7 eq) were mixed and heated to 150° C. Dihydrocoumarin (75) (100 g, 675.7 mol, 1 eq) was added slowly maintaining the internal temperature between 150-160° C. After the addition, the temperature was increased to 200° C. and the reaction mixture stirred for 1.5 h, and while hot, poured into a porcelain dish to cool. The solidified mass was broken and added to a vigorously stirred mixture of ice and water (4 L) containing 400 mL conc. HCl. The resulting suspension was stirred for 1 h, filtered, washed with water and dried to give 85 g (85%) of crude 4-hydroxy-1-indanone (76) as a grey solid. It was sufficiently pure to be used in the next step.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C1N2CCN(CC2)C1.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]([CH3:22])([NH:1][S:38]([CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:40])=[O:39])[C:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:4])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOc1ccc(OCC(C)(N)C(=O)N2CCOCC2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CCOc1ccc(OCC(C)(NS(=O)(=O)Cc2ccccc2)C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.370 g 2-Amino-3-(4-ethoxy-phenoxy)-2methyl-1-morpholin-4-yl-propan-1-one and 0.276 g DABCO are dissolved in 8 ml tetrahydrofurane. After addition of 0.274 phenyl-methane sulfonyl chloride the mixture is stirred for 20 h at room temperature. This mixture is then subjected to flash chromatography without further work-up to yield 260 mg of a white solid. M.p. 109-111° C.
Reaction SMILES: [CH2:1]([C:3]1([S:6]([NH:9]C(=O)OC(C)(C)C)(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(S(N)(=O)=O)CC1
Reaction time: 3 h
Yield: 87 %

Procedure:
To tert-butyl (1-ethyl cyclopropyl)sulfonylcarbamate (4.8 g, 19.25 mmol) was added HCl in 1,4-Dioxane (20 ml, 4M solution) at room temperature. The reaction mass was stirred for 3 hr. The reaction mass was evaporated under reduced pressure to get desired compound (2.5 g, 87%) as brown semi solid. 1H NMR (400 MHz, DMSO): δ ppm 6.70 (br, s, 2H), 1.85-1.81 (m, 2H), 1.10-1.08 (m, 2H), 0.95 (t, J=8 Hz, 3H), 0.89-0.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([F:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([F:12])[CH2:7][CH2:8][N:9]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(F)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
4-Fluoro-piperidine-4-carboxylic acid ethyl ester (1.263 g), synthesis described in patent application US2004/10013, was dissolved in pyridine (70 ml) and p-toluenesulfonyl chloride (1.512 g) was added and the mixture was stirred at RT for 48 h under an argon atmosphere. Then the solvent was evaporated off, the residue partitioned between AcOEt and aqueous HCl, the organic layer was separated, washed with brine, dried over sodium sulphate and concentratedin vacuo to give a brown oil which was purified by flash chromatography (AcOEt/Heptane, gradient from 0 to 25%) to give the desired 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.086 g) as a white solid. MS (ESI): 330.0 (MH+).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:7]=1[NH2:8].[NH2:14][C:15]1[C:20]([C:21](OC)=[O:22])=[CH:19][C:18]([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:29]=2)=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[NH2:14][C:15]1[C:20]([C:21]([NH:8][C:7]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:6]=2[Br:5])=[O:22])=[CH:19][C:18]([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:29]=2)=[CH:17][N:16]=1
Reactant: COC(=O)c1cc(-c2cnn(C3CCN(C)CC3)c2)cnc1N
Reactant: Nc1c(F)cccc1Br
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CN1CCC(n2cc(-c3cnc(N)c(C(=O)Nc4c(F)cccc4Br)c3)cn2)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2M Trimethylaluminium in toluene (0.75 ml) was added to a solution of 2-bromo-6-fluoro-aniline (0.229 g) in toluene (30 ml). The mixture was stirred for 30 minutes, then methyl 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylate (0.19 g) was added. The mixture was heated to 120° C. for 18 hours, allowed to cool and then quenched with 10% aqueous Rochelle's salt solution. The organic fraction was purified by SCX ion-exchange chromatography to give crude 2-amino-N-(2-bromo-6-fluorophenyl)-5-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]pyridine-3-carboxamide; Mass Spectrum: M+H+ 472.1; RT 0.87 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([OH:14])=O)[CH:4]=1.[NH:17]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18]2)=[O:14])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)COCc1cc(C(F)(F)F)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of {[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetic acid (450 mg, 1.9 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (360 mg, 1.9 mmol) in DMF (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (880 mg, 2.0 mmol) followed by triethylamine (0.80 mL, 5.7 mmol). After being stirred at room temperature overnight, ethyl acetate was added. The solution was washed with 1 N NaOH and water. Purification on silica gel column eluting with EtOAc provided the title compound (300 mg) as a clear oil. MS (M+H) 404.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(O)=C([Cl:44])C=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[CH:15][C:14]=1[Cl:44])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Reactant: Oc1ccc(Br)cc1Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-2-chloro-phenol at Stage 6 of Scheme 2. m/z 524 [M+H]+.