Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29]Cl)=[O:27])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:31].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][I:31])=[O:27])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CC(=O)OCCl)cc1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CC(=O)OCI)cc1
Yield: 80.1 %

Procedure:
Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate (0.83 g, 1.9 mmol) and sodium iodide (1.15 g, 7.6 mmol) were heated in acetonitril (45 ml) for 5 h. The mixture was filtrated, the solvent removed, taken up in dichloromethane and filtrated again. Evaporation and purification by chromatography (ether-hexane, 2:3) yielded the title product (0.8 g, 80%).
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.[C:29]([CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)([O:31]CC)=[O:30].S([O-])([O-])(=O)=[O:42].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:42])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:37]2[CH2:38][CH2:39][CH:34]([C:29]([OH:31])=[O:30])[CH2:35][CH2:36]2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(C2CCC(C(=O)O)CC2)C[C@@H]1CCCB(O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and 4-carbethoxycyclohexanone (0.170 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(4-carboxycyclohexyl)pyrrolidine-3-carboxylic acid (135 mg, 65%) as a white solid. NMR (D2O) δ 3.97 (dd, J1=13 Hz, J2=7 Hz, 1 H), 3.75-3.90 (m, 2 H), 3.15-3.35 (m, 2 H), 2.20-2.70 (m, 2 H), 1.90-2.20 (m, 4 H), 1.50-1.65 (m, 3 H), 1.15-1.45 (m, 5 H), 0.60-0.70 (m, 2 H). MS (m+1): 343.1; MS (m−H2O+1): 325.0.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:24])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([NH:59][CH2:60][C:61]4[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=4)=[O:23])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:24])=[CH:26][CH:27]=1
Reactant: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reaction time: 18 h
Yield: 27 %

Procedure:
To a stirred mixture of crude 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.18 g, 0.46 mmol), 1-hydroxybenzotriazole (0.09 g, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.13 g, 0.69 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.24 mL, 1.38 mmol) and 3-(aminomethyl)pyridine (0.05 mL, 0.46 mmol). The resulting reaction mixture was stirred for 18 h and diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 5-15% methanol in dichloromethane to afford the title compound as a colorless foamy solid (0.06 g, 28%): 1H NMR (300 MHz, CDCl3) δ 8.57-8.54 (m, 1H), 8.51-8.47 (m, 1H), 7.71-7.65 (m, 1H), 7.30-7.22 (m, 3H), 6.97-6.90 (m, 2H), 6.43 (br s, 1H), 6.05 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 4.51 (s, 2H), 4.01 (s, 2H), 3.63-3.53 (m, 4H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 167.7, 162.4, 160.7, 157.1, 154.2, 149.1, 148.8, 135.7, 134.1, 131.6 (d, JC-F=3.2 Hz), 130.4 (d, JC-F=8.2 Hz), 123.6, 115.5 (d, JC-F=21.5 Hz), 113.2, 50.3, 42.9, 42.6, 41.8, 41.3, 17.5; MS (ES+) m/z 483.2 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1.C(OC(C)C)(C)C>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:10][CH2:9]1
Reactant: CC1CCC(N)CC1
Reactant: C=C1CC(=O)O1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCC(C)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
29 g of diketene were added over 20 minutes to a stirred mixture of 39 g of 4-methylcyclohexylamine in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 3 hours. Isopropyl ether was added thereto and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 46 g of N-(4-methylcyclohexyl)-acetylacetamide melting at 111° C. A mixture of 46 g of the latter product, 37 g of methyl orthoformate, 1.5 g of p-toluene sulfonic acid and 100 ml of methanol was stirred for 2 hours at 20° C. and after standing for 16 hours, 3 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The stirred mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then cooled and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 24 g of N-(4'-methylcyclohexyl)-3-methoxy-crotonamide melting at 125° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:33]=[N:32]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: c1cnc2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (845 mg, 2.48 mmol) in DME (16 mL) was added 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (800 mgs, 2.48 mmol) and Cs2CO3 (2.42 g, 7.43 mmol) in H2O (4 mL). The reaction mixture was degassed and charged with nitrogen for three times. The palladium catalyst Pd(dppf).CH2Cl2 (101 mg, 0.124 mmol) was added and the reaction mixture was degassed and charged with nitrogen for three times, and stirred for 16 hours at 80° C. under nitrogen. The reaction mixture was then filtered over a pad of Celite, and washed with EtOAc (50 mL) and water (25 mL). The filtrate was extracted with EtOAc (3×50 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified with a Biotage silica gel column chromatography (40+S, 0-50% EtOAc/Hexanes 5CV (column volume), 50-100% EtOAc/Hexanes 10 CV, 100% EtOAc 10 CV) to provide 6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (910 mgs, 81% yield) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H) 8.82-8.95 (m, 1H) 8.67 (s, 1H) 8.28-8.45 (m, 2H) 7.92-8.08 (m, 2H) 7.77-7.90 (m, 1H) 7.53 (dd, J=8.29, 4.14 Hz, 1H) 6.15 (s, 2H) 4.49-4.62 (m, 2H) 4.30-4.47 (m, 2H) 3.91-4.00 (m, 1H) 3.67-3.87 (m, J=5.46 Hz, 1H) 3.47-3.60 (m, 1H) 3.35-3.42 (m, 1H) 1.48-1.66 (m, 2H) 1.32-1.45 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)OCc1ccccc1
Yield: 69.5 %

Procedure:
2-Amino-5-chlorobenzoic acid methyl ester (5 g, 27 mmol) was dissolved in 36 mL pyridine. CBz-Cl (4.2 mL, 29.6 mmol) was then added and the resultant solution was stirred at 60° C. overnight. The following day, LCMS analysis indicated the reaction was complete. The reaction mixture was subsequently poured in a slow stream into 200 mL of rapidly stirring 2 M HCl/H2O. The mixture was transferred to a separatory funnel and extracted with 2×50 mL of EtOAc. The aqueous phase was discarded and the combined organics were dried over sodium sulfate and concentrated in vacuo to provide 6 g of 2-benzyloxycarbonylamino-5-chloro-benzoic acid methyl ester (pale yellow oil, 70% yield): HPLC retention time=3.15 minutes; MS (ES) M+H expected 320.0, found 320.0.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28][CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28](=[O:40])[CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:18][CH:19]=3)[N:12]=2)=[CH:30][CH:31]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (103 mg, 0.24 mmol) was dissolved in DCM (3 mL). mCPBA (61.8 mg, 0.36 mmol) was added and the reaction was stirred at rt for 2 h. Water was added and the product was obtained by separating the organic phase and evaporating the solvent. The crude product was purified using preparative HPLC yielding 4-(4-fluorobenzyl)-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (21.0 mg, 18.9%). MS (ES+) m/z 448.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[C:34]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:16][CH:17]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 mg of (6-hydroxy-2-cyclohexylbenzo[b]thien-3yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone is dissolved in 1 mL of pyridine, 0.1 mL of benzoyl chloride is added, and this mixture is agitated for one hour at room temperature. Ice is added to the reaction mixture, and the system is agitated for one hour. The organic layer is extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent is distilled off, and the crude product thus obtained is refined by TLC (developing solvent was chloroform:methanol=9:1), which gives 37 mg of (6-benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1([NH2:27])[CH2:26][O:25][CH2:24]1>>[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1([NH:27][C:14]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=2)=[O:16])[CH2:26][O:25][CH2:24]1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Reactant: NC1(c2nccs2)COC1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1ccc(Br)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=438.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=2)=[C:7]([OH:9])[CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:25](O)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)(=[O:27])[CH3:26]
Reactant: CCc1ccc(Oc2cccc(F)n2)c(O)c1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2cccc(F)n2)c(OC(C)=O)c1
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol (20 mg; 0.09 mmol), under argon, in dimethylformamide (2 mL), cooled to 0° C., was added triethylamine (36 μL; 0.26 mmol) and acetic acid (10 μL; 0.18 mmol). The reaction mixture was allowed to stir overnight, with gradual warming to roomtemperature. The reaction was concentrated, diluted with saturated NaHCO3 (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (8 mg; 34%) was obtained as clear oil, after purification on neutral alumina gel (cyclohexane/ethyl acetate: 9/1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:33](=[O:42])[C:32]=1[C:43]#[N:44]>O1CCOCC1.CCOC(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>[Cl:1][C:2]1[CH:14]=[C:13]([C:31]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[C:33](=[O:42])[C:32]=2[C:43]#[N:44])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CCC2CC2)c1=O
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: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(OC3CCOCC3)c(Cl)c2)ccn(CCC2CC2)c1=O
Yield: 15.9 %

Procedure:
To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 9 (0.45 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.108 g, 17%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>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>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:24]2[N:23]=[C:22]([NH:21][C:20](=[O:29])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
To a solution of 4-(N-methylsulfamoyl)phenylboronic acid (17.2 g, 0.08 mol) and (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (21.9 g, 0.08 mol) in DMF (125 mL) and H2O (125 mL) were added Pd(PPh3)4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g, 0.12 mol). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. for 16 h. The mixture was evaporated under reduced pressure, then poured into H2O, and extracted with EtOAc. The organic phase was dried over Na2SO4, and was evaporated under reduced pressure to give tert-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyridin-2-ylcarbamate (21 g, 58%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].[F-].[K+].O.C(OCC)(=O)C>CO>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 10 h
Yield: 17 %

Procedure:
To a solution of 0.27 g (0.77 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2S,3R)/(2R,3R)=91/9) in 3 mL of methanol was added 0.06 g (0.94 mmol) of potassium fluoride, and reaction was performed for 10 hours and then at 50° C. for another 25 hours. Next, 5 mL of water was added to stop the reaction, and extraction was performed with 10 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. The resulting crude product was quantitatively analyzed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 17% ((2S,3R)/(2R,3R)=95/5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1c(Br)cccc1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 79 °C
Reaction time: 3.5 h

Procedure:
2,6-dibromo pyridine 1-oxide (10 g, 39.5 mmol) was added to 65 mL of concentrated sulfuric acid at room temperature without cooling. Concentrated sulfuric acid (15 ml) and nitric acid (13.3 ml) were mixed and placed in a pressure equalising dropping funnel. The reaction mixture was heated to 79° C. then the nitrating mixture was added in portions over 25 minutes. When the addition was complete the mixture was stirred at 83-85° C. for 3.5 hours. The mixture was cooled to room temperature and slowly poured onto ˜250 g crushed ice. A very pale yellow solid formed which was filtered off and washed with water (100 ml), dried in vacuum oven at 50° C. overnight to give 10.9 g of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].O>ClCCl>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:2][CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CN
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To 22.5 mL (0.045 mol) of a 2M solution of methylamine in dichloromethane, cooled to 0° C., was added a solution of 3.67 g (0.015 mol) of 4-but-2-ynyloxy-benzenesulfonyl chloride in 45 mL of dichloromethane. The reaction was allowed to warm to room temperature and stirred for 48 h. The resulting solution was poured into water and extracted with dichloromethane. The combined organics were washed with 2N citric acid solution, water and brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo to provide 3.23 g (92%) of the N-methyl sulfonamide as a white solid; m.p.78-80° C.