Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: COCOc1ccc(Br)nc1
Solvent: C1CCOC1
Product: COCOc1ccc(CC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-5-(methoxymethoxy)pyridine (30.5 g, 140 mmol) in THF (5 mL) at 0° C. under N2 is added dichloro-((bis-diphenylphosphino)ferrocenyl)-palladium(II) (4.88 g, 5.5 mmol) followed by dropwise addition of neopentylmagnesium chloride (155 mL, 155 mmol) over 2 min. After addition, the cooling bath was removed and the reaction stirred 3 h at rt. The reaction was cooled to 0° C. and saturated NH4Cl (500 mL) was added, and the aqueous layers extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated to give a red oil. Purification by vacuum filtration through a silica plug (9×7 cm, dry load, 10-20%% EtOAc/Hexanes) gives 5-(methoxymethoxy)-2-neopentylpyridine as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][N:20]=[N+]=[N-])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N:51]=[C:52]=S)[CH:46]=1.O>O1CCOCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:23][C:52]([NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([Cl:44])[CH:46]=4)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CN=[N+]=[N-])cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
To a solution of {4-[4-(2-azidoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (154 mg, 0967 mmol) in 1,4-dioxane (5 mL) is added triphenylphosphine (122 mg, 0.967 mmol) and 1-chloro-3-isothiocyanatobenzene (0.051 mL, 0.389 mmol). The reaction mixture is then heated at 90° C. for 30 min. Water (10 mL) is added and EtOAc (20 mL) is used to extract. The organic phase is washed with brine (1×15 mL), dried with MgSO4, and concentrated to give the title compound (109 mg) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.20 Hz, 3 H) 1.12-1.19 (m, 2 H) 1.43-1.52 (m, 2 H) 1.81 (d, J=10.61 Hz, 4 H) 1.73-1.84 (m, 1 H) 2.23 (d, J=6.82 Hz, 2 H) 4.07 (q, J=7.07Hz, 2 H) 6.99 (ddd, J=7.83, 2.02, 0.76 Hz, 1 H) 7.28-7.36 (m, 3 H) 7.41 (s, 1 H) 7.47-7.53 (m, 3 H) 7.85 (t, J=2.02 Hz, 1 H) 10.52 (s, 1 H); (M+H)+ 439.2.
Reaction SMILES: [CH2:1](N(CC)CC)C.ClCCl.C(OC(NC(C)(C)CN(C(OC(C)(C)C)=O)CCCO)=O)C1C=CC=CC=1.[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C@@H:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]>O>[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])([CH3:1])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCN(CC)CC
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Agent: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.7 mL of triethylamine was added to a dichloromethane (20 mL) solution of 550 mg of 2-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl-3-hydroxypropylamino)-2-methylpropane (Reference Compound 37). To this reaction solution, a dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) synthesized according to Reference Example 2 was added, and the mixture was stirred at room temperature for 16 hours. After the completion of reaction, water was added, followed by extraction with dichloromethane (20 mL×3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel chromatography (acetone:hexane=1:1) to obtain 140 mg of the compound of interest as a brown oil (14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:36][C:37]1[C:45](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:44]2[C:40]([C:41]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:42][NH:43]2)=[CH:39][CH:38]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:47]=[C:46]([C:45]3[C:37]([F:36])=[CH:38][CH:39]=[C:40]4[C:44]=3[NH:43][CH:42]=[C:41]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1c(F)ccc2c(CCC(=O)OCC)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To the solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (1.39 g) in tetrahydrofuran (50 mL) were added EDCI (1.69 g) and HOBT (1.35 g). The resulting solution was stirred at room temperature for 1 hour. Then ethyl 3-{6-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D145) (1.72 g) was added and the solution was stirred at room temperature for another 2 hours. THF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×10 mL), dried over sodium sulphate and concentrated. The residue was dissolved in THF (3 mL), TBAF (6.13 g) was added and the reaction solution was stirred in the microwave (120° C., 2.5 hours). The reaction solution was poured into ethyl acetate (100 mL), washed with water (3×20 mL) and dried over sodium sulphate. The organic solution was concentrate and the residue was purified by column chromatography to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D149) (520 mg) as a white solid. MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)[O:13][N:12]=1
Reactant: COc1ccc(-c2cc(CCC=O)on2)c(OC)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)c(OC)c1
Yield: 80.1 %

Procedure:
About 2 min after dissolving 3-[3-(2,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (6.7, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3.5 hr and followed the same processes as in Example 1 to obtain 13.5 mg (83.6%) of the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19].CCN(C(C)C)C(C)C.[H-].[Na+]>CN1C(=O)CCC1.O>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([O:18][C:15]3[CH:16]=[CH:17][C:12]([NH2:11])=[C:13]([F:19])[CH:14]=3)=[C:3]2[CH:10]=[CH:9]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Nc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Temperature: 250 °C
Yield: 18.7 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.33 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) in NMP (0.5 mL) were added 4-amino-3-fluorophenol (51 mg, 0.40 mmol) and DIEA (0.1 mL, 0.57 mmol). The mixture was heated at 250° C. in a microwave oven for 1 h and then cooled to room temperature. To the mixture was added NaH (10 mg, 0.4 mmol) and the mixture was again heated at 250° C. for 3 h. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the title compound (15 mg, 19%). MS (ESI) m/z 244.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc32)cc1
Reaction time: 72 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO is added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 4-cyanophenylboronic acid (4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture is stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture is concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 4-[5-(5-Nitro-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].O>ClCCl>[CH3:31][O:32][CH2:33][C:34]([NH:1][CH2:2][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
3.7 g of commercial tert-butyl 4-aminomethyl-4-phenyl-piperidine-1-carboxylate and 3 ml diisopropylethylamine are placed in 30 ml dichloromethane. Then 2.25 ml methoxyacetyl chloride are slowly added. The reaction mixture is stirred at ambient temperature until there is no further reaction, then mixed with water. The organic phase is evaporated to dryness. 4.7 g product are obtained in the form of an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1>>[CH2:35]([C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)[CH3:36]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Example 15. LC (method 3): tR=1.03 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3I)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1-c1cn[nH]c1
Temperature: 90 °C

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide (Preparation 240, 50 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.14 mmol) palladium (0) tetrakis(triphenylphosphine) (10 mg, 0.009 mmol) and sodium carbonate (30 mg, 0.28 mmol) were dissolved in dimethylformamide:water (2:1, 1.5 ml.) and heated to 90° C. for 18 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to afford a brown oil. Purification by preparative HPLC afforded the title compound. Yield 12.5 mg 30%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C)C=O.O>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:43][CH:42]=[CH2:41])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (1.78 g. of 50 wt. % dispersion in mineral oil, 37 mmoles) was added at 60° C. to a solution of 1,2-di-O-(n-hexadecyl)-glycerol (10 g., 18.5 mmoles) in N,N-dimethylformamide (100 ml.), and the resulting solution stirred for 20 minutes at 60° C. Allyl bromide (4.47 g., 37 mmoles) was then added dropwise and the resulting mixture stirred for 3 hours at 90° C., cooled, cautiosly diluted with water (200 ml.) to quench the reaction, and extracted with ether (3×150 ml.). The combined ether extract was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [10 g., 93% yield, oil, n.m.r. (CDCl3) δ5.66-6.16 (m, 1, --OCH2CH=CH2), 5.25 (d of doublets, 2, --OCH2CH=CH2) and 4.03 (d, 2, --OCH2CH=CH2)].
Reaction SMILES: C[C:2]1[C:9]([OH:10])=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22][C:21](C)(C)C(C)(C)[O:19]3)=[C:14](C=O)[CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+]>CO>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[B:18]([OH:19])[O:22][CH2:21][C:16]=3[CH:17]=2)=[C:9]([OH:10])[CH:2]=1)#[N:5]
Reactant: Cc1c(C#N)ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of methyl 4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-hydroxybenzonitrile (25.1 g) in methanol (300 mL) was added sodium borohydride (2.45 g, 64.5 mmol) portionwise at 0° C. The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to about a third of volume. The mixture was acidified with 6 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (7:3 to 6:4 hexane/acetone) followed by recrystallization from acetone/water and trituration with ethyl acetate to give 5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (10.9 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:13](Cl)([C:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:21]([N:22]([CH3:24])[CH3:23])[C:20]=2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:23][N:22]([CH3:24])[C:21]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:20]=1[CH:19]=[CH:18][CH:17]=[C:16]2[S:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and dansyl chloride as described in the synthetic METHOD B to give a yellow solid (10.0 mg) with purity >90%. LCMS (pos) m/z 420.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[H-].[Na+].I[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Reaction time: 0.33 h

Procedure:
A solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-4, 500 mg, 2.20 mmol) in DMF (10 ml) was treated with Sodium hydride (176 mg, 4.40 mmol, 2.0 eq) followed by the 1-Iodo-2,2-Dimethylpropane (585 pt, 4.40 mmol, 2.0 eq). The reaction was irradiated at 175 deg C. for 20 min in a microwave. The reaction was complete by LC/MS, so it was partitioned between EtOAc (2×125 ml) and water (150 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude maroon-orange oil was purified via flash column chromatography (SiO2: 100% Hex to 60:40 Hex:EtOAc), affording the title compound, 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5), as a yellow solid with >95% purity. 1H NMR (600 MHz, CDCl3) δ 7.18 (dd, 1H, J=Hz), 7.10 (s, 1H), 6.88 (d, 1H, J=Hz), 3.63 (s, 2H), 3.40 (s, 3H), 1.02 (s, 9H). LRMS m/z: Calc'd for C7H7BrN2O2 (M+H) 232.1, found 232.8.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cnc(Br)nc1
Product: Cc1cnc(-c2cc(C)c(Br)c(C)c2)nc1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-methyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.20 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)C#CC.C(OC1C=CC(S(Cl)(=O)=O)=CC=1)C#CC>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:21])([CH3:22])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Agent: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(O)cc2)C1C(=O)O

Procedure:
Alternatively, 4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid may be prepared in 31% yield according to the procedure of Example 36 using 4-but-2-ynyloxy-benzenesulfonyl chloride as the sulfonylating agent.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1)=[O:4].[CH2:11]([C:13]1[CH:56]=[CH:55][C:16]2[CH:17]([C:27]3[C:28](=[O:54])[NH:29][C:30](=[O:53])[N:31]([C:33]4[CH:38]=[CH:37][N:36]=[C:35](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:34]=4)[CH:32]=3)[C:18]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=3[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:56]=[CH:55][C:16]2[CH:17]([C:27]3[C:28](=[O:54])[NH:29][C:30](=[O:53])[N:31]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([NH:1][CH2:2][C:3]([NH:5][C:6]5[NH:10][N:9]=[N:8][N:7]=5)=[O:4])[N:34]=4)[CH:32]=3)[C:18]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=3[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH3:12]
Reactant: NCC(=O)Nc1nnn[nH]1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nnn[nH]3)n2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of step (ii) and the product of example 15 step (viii) by the method of example 7 step (i).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CN(C)[CH:16]=[CH:17][C:18](=O)[CH:19](OC)[O:20]C>C(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[N:13]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)phenylhydrazine hydrochloride (0.75 g, 4.02 mmol, 1.00 equiv) in ethanol (20 mL) was added 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (0.7 g, 4.0 mmol, 1.0 equiv). The resulting mixture was heated at reflux (48 hr) then concentrated. To a solution of the crude residue in acetone (10 mL) was added 6N HCl (2 mL). The resulting solution was allowed to stir at room temperature for 30 min, then was partitioned between ethyl acetate and water. The organic extract was washed with water, saturated sodium bicarbonate, brine and dried (sodium sulfate). Concentration afforded 2-(4-methanesulfonyl-phenyl)-2H-pyrazole-3-carbaldehyde admixed with regioisomer 1-(4-methanesulfonyl-phenyl)-1H-pyrazole-3-carbaldehyde (ca. 10/1). The crude material was used without further purification.