Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[N:14][OH:15])=[CH:12][C:4]1=2)[CH3:2].C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.CC(=O)OCC>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]2([C:35]([F:38])([F:36])[F:37])[O:15][N:14]=[C:13]([C:11]3[CH:10]=[CH:9][C:5]4[B:6]([OH:8])[O:7][C:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[C:4]=4[CH:12]=3)[CH2:34]2)[CH:30]=[C:29]([Cl:39])[CH:28]=1
Reactant: CCC1(CC)OB(O)c2ccc(C=NO)cc21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1(CC)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (251 mg, 1.07 mmol) in DMF (15 ml) at rt was added NCS (151 mg, 1.13 mmol). The reaction mixture was warmed to 45° C., stirred for 1.5 h and cooled to −10° C. To this mixture was successively added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (516 mg, 2.15 mmol) and TEA (326.3 mg, 3.23 mmol) below −10° C. The mixture was stirred at this temperature for 2 h, poured into ice-water and extracted with EA (40 ml×2). The combined organic layers were washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 5:1) to give the desired title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg, yield 35.5%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.85-7.45 (m, 6H), 4.48-4.22 (m, 2H), 2.00-1.70 (m, 4H), 0.68-0.42 (m, 6H) ppm. MS: m/z=472 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-:12].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (2.29 g, 9 mmol) in CH3CN (45 mL) was added KF (2.1 g, 36 mmol) and 18-crown-6 (0.5 g), then the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude product which was purified by column to give the reagent R-10a (1.6 g, 74.4%) as a pale yellow solid. ESI-MS (M+1): 239.2 calc. for C6H4BrFO2S.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[N:19]2)=[C:14]([F:26])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>ClCCl.C(O)C>[NH2:34][C:23]([C:21]1[CH:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][C:14]=2[F:26])[CH:22]=1)=[O:25]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(Nc1ccc(-n2cc(C(=O)O)cn2)c(F)c1)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
1-(4-{[Benzyloxycarbonyl]amino}-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid (1.1 g, 3.1 mmol) (Intermediate 41) and benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (PyBob) (1.61 g, 3.1 mmol) were slurried in dichloromethane (25 ml), and triethylamine (0.43 ml, 3.1 mmol) was added. Excess ammonia solution in ethanol (2M) was added and the resulting mixture was stirred for 1 hour. The solvent removed under reduced pressure and the residue was taken up in water. It was basified by adding 1M sodium hydroxide solution, and then extracted with ethyl acetate, dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with 0-1% methanol in ethyl acetate gave the title compound (0.82 g).
Reaction SMILES: [C:1]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](OCC(C)C)=[O:30])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][OH:30])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of the crude isobutyl 1-tritylindazole-3-carboxylate (180 g; 0.39 mol) in THF (1 L) stirred at room temperature was added slowly a suspension of LiAlH4 (18 g; 0.48 mol) in THF (100 ml). Once the addition was complete, the mixture was stirred at room temperature for 30 minutes, and the reaction was then stopped by cooling the mixture to 0° C. and successively adding water (40 ml), 2N NaOH (40 ml) and water (60 ml). The solid thus formed was filtered off and the solution was concentrated under reduced pressure. The crude residue obtained was purified by crystallization from a 1/1 hexane/ethyl acetate mixture. 120 g of (1-tritylindazol-3-yl)methanol were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C@H:4]([OH:14])[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:15]([O:14][C@H:4]1[CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1C[C@@H](O)C[C@@H](c2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1C[C@@H](OC(=O)c2ccccc2)C[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-1-methyl-5-phenyl-3-piperidinol (3 g.) in dichloromethane (50 ml) was treated with benzoyl chloride (2.5 ml), the resulting mixture stirred for 2 hours at ambient temperature, and the solvent then removed under reduced pressure. The residue was partitioned between ether (100 ml) and 2 N HCl. The lower two of the three layers formed were basified to pH 9 with sodium carbonate and extracted with ether (2×100 ml). The organic phase was dried (over magnesium sulphate) and treated with excess ethereal HCl. The resulting oil crystallised on trituation with methanol/ethyl acetate to give the title compound as the hydrochloride hemi-hydrate (3.1 g;) m.p. 50°.
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:4]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CC1(Cl)C(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
Sodium borohydride (103 mg, 1.81 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of di-tert-butyl 1-chlorocyclopropane-1,2-dicarboxylate (cis/trans=26/74) (hereinafter the compound will be referred to as “compound (4b)”) (500 mg, 1.81 mmol) at 10° C. Cobalt chloride hexahydrate (2.4 mg, 0.010 mmol) was added to the resultant solution at the same temperature. After completion of addition, the resultant mixture was stirred at 40° C. for six hours. After completion of reaction, the whole reaction mixture was diluted with an HPLC mobile phase to 50 mL, to thereby yield a solution containing 418.8 mg (yield: 96%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=O)[CH2:10][CH2:11][S:12][C:6]=2[CH:5]=1.[AlH4-].[Li+].O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=1
Reactant: O=C1CCSc2cc(OC(F)(F)F)ccc2N1
Agent: [AlH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc2c(c1)SCCCN2
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
8-Trifluoromethoxy-2,3,4,5-tetrahydro-[1,5]-enzothiazepine may be prepared in the following manner: a solution of 2.5 g of 8-trifluoromethoxy-2,3-dihydro-5H-[1,5]benzothiazepin-4-one in 25 ml of tetrahydrofuran is added dropwise over 15 minutes to 21.4 ml of an approximately 0.5 M solution of lithium tetrahydroaluminate in tetrahydrofuran, kept under argon at 5° C. The reaction mixture is then stirred for 2 hours at 20° C. and 500 ml of distilled water, 100 ml of ethyl acetate and 100 ml of a saturated sodium chloride solution are added successively. After decantation, the aqueous phase is extracted three times with 50 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). 2 g of 8-trifluoromethoxy-2,3,4,5-tetrahydro-[1,5]benzothiazepine are thus obtained in the form of a yellow oil [1H NMR spectrum in DMSO-d6, T=300K, δin ppm (300 Mhz): 1.95 (2H, m, CH2); 3.00 (2H, m, SCH2); 3.30 (2H, m, NCH2); 5.90 (1H, m, NH); 6.85 (1H, d, J=8 Hz, arom. CH); 7.00 (1H, d, J=8Hz, arom. CH); 7.12 (1H, s, arom. CH)].
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:20])([CH3:19])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[CH2:18])[CH:12]=2)[OH:10])[C:4](=[O:21])[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:19])([CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[CH2:18])[CH:12]=2)=[O:10])[C:4](=[O:21])[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=Cc1cccc(C(O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=Cc1cccc(C(=O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)c1

Procedure:
A solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(3-vinylphenyl)propan-1-ol) (0.28 g) in dichloromethane was added to a stirred mixture of pyridinium chlorochromate (0.38 g) and powdered molecular sieve (4A) in dichloromethane at 20° C. After 3 hours the mixture was purified by dry column chromatography on silica gel, eluting with hexane, increasing the polarity to hexane/ethyl acetate (1:1), to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(3-vinylphenyl)propan-1-one (Compound 444, 0.05 g) as a white solid, NMR 1.6 (s,6H), 1.8 (s,3H), 5.2 (d,1H), 5.3 (s,2H), 5.7 (d,1H), 6.6 (m,1H), 6.9 (m,2H), 7.2 (m,5H), 7.4 (d,1H), 7.8 (d,1H), 8.0 (s,1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]([OH:23])=[O:22]>>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]([OH:23])=[O:22])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c(Br)cccc12
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1cccc2c(-c3ccncc3)cccc12

Procedure:
The title compound was prepared from 4-pyridylboronic acid and 5-bromo-1- naphthoic acid (J. Chem. Soc., 1950, 991) using a similar procedure to Example 4, obtained as a white solid (55%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N:18]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:30]([F:40])[CH:29]=2)[CH2:23]1)=[N+:19]=[N-:20]>C(O)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:40][C:30]1[CH:29]=[C:28]([N:24]2[CH2:23][C@H:22]([CH2:21][N:18]3[CH:3]=[C:2]([CH2:1][OH:4])[N:20]=[N:19]3)[O:26][C:25]2=[O:27])[CH:33]=[CH:32][C:31]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: C#CCO
Reactant: Cc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4cc(CO)nn4)OC3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Propargyl alcohol (79 μl, 1.3 mmol), copper sulfate (37 μl of 0.30 M aqueous solution, 11 mmol), and sodium ascorbate (112 μl of 1.0 M aqueous solution, 0.11 mmol) were added to a solution of (5R)-5-(azidomethyl)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1,3-oxazolidin-2-one (Intermediate 7) (0.355 g, 1.12 mmol) in ethanol (2 ml) and water (2 ml). The reaction mixture was allowed to stir at room temperature for 24 h. The aqueous phase was extracted three times with dichloromethane, the organic layers were combined and washed once with brine and dried over magnesium sulfate. Chromatography on silica gel with 10% to 14% methanol in dichloromethane gave 0.197 g. of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(Cl)(Cl)Cl.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]([CH3:34])[C:14]=1[C:35]#[N:36]>O>[NH2:12][C:13]1[C:14]([C:35]#[N:36])=[C:15]([CH3:34])[C:16]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:18]=1[NH:19][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(C#N)c(N)c(N)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(C#N)c(N)c(NC(=O)C(C)(C)C)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Reaction time: 3 h
Yield: 43 %

Procedure:
With cooling with ice, pivaloyl chloride (0.46 ml, 3.73 mmol) was dropwise added to a chloroform (40 ml) solution of 4,5-diamino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-methylbiphenyl-3-carbonitrile (I-269) (1.25 g, 3.73 mmol). After stirring for 3 hours, water was added to the reaction liquid to stop the reaction, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform/methanol (95:5, v/v) to obtain the entitled compound (675 mg, 43%) as a brown amorphous substance.
Reaction SMILES: Br[C:2]1C=C(NC2C=CC(N3CCN(C(C)C)CC3)=CN=2)C(=O)N(C)[CH:7]=1.[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][NH:41][CH2:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][N:41]([CH2:2][CH3:7])[CH2:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Product: CCN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1

Procedure:
Following the procedures as described for 220a and starting with 385 mg of 5-bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one (221a), 248a was obtained as yellow solid (292 mg, 70%). MS: [M+H]+ 364.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=2[O:23]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][C:24]5[O:23][CH2:22][O:30][C:29]=5[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3,4-methylenedioxyphenylboronic acid (285 mg, 1.71 mmol) the subtitle compound was obtained (270 mg, 48%). The product was used directly in the next step without purification.
Reaction SMILES: C([O:8][CH2:9][C:10]1([S:13]([NH:16][C:17]2[C:25]3[O:24][CH:23]=[N:22][C:21]=3[C:20]([F:26])=[C:19]([F:27])[C:18]=2[NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])(=[O:15])=[O:14])[CH2:12][CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:26][C:20]1[C:21]2[N:22]=[CH:23][O:24][C:25]=2[C:17]([NH:16][S:13]([C:10]2([CH2:9][OH:8])[CH2:12][CH2:11]2)(=[O:15])=[O:14])=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])[C:19]=1[F:27]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1(COCc2ccccc2)CC1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1(CO)CC1
Yield: 41.1 %

Procedure:
1-(Benzyloxymethyl)-N-(4,5-difluoro-6-(2-fluoro-4-iodophenylamino)-benzo[d]oxazol-7-yl)cyclopropane-1-sulfonamide (100 mg, 0.158 mmol) in DCM (10 mL) was reacted with 1.0M solution of BCl3 in DCM (0.476 mL, 0.476 mmol) to afford the crude product. The reaction mixture was quenched with ice and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by preparative TLC (70% ethyl acetate in hexane) afforded 35 mg of the product (42% yield). H1NMR (CDCl3, 300 MHz): δ 8.1 (s, 1H), 7.4 (d, 1H), 7.3-7.2 (m, 1H), 7.1 (s, 1H), 6.8 (s, 1H), 6.5-6.4 (m, 1H), 4.1 (s, 2H), 2.7 (s, 1H), 1.4 (t, 2H), 1.0 (t, 2H). LCMS: 97.25%, m/z=537.8 (M−11). HPLC: 95.5%
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Yield: 117.5 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (1.80 g, 6.00 mmol), DIPEA (3.096 g, 2.4 mmol) and pivaloyl chloride (1.2 mL, 9.0 mmol) in THF (20 mL) to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO d6): 8.16 (m, 1H), 7.65 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.25 (d, J=5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Yield: 121 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (350 mg, 0.73 mmol), 4-(N-methylaminocarbonyl)phenylboronic acid (160 mg, 0.88 mmol) and dichlorobis(triphenylphosphine)palladium (II) (52 mg, 0.073 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and stirred at 60° C. for 5 hrs. Water was added and the mixture was extracted with DCM, combined organic phases were dried and evaporated to yield 428 mg (121%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.50 (d, J=1.3 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.09 (d, J=5.1 Hz, 2H), 7.94 (s, 1H), 7.87 (d, J=5.1, 2H), 7.61 (d, J=5.0 Hz, 2H), 7.31 (d, J=5.0 Hz, 2H), 6.21 (bd, J=2.5 Hz, 1H), 3.06, (d, J=2.9 Hz, 3H), 2.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9](I)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][CH:36]([OH:39])[C:37]#[CH:38].C(NC(C)C)(C)C.N#N>[Cu]I.CC#N.CC#N.Cl[Pd]Cl.C(OC)(C)(C)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:38]#[C:37][CH:36]([OH:39])[CH3:35])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2cccc(I)c2)cc1
Reactant: C#CC(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: N#N
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC(O)C#Cc1cccc(Oc2ccc(F)cc2)c1

Procedure:
A 30-gallon, glass-lined reactor was charged with 3-(4-fluoro-phenoxy)-iodobenzene (10.0 kg), copper(I) iodide (60.6 g), triphenyl-phosphine (95.0 g), bis(acetonitrile)palladium(II) chloride, and methyl t-butyl ether (27 kg). The mixture was cooled to 0°-10° C. and 55% aqueous 3-butyn-2-ol (4.20 kg) was added. Diisopropylamine (3.8 kg) was added to initiate the reaction and N2 was bubbled up from the bottom valve for a few minutes to agitate the reaction mixture. The reaction mixture was agitated at 15°-25° C. for 1.5 hours and then quenched by addition of 28% aqueous ammonia (12 kg) and brine (30 kg). The layers were separated and the organic phase was washed sequentially with brine (35 kg), 10% aqueous HCl (18 kg), 10% aqueous NaHCO3 (18 kg), and brine (35 kg). The organic phase was then stirred for 45 minutes with anhydrous MgSO4 (1.5 kg), PWA carbon (1.0 kg), and Ultra Norit C (1.0 kg) and filtered to give a solution of 4-[3-(4-fluorophenoxy)phenyl]-3-butyn-2-ol in methyl t-butyl ether which was used in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCNCC
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1cccc(Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
A mixture of methyl 2-(bromomethyl)-6-chlorobenzoate (4.0 g, 15.6 mmol), diethylamine (5 mL, 48.1 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in acetone (60 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording methyl 2-chloro-6-[(diethylamino)methyl]benzoate (3.97 g, 99% yield), which was used without further purification.