Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCOC1>O>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:22]=1[O:21][CH3:20])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1nccc2cc(SCc3ccccc3)ccc12
Agent: C1COCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(SCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinoline (3.101 g, 10.85 mmol)-(2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (2.86 g, 13.02 mmol), Pd(AmPhos)2Cl2 (0.384 g, 0.543 mmol), potassium phosphate (6.91 g, 32.6 mmol), 1,3-dioxane (27.1 ml), and water (9.04 ml). The vial was flushed with Ar (g), fitted with a reflux condenser, and placed in a 100° C. heating bath for 45 min. The mixture was cooled to room temperature, then diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (120-g, 10 to 40% EtOAc/Heptane) to give 6-(benzylthio)-1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline (4.47 g, 10.51 mmol, 97% yield) as a light-yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.58 (d, J=5.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.26 (m, 8H), 4.31 (s, 2H), 3.76 (s, 3H); m/z (ESI) 426.2 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]([CH2:42][CH3:43])[N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([N:35]1[C:36]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)[C:33]([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)=[N:34]1)[CH3:43]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: CCOC(=O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
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: COCCOC
Solvent: O
Product: CCOC(=O)Cn1c(Oc2ccc(-c3nn(CC)c4cccnc34)cc2)nc2ccccc21
Yield: 18.6 %

Procedure:
A mixture of ethyl {2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (540 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (289 mg), Pd(PPh3)4 (44.3 mg), Na2CO3 (474 mg) in DME (10 mL) and water (2 ml) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (105 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([CH2:15][OH:16])=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([CH2:15][OH:16])=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: OCc1ccc(Cl)nc1CN1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(CO)c(CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using [6-chloro-2-(morpholin-4-ylmethyl)pyridin-3-yl]methanol (66.0 mg, 0.27 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (80 mg, 0.27 mmol) as the starting materials.
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].C(OP([O-])OCC)C.C(N(CC)CC)C>O1CCCC1>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(N2CCCCC2)cc1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(N2CCCCC2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
2,2-Dibromo-1-[4-(1-piperidinyl)phenyl]ethanone (3 g, 8.3 mmol) (from Step A above) was dissolved in tetrahydrofuran (15 mL), and cooled to 0° C. To the resulting solution were added dropwise diethylphosphite (1.13 mL, 8.7 mmol) and triethylamine (1.21 mL, 8.7 mmol) in tetrahydrofuran (7 mL) at 0° C. with stirring. The mixture was slowly warmed to room temperature and stirred for 6 h. The reaction mixture was concentrated in vacuo and poured into ice/water. The precipitate was collected by filtration, washed with water and dried in vacuo to provide 2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (2.3 g, 100% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27](I)=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1[C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:15]3[CH:14]=[C:13]([C:11]([N:8]4[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:37])[CH3:1])[CH2:6][CH2:7]4)=[O:12])[CH:18]=[CH:17][CH:16]=3)[CH:20]=2)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:26]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
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: O
Solvent: CC#N
Product: COc1cccc(OC)c1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 2,6-dimethoxyphenylboronic acid (22 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (9.1 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (3-(3-(2,6-dimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone as a clear oil. MS: m/z 645.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH:19](Br)[CH3:20].C(C(C)=O)C>C(OCC)(=O)C.CCCCCC>[Br:18][CH2:19][CH2:20][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(OCCBr)cc1
Reaction time: 24 h

Procedure:
A mixture of 100 g. of methyl p-hydroxybenzoate, 200 g. of anhydrous potassium carbonate, 400 g. of dibromoethane and 1500 ml. of methyl ethyl ketone is refluxed under vigorous stirring for 24 hours, at the end of which time the reaction is essentially complete, as demonstrated by t.l.c. using an ethyl acetate-hexane mixture (60:20) as gradient. The solid is separated by filtration, and the filtrate is evaporated to dryness under vacuo. The oily residue is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate and evaporated to dryness under vacuo, to yield methyl 4-(2-bromoethoxy)benzoate.
Reaction SMILES: N[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH2:3]1.[CH2:14]=O.S([O-])([O-])(=O)=O.[Mg+2].[C:22]([BH3-])#[N:23].[Na+]>O.C(O)(=O)C.CO>[CH3:14][N:23]([CH3:22])[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH2:3]1
Reactant: C=O
Reactant: CCCCOC(=O)N1CC[C@@H](N)C1
Reactant: [BH3-]C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCOC(=O)N1CC[C@@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 1773.2 %

Procedure:
To a dried 100 mL single-mouth round bottom flask were added absolute methanol (40 mL), (R)-butyl 3-aminopyrrolidine-1-carboxylate (1.86 g, 1.0 mmol), paraformaldehyde (3 g), anhydrous magnesium sulfate (2.5 g), acetic acid (1.2 g) and sodium cyanoborohydride (2.5 g, 39.8 mmol). The mixture was stirred at room temperature for 24 hr. The reaction system was poured into water to quench, The solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The combined organ layer was dried, and was concentrated under reduced pressure to obtain a crude yellow viscous product (3.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
m-Nitrobenzyl bromide (500 mg, 2.31 mmol) was added to a mixture of 1-methylpiperazine (277 mg, 2.77 mmol) and potassium carbonate (414 g, 3.0 mmol) in 5 mL of DMF. The mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 510 mg of 1-methyl-4-(3-nitro-benzyl)-piperazine, which was converted to the title compound under normal hydrogenation conditions. The titled compound was obtained as a yellow solid (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.02 (t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 3.43 (s, 2H), 2.76 (br, 4H), 2.65 (br, 4H), 2.82 (m, 4H), 2.46 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=2[O:14]1.C(O)(C(F)(F)F)=O>>[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH:18]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:16][C:15]=2[O:14]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Yield: 62.7 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (20.0 g, 120 mmol), 3,4-methylenedioxybenzaldehyde (20.6 g, 1.1 equiv.) and TFA (18 mL, 2 equiv.) to give the title compound (22 g, 60%) as white crystals after recrystallization from ethanol.
Reaction SMILES: [SH:1][CH:2](O)C.[Cl:5][C:6]1[C:7]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH2:20][CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17]1)[CH:10]=[CH:9]2.[C:36](=[O:39])([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][C:6]1[C:7]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH2:20][CH2:19][C@H:18]([S:1][CH2:2][CH2:36][OH:39])[CH2:17]1)[CH:10]=[CH:9]2
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CC(O)S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](SCCO)C3)ccc12
Temperature: 60 °C

Procedure:
Mercaptoethanol (0.073 mL) was added to N-[6-chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (0.1 g) and potassium carbonate (0.24 g) in dry N,N-dimethylformamide. The reaction mixture was heated at 60° C. in a microwave for 2 hours and then partitioned between water and ethyl acetate. The combined organics were washed with brine, dried and concentrated. Purification (SiO2, methanol:dichloromethane 3:97 as eluant) gave the sub-titled compound as a solid (0.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
4-(tert-butoxycarbonylamino)piperidine (1.2 g) and potassium carbonate (1.2 g) were suspended in dimethylformamide (20 mL), and then methyl bromoacetate (0.62 mL) was added. The reaction solution was stirred for one hour and water was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:10:1) to obtain the title compound (1.36 g) having the following physical properties.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:67])[C:58]2[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=2[Br:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Br:66][C:59]1[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:56][CH2:55]1)=[O:67]
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)on3)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
HOBt (21.5 mg, 0.16 mmol) and DIPEA (66 mg, 0.51 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (24 mg, 0.13 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (30.5 mg, 0.16 mmol) followed by 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.13 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration under reduced pressure and dried to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 53.8% yield. LC-MS purity: 92.97%, 1H-NMR (DMSO): δ 8.7 (t, 1H), 8.0 (m, 2H), 7.58 (m, 4H), 7.41 (s, 1H), 7.0 (m, 2H), 4.2 (m, 2H), 3.78 (s, 3H), 3.5 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:9]2[C:25](=[O:28])[NH:26][N:27]=[C:8]2[N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:6]=1[CH3:39])=[O:4].Br[CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45]>CC#N>[CH:3]([O-:4])=[O:2].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C@H:10]2[N:9]3[C:25](=[O:28])[NH:26][N:27]=[C:8]3[N:7]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)[C:6]([CH3:39])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[C:12]([CH2:19][CH2:20][CH2:21][N+:22]([CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])([CH3:24])[CH3:23])[CH:13]=1)#[N:18]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2[C@@H]1c1ccc(C#N)cc1CCCN(C)C
Reactant: CS(=O)(=O)CCCBr
Solvent: CC#N
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2[C@@H]1c1ccc(C#N)cc1CCC[N+](C)(C)CCCS(C)(=O)=O
Product: O=C[O-]
Temperature: 90 °C
Yield: 65.7 %

Procedure:
To a solution of Example 12 (150 mg, 0.28 mmol) in MeCN (2 mL) was added 1-bromo-3-methanesulfonyl-propane (225 mg, 1.12 mmol). The resulting mixture was heated at 90° C. for 40 minutes using microwave irradiation. The solvent was removed in vacuo and the resultant residue was purified by reverse phase chromatography (MDAP), giving the title compound as an off-white solid (65 mg)
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:14]=[C:15]([NH2:17])[CH:16]=1)=[O:10].C(N(CC)CC)C>ClCCl.C(OCC)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:14]=[C:15]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:16]=1)=[O:10]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1cc(N)cc(-c2ccccc2Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(=O)Nc1cc(C(=O)OC)cc(-c2ccccc2Br)c1
Reaction time: 0.5 h

Procedure:
Butyryl chloride (55 mg, 0.52 mmol) was added to a solution of 5-amino-2′-bromo-biphenyl-3-carboxylic acid methyl ester (153 mg, 0.5 mmol) and triethylamine (76 mg, 0.75 mmol) in dichloromethane (5 ml) and the mixture left at room temperature for 30 minutes. The resulting solution was diluted with diethyl ether, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4) and evaporated to dryness to yield the title compound as a light yellow gum. (161 mg, 88%).
Reaction SMILES: [C:1]1(=[C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:16]#[N:17].[K+]>>[CH3:14][C:9]1([CH3:13])[O:10][C:11](=[O:12])[CH:6]([C:1]2([C:16]#[N:17])[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:15])[O:8]1
Reactant: [C-]#N
Reactant: CC1(C)OC(=O)C(=C2CCCC2)C(=O)O1
Agent: [K+]
Product: CC1(C)OC(=O)C(C2(C#N)CCCC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-cyclopentylidene-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-]>C(Cl)Cl>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([O:26][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:25])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl -5-{4-[6-(1-hydroxy-ethyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidin-3-yl)-ethanone (2.2 g, 5.39 mmol) in CH2Cl2 (25 mL) is added triethylamine (1.51 mL, 10.78 mmol) and methane sulfonyl chloride (0.527 mL, 6.47 mmol). Reaction mixture is stirred at 0° C. for 30 minutes then diluted using saturated bicarbonate solution and extracted with CH2Cl2 (30 mL) Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 45% ethyl acetate in hexane as an eluent to afford the title compound (1.8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (s, 3H), 1.68 (d, J=6.56 Hz, 3H), 3.21 (s, 3H), 4.54-4.58 (m, 0.5H), 4.66-4.71 (m, 1H), 4.81-4.84 (m, 0.5H), 4.90-4.95 (m, 1H), 5.27 (d, J=3.92 Hz, 1H), 5.79-5.84 (m, 1H), 6.64 (t, J=52.24, 1H), 7.60-7.63 (m, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.17-8.20 (dd, J1=8.08 Hz, J2=2.24 Hz, 1H), 8.92 (d, J=2.00 Hz, 1H). LC-Ms (m/z): 487.1 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)COc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)COc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-2-phenoxy-ethyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][C:11]2([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[S:15](Cl)(=[O:18])(=O)[NH2:16].[OH-:20].[Na+]>CC(N(C)C)=O.O>[CH3:13][C:11]1([CH3:14])[CH2:12][CH:10]1[C:6]1[C:3]2[C:4]([NH2:5])=[N:16][S:15](=[O:18])(=[O:20])[NH:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC1(C)CC1c1cccc(N)c1C#N
Reactant: [OH-]
Reactant: NS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C)CC1c1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 2-amino-6-(2,2-dimethylcyclopropyl)benzonitrile (381 mmol, 71 mg) (Example 270a) and sulfamoyl chloride (572 mmol, 66 mg) in DMA (1 mL) was stirred at room temperature. After 1 hour, the reaction mixture was diluted with NaOH (1N, 572 mmol, 572 μL) and water (˜30 mL). The precipitate was filtered off, washed with water (3×5 mL) then dissolved in EtOH (10 mL) and NaOH (1N, 953 μL) was added. The reaction was heated to 80° C. with stirring. After completion the solvent were evaporated and the residue was partitioned between water (20 mL) and ether (5 mL). The aqueus layer was extracted with ether (2×5 mL), then acidified to pH˜3 with 1N HCl. The precipitate was collected, washed with water, dried in vacuo to give the desired product (59 mg, 58%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.610 (m, 1H), 0.63 (s, 3H), 0.89 (m, 1H), 1.20 (s, 3H), 2.48 (m, 1H), 6.88 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.21 (br. s, 1H), 7.39 (t, J=8 Hz, 1H), 8.42 (br. s, 1H), 10.74 (s, 1H). MS 266 (MH+).