Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:38])[C:9]2[C:10]([C:36]#[N:37])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](C3CCCCO3)[N:15]=2)=[CH:4][CH:3]=1.O1CCOCC1.Cl.O>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:38])[C:9]2[C:10]([C:36]#[N:37])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:26]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C(O)c3ccc(Cl)cc3)c2C#N)ccn1
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(C(O)c3ccc(Cl)cc3)c2C#N)ccn1
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a suspension of methyl (4-{4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (0.0450 g, 0.0817 mmol) in 1,4-dioxane (4.0 mL, 51 mmol) and cooled in an ice bath was added 6.0 M hydrochloric acid in water (4.0 mL, 24 mmol). The resulting solution was brought to room temperature. Hexane (5.0 mL) was added and the bi layer mixture was stirred for 4 hours. The hexane was separated and the aqueous layer was washed with hexane twice. The aqueous layer was concentrated on a rotavapor to ˜half volume; diluted with ice and water, basified with saturated aqueous NaHCO3 to pH ˜7.5, extracted with EtOAc (4×). The combined EtOAc solutions were washed with brine, dried over Na2SO4, filtered, and rotavaped to give a crude solid. The crude solid was chromatographed on a silica gel column using MeOH/DCM (0/100 to 5/95) to afford a solid product (33 mg, yield 82%). LC/MS: (FA) ES+ 467, 469. 1H NMR (400 MHz, d6-dmso) δ 10.50 (s, 1H), 8.82 (s, 1H), 8.41 (m, 1H), 8.20 (s, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 7.06 (s, 1H), 6.59 (s, br, 1H), 3.69 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>C1COCC1.CCOCC>[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH3:28])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 113 mg, 2.82 mmol) in THF (20 mL) at 0° C. under nitrogen was added a solution of 1-Boc-4-[2-(methanesulfonylamino-methyl)-phenyl]-piperazine (0.99 g, 2.68 mmol) in THF (5 mL). The mixture was stirred for about 1 hour at room temperature. It then was cooled back to 0° C. and treated with methyl iodide (0.184 mL, 2.95 mmol). After stirring for about 20 hours, the reaction mixture was diluted with ether (150 mL) and then quenched by addition of saturated aqueous ammonium chloride (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL) and then dried over magnesium sulfate. Concentration under reduced pressure followed by silica gel chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.96 g, 94%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:15])[CH3:14].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([B:5]2[O:4][C:3]([CH3:15])([CH3:14])[C:2]([CH3:16])([CH3:1])[O:6]2)=[CH:8][CH:9]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.72 mmol, 1.00 equiv) in dichloromethane (100 mL), (3-fluorophenyl)boronic acid (3.5 g, 25.01 mmol, 1.10 equiv), Cu(AcO)2 (5 g), 4 A molecular sieves (15 g), and triethylamine (4.6 g). The resulting solution was stirred overnight at room temperature. The solids were filtered out and the filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100-1:50) to give 1.8 g (25%) of 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil.
Reaction SMILES: C(O)C.[NH:4]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[NH:4]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a suspension of ethanol 2.0 mL of methyl 4-anilino-2-(4-fluoroanilino)benzoate 0.25 g was added water 1.0 mL solution of sodium hydroxide 0.060 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature,1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-anilino-2-(4-fluoroanilino)benzoic acid 0.24 g of white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]([F:34])([F:33])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:34][C:15]([F:14])([F:33])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.32 g (26.4 mmol) of 4-nitrophenyl chloroformate were added slowly to 8.0 g (26.4 mmol) of methyl 5-(4-(trifluoromethoxy)phenyl)piperidine-3-carboxylate and 5.34 g (26.3 mmol) of triethylamine in 666 ml of dichloromethane. The mixture was stirred at RT for 2 h. For workup, the reaction mixture was washed first with saturated aqueous sodium hydrogencarbonate solution, then with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2->1:1). Yield: 7.32 g (54% of theory)
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:26][CH2:27][CH3:28])=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:26][CH2:27][CH3:28])=[CH:9][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:29]
Reactant: CCCc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1OC(C)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(CN2CCNCC2)cc2c1OC(C)C(=O)N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
In a 20 mL scintillation vial was added tert-butyl 4-((2-methyl-3-oxo-8-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)piperazine-1-carboxylate 358D (90 mg, 0.223 mmol) and TFA (2.0 mL, 26.0 mmol) in DCM (2.0 mL) and stirred at 23° C. for 1 h. The reaction was concentrated in vacuo, taken up in MeOH, and filtered through a PL-HCO3 MP resin column to give the free base. The MeOH filtrate was concentrated in vacuo to give the title compound as a yellow solid (68 mg, 0.224 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H) 1.38 (d, J=6.82 Hz, 3H) 1.53 (dt, 2H) 2.43-2.49 (m, 4H) 2.52 (br. s., 2H) 3.00 (d, J=4.29 Hz, 4H) 3.33 (br. s., 1H) 3.39 (s, 2H) 4.60 (q, J=6.74 Hz, 1H) 6.63-6.76 (m, 2H) 10.58 (s, 1H). ESI-MS: m/z 304.3 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([OH:19])([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:15]([F:18])([F:17])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 11 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(Br)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10.0 g (34.6 mmol) of the compound of Example 6A and 11.3 g (34.6 mmol) of the compound of Example 15A were dissolved in 120 ml anhydrous DMF, and 15.8 g (41.5 mmol) of HATU and 7.2 ml (41.5 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT overnight (about 15 h) and then stirred into 1.6 liters of water. After 40 minutes, the resulting precipitate was filtered off with suction, washed thoroughly with a further 0.5 liter of water and finally dissolved in 1.8 liters of ethyl acetate. The organic solution was washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The crude product obtained in this manner was purified by filtration with suction (about 330 g of silica gel, mobile phase gradient cyclohexane/ethyl acetate 1:1→1:3). This gave 11.95 g (57% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.[C:22]([O:26][C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH:30]=O)([CH3:25])([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:26][C:27](=[O:33])[N:28]([CH2:29][CH2:30][N:19]1[CH2:20][CH2:21][N:16]([C:11]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[N:15][CH:14]=[CH:13][N:12]=2)[CH2:17][CH2:18]1)[CH3:32])([CH3:25])([CH3:24])[CH3:23]
Reactant: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COCc1ccc(-c2nccnc2N2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
Dissolve 3′-(4-methoxymethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.76 g, 6.2 mmol, 1 eq.) in 1,2 dichloroethane (20 mL). Add methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.13 g, 6.51 mmol, 1.05 eq.). Add sodium triacetoxyborohydride (1.97 g, 9.3 mmol, 1.5 eq.). Stir at room temperature for 18 hr. Partition the reaction mixture between aqueous saturated NaHCO3 and dichloromethane. Separate the layers. Extract the organic layer with dichloromethane (2×100 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 30% EtOAc/hexane—100% EtOAc to afford the title preparation (1.01 g, 37% yield). MS (loop): m/z=442.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.N1C=CC=CC=1.Cl[S:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=1[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:21])=[O:20]>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])=[CH:24][C:23]=3[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:20])=[O:21])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.7 g, 4.7 mmol), pyridine (1 mL, 12.4 mmol) in DCM (10 mL) was added ethyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (1.5 g, 4 mmol). The reaction was stirred at r.t. for 2 hr and monitored by LC/MS. Purification: The solvent was removed and worked up with EtOAc and 1N HCl, brine, dried over Na2SO4. A portion of the crude material was purified by the preparative HPLC give the title product ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate 18 mg as white powder 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.54 (s, 1H), 10.36 (s, 1H), 9.21 (bs, 1H), 7.85 (d, J=8 Hz, 1H), 7.71 (m, 2H), 7.44 (d, J=2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.87 (s, 2H), 4.06 (m, 4H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z=485.1 (M−H, negative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-chloro-4-ethynyl-benzene (240 mg, 1.76 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (106 mg, 0.207 mmol, example 6), Pd(PPh3)4 (23 mg, 0.021 mmol), CuI (11 mg, 0.058 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 120 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 63 mg (54%) yield.
Reaction SMILES: Cl[CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([N:5]([CH2:15][C:16]1([OH:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+]>CN(C=O)C.O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:5]2[CH2:15][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[O:29][CH:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:3]2=[O:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (322 mg, 0.64 mmol) in DMF (3 mL) at 0° C. was added NaH (27 mg, 0.67 mmol). The reaction mixture was allowed to warm to room temperature overnight, then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0-40% EtOAc/DCM to give tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 72%) as a colorless oil. ESI-MS m/z calc. 502.2. found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C=O)C>[CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CO1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, prepared as described in Procedure 59, (20 mg, 0.039 mmol) in DMF (0.1 mL) was added K2CO3 (12 mg, 0.086 mmol), followed by 2,2-dimethyloxirane (28 mg, 0.39 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was washed with H2O, sat. NaCl and dried over Na2SO4 and filtered. The organic solvent was evaporated under reduced pressure and the residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (Example 304) as white lyophillate (11 mg, 56% yield). LCMS: RT=4.066 min [M+H] 577.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm (retention time, column type, size, solvent, flow rate, gradient). NMR: 400 MHz 1H (CD3OD) ppm 1.27 (d, J=2.20 Hz, 6H), 1.32-1.49 (m, 2H), 1.54-1.76 (m, 4H), 1.81-1.98 (m, 2H), 3.53 (d, J=9.23 Hz, 1H), 3.69 (d, J=9.23 Hz, 1H), 3.78 (d, J=12.74 Hz, 1H), 3.91 (t, J=6.15 Hz, 1H), 4.02 (d, J=12.74 Hz, 1H), 6.63-6.70 (m, 1H), 6.72-6.79 (m, 3H), 7.01 (dd, J=10.99, 8.79 Hz, 1H), 7.09-7.20 (m, 3H), 7.27-7.42 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (100 mg, 0.21 mmol) and 2-thienylboronic acid (54 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (212 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. Additional 2-thienylboronic acid (27 mg, 0.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were then added and the mixture stirred in a microwave (set at high absorbance) at 100° C. for a further 45 minutes. The solvent was evaporated with addition of a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The abasic fractions were combined and the solvent evaporated. The crude product was purified by mass directed autoprep HPLC, the relevant fractions collected and solvent evaporated to afford the title compound (E114). MS (ES+) m/e 476 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].N1C=CN=C1.[CH3:16][CH:17]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH3:18].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:16]
Reactant: Cc1cc(O)c(F)cc1F
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirred solution of 2,4-difluoro-5-methylphenol (780 mg, 5.41 mmol, 1.0 eq) and imidazole (442 mg, 6.5 mmol, 1.2 eq) in DMF (10 mL) at 0° C. was added TIPSCl (1.15 g, 5.95 mmol, 1.1 eq) dropwise. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether: EtOAc, 100:1) to give the title compound as a colorless oil (1.2 g, 80%).