Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][CH:47]([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][CH:47]([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)F)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as a solid (0.011 g, 4%). 1H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.55 (s, 1H); 7.31-7.44 (m, 4H), 7.01 (d, 1H), 5.90 (tt, 1H), 5.81 (s, 1H), 4.58 (m, 1H), 4.04 (s, 3H), 2.93 (m, 2H), 2.80 (td, 2H), 2.53 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 597 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 70.2 %

Procedure:
The target compound was prepared as a colorless solid substance in an amount 5.94 g at a yield of 70.2% in the same manner as in Example 1 except that 5.0 g (19.9 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 50 ml of THF and 3.55 g (21.9 mmol) of CDI was added; 7.83 ml (59.7 mmol) of diisopropylamine and 30 ml of THF were added and 37 ml (59.7 mmol) of 1.63N BA solution was added dropwise; 11.5 g (59.7 mmol) of t-butyl phenylacetate instead of methyl phenylacetate was dissolved in 30 ml of THF; and 50 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 40 g of 4N hydrochloric acid was added, and 140 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.Cl.O1CCOCC1>C(O)CCC>[F:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:18])[CH:9]=4)=[CH:6][CH:7]=3)[S:21][C:22]=2[CH:28]=1
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1C
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1C
Temperature: 65 °C
Yield: 58.2 %

Procedure:
As shown in Reaction Scheme 7, a mixture of methyl 4′-amino-3-methylbiphenyl-4-carboxylate (0.34 g, 1.40 mmol) and 2-chloro-6-fluoro-1,3-benzothiazole (0.26 g, 1.40 mmol) in n-butanol (4 mL) was heated to 60-70° C., and then 4N HCl in 1,4-dioxane (0.16 mL, 0.63 mmol) was added dropwise with stirring. The reaction mixture was heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo. The residue was triturated with ethanol and collected by filtration, yielding 0.32 g (58%) of the title compound as a pale yellow solid. LC/MS m/z 393.3 (MH+), retention time 4.02 min. 1H NMR (400 MHz, CD2Cl2) δ 2.62 (s, 3H), 3.95 (s, 3H), 7.05 (t, 1H), 7.39-7.60 (m, 4H), 7.65 (s, 4H), 7.96 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 13a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N(C)c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Propane-1-sulfonyl chloride (27 uL, 34 mg, 0.24 mmol) was added to a solution of N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (see following steps B, C, D, E, F and G for preparation), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with DCM (50 mL), washed with saturated NaHCO3 (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 40 mg (47%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.00 (t, J=7.42 Hz, 3 H), 1.38-1.53 (m, 4 H), 1.70-1.88 (m, 2 H), 2.15-2.30 (m, 1 H), 3.01-3.11 (m, 2 H), 3.28-3.33 (m, 2 H), 3.35 (s, 3 H), 3.88-3.91 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.55 (dd, J=8.79, 1.76 Hz, 1 H), 7.75 (d, J=8.98 Hz, 1 H), 7.82 (d, J=1.56 Hz, 1 H). MS (ESI) (M+H)+=420.0. Anal. Calcd for C18H24F3N3O3S+0.20 H2O+0.30 CH3OH (432.68): C, 50.80; H, 5.96; N, 9.71. Found: C, 50.79; H, 5.91; N, 9.69.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 2-liter, 3-necked flask equipped with a stirrer, condenser, thermometer and nitrogen inlet were placed 197.3 g (1.0 moles) of 2,6-diethyl-2,3,6-trimethylpiperidin-4-one, 500 ml of 2N sodium hydroxide and 500 ml of absolute ethanol. To the stirred reaction mixture, maintained under nitrogen, was added portionwise 18.92 m (0.5 moles) of sodium borohydride over a 11/2 hour period. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was decanted into a 4-liter separatory funnel and 2 liters of water were added. The aqueous layer was separated and the organic layer diluted with 500 ml of ether. The ether solution was washed with 2 × 1 l water. The first aqueous layer was extracted with 2 × 50 ml of ether, then the combined ether extracts were washed with 500 ml of water. The ether layers were combined, dried over 4A molecular sieves and evaporated under reduced pressure, giving 187.4 g of the desired 2,6-diethyl-2,3,6-trimethylpiperidin-4-ol which was purified further by vacuum distillation, b.p. 111°-115°/6mm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: Cl
Product: NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl [2-({1-[1-(6-chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (300 mg, 0.658 mmol) were dissolved in isopropanole (4 ml). 5N isopropanolic hydrochloric acid (2 ml) was added and the reaction mixture stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and dichloromethane (20 mL) was added. 1N aqueous sodium hydroxide solution was added dropwise until pH 10 was reached. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organich layers were dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 150 mg (0.422 mmol, 64%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: Clc1ccccn1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccccn4)CC3)cc2)C1
Temperature: 160 °C

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160° C. for 2 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 160° C. for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 393.54 (C23H31N5O); MS (ESI): 394 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of methyl 6-chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylate (360 mg, 0.973 mmol) in methanol (10 mL) was added sodium hydroxide (1 M, 4.0 mL, 4 mmol) and the reaction was heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure. The crude reaction was diluted with methanol (9 mL) to which was added additional sodium hydroxide (1M, 6.0 mL, 6 mmol) and heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure and acidified using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the Biotage Isolera One (SNAP 50 g silica gel column) and eluting with a gradient of 0-20% methanol/dichloromethane yielding 215 mg of the title compound as a solid. To a round bottom flask containing the title compound was added methanol (10 mL) and the reaction was heated to reflux. Additional methanol (5 mL) was added and the solution was allowed to cool to room temperature and stirred overnight at room temperature. The resulting precipitate was filtered and washed with 1 mL of methanol and dried by pulling high vacuum yielding 119 mg of the title compound. MS (ES−) 354.0 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1 H), 11.93 (br. d, 1 H), 8.07 (d, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.21-7.46 (m, 4 H), 3.86-4.02 (m, 2H), 3.46 (td, 2 H), 2.71-2.93 (m, 1 H), 1.60-1.85 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][O:5][C:4](=[O:7])[C:3]1=[O:8].O=O.[H][H]>C1(C)C=CC=CC=1>[OH:8][CH:3]1[C:2]([CH3:9])([CH3:1])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC1(C)COC(=O)C1=O
Reactant: [H][H]
Agent: O=O
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)C1O
Temperature: 40 °C

Procedure:
200 g (1.561 mol) of dihydro-4,4-dimethyl-2,3-furandione (ketopantolactone) and 600 ml of toluene were placed in a 1 liter stirring autoclave. After heating to 40° C. the air was removed from the autoclave by evacuation 5 times with a high vacuum pump (0.05-0.1 bar) and gasification with 10 bar of hydrogen each time. The temperature of the ketopantolactone solution was then adjusted to 35° C., the pressure was lowered to 0.5 bar and immediately 50 ml of the catalyst solution prepared in accordance with Example 1 were sucked in with the complete absence of O2. After pressurizing to 40 bar of hydrogen the mixture was hydrogented while stirring and at constant pressure (40 bar) at 35° C. for 1 hour and at 45° C. for 4 hours. After a total hydrogenation time of 5 hours the pale yellow hydrogenation solution was removed under pressure from the autoclave and the autoclave was subsequently rinsed 3 times with 100 ml of toluene each time. The combined toluene solutions were evaporated on a rotary evaporator at 60° C./17 mbar. The residue (210 g) was distilled at 130°-150° C. bath temperature and 12 mbar. There were obtained 201.6 g (99.3%) of R-(α-hydroxy-β,β-dimethyl-γ-butyrolactone (=R-(-)-pantolactone) with an optical purity of 90.7%. [α]D20 =-46.8° (c=3 in H2O).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:7][CH:6]=1)(=O)C.[NH+]1C=CC=CC=1.Cl>O>[NH2:4][C:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2cccnc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c2cccnc12

Procedure:
In a 250 ml 1-neck round-bottomed flask fitted with a reflux condenser was placed 25.0 g (0.0724 m) of the pyridinium 8-acetamido-5-quinolinesulfonate and 30 ml water. The slurry was heated to effect solution, 30 ml concentrated hydrochloric acid added and the mixture heated to reflux for 1 hour with stirring. A thick crystalline mass separated during the heating period. The thick slurry was then chilled to 0°-5° C. for several hours, filtered and washed with cold 6 N hydrochloric acid and THF. The yield was 11.3 g (70 percent) of product was off-white needles.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23].CCN(CC)CC.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: C#CC(C)(C)O
Reactant: Cc1ccc(Cn2c(OS(=O)(=O)C(F)(F)F)cc3ccccc3c2=O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2c(C#CC(C)(C)O)cc3ccccc3c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of trifluoromethanesulfonic acid 2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydro-isoquinolin-3-yl ester (50 mg, 0.12 mmol) in THF (1.5 mL) was added Et3N (83 μL, 0.59 mmol). The resulting mixture was then degassed by bubbling argon through the solution for twenty minutes. The degassed solution was then treated with 2-methyl-but-3-yn-2-ol (23 μL, 0.24 mmol) followed by tetrakistriphenylphosphine Pd(0) (13 mg, 12 μmol) and Cul (˜2 mg, ˜12 μmol). The resulting suspension was stirred at ambient temperature for 16 hours, then filtered through a short plug of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 50% ethyl acetate/hexane on a silica column. The product peak was collected to afford 2-(2,4-dimethylbenzyl)-3-(3-hydroxy-3-methylbut-1-ynyl)-2H-isoquinolin-1-one (27 mg, 65% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.43 (1H, d, J=8.1 Hz), 7.70-7.64 (1H, m), 7.75-7.49 (2H, m), 7.0 (1H, s), 6.89-6.85 (2H, m), 6.65-6.61 (1H, m), 5.42 (2H, s), 2.40 (3H, s), 2.26 (3H, s), 1.40 (6H, s). ppm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:21][O:20][C:17]1[N:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
4-Carboxybenzeneboronic acid (2.87 g, 17.3 mmol), 5-bromo-2-methoxypyridine (3.25 g, 17.3 mmol), 0.4M aqueous sodium carbonate (87 ml, 34.8 mmol) and acetonitrile (86 mL) were combined under nitrogen, and palladium tetrakistriphenylphosphine (1.00 g, 0.87 mmol) added. The reaction mixture was refluxed for 3 hours, cooled to room temperature, and filtered through celite (washed celite with 50:50 acetonitrile/water). Removed acetonitrile in vacuo, diluted residue with water (100 mL) and acidified to pH 2 with 2M HCl. The precipitate which formed was collected, washed with water, and dried under high vacuum to give the product as a white powder (3.6 g, 15.7 mmol). 1H NMR (DMSO) δ 12.90 (br s, 1H), 8.56 (s, 1H), 8.08 (dd, 1H), 7.98 (d, 2H), 7.75 (d, 2H), 6.94 (d, 1H), 3.90 (s, 3H). ESI MS (M+1)+: 230.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26](=O)[CH2:27][CH2:28][CH3:29]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:26]([CH3:25])[CH2:27][CH2:28][CH3:29])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CCCC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCC(C)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with pentan-2-one (0.9 g, 10.4 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(O)CCNCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-methyl-piperidin-4-ol and pyridine in chloroform. [α]D20=+25.2° (c=1.07, CHCl3), ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Oc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 500 ml flask was charged with 3-bromophenol (A) (25 g, 144 mmol), THF (200 ml) and triethylamine (14.67 g, 145 mmol). The flask was cooled to 0° C. in an ice bath, and chlorotriethylsilane (21.8 g, 144 mmol) was added dropwise. The mixture was allowed to stir at room temperature to completion over 2 h. The hydrochloride salt was then filtered. Removal of solvents followed by flash chromatography afforded 3-bromo-O-triethylsilylphenol (J) as a clear liquid (30.4 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:26]2[C:27]([F:41])=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (46 mg, 0.077 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 22 mg of the title compound. MS (ESI): 501.1 [M+1]+.