Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCC(=O)c1ccc(F)c(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)c1ccc(F)c(F)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
30.1 g (161 mmol) of 2,3-difluorophenyl propionate in 16 ml of 1,2-dichlorobenzene are added dropwise to 21.5 g (161 mmol) of aluminum trichloride in 16 ml of 1,2-dichlorobenzene and the mixture is subsequently stirred at 100° C. for 6 hours. It is cooled, diluted with dichloromethane and poured cautiously onto a mixture of 2 M hydrochloric acid and ice. The phases are separated, extraction is carried out with dichloromethane and the extracts are washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 10-20%) to give 21.5 g of 1-(3,4-difluoro-2-hydroxyphenyl)propan-1-one. 21.4 g (115 mmol) of 1-(3,4-difluoro-2-hydroxyphenyl)propan-1-one are dissolved in 170 ml of acetone, and the solution is admixed with 29.5 g of potassium carbonate and 13 ml (209 mmol) of methyl iodide. The mixture is boiled under reflux for 4 hours and stirred at room temperature for 12 hours and then the solvent is largely removed. The residue is poured into water and subjected to extraction with diethyl ether. The extracts are washed with water, dried over sodium sulphate and, following the removal of the solvent in vacuo, give 21.2 g of 1-(3,4-difluoro-2-methoxyphenyl)propan-1-one.
Reaction SMILES: CO[CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1>ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[CH:3][C:7]=2[CH:8]=1
Reactant: COc1ccc(SCC(OC)OC)cc1
Solvent: Clc1ccccc1
Product: COc1ccc2sccc2c1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
Under a nitrogen atmosphere, polyphosphoric acid (10 g) was added to anhydrous chlorobenzene (150 ml). To the resulting mixture, 1-(2,2-dimethoxyethylsulfanyl)-4-methoxybenzene (5.2 g, 22.7 mmol) was added under refluxing over 1.5 hours and the reaction mixture was heated to reflux overnight. The reaction was cooled to room temperature, and then the organic layer was separated. To the polyphosphoric acid layer, water was added and the obtained solution was extracted with methylene chloride. All organic layers thus obtained were washed with water and a saturated sodium chloride aqueous solution and dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:40)] to obtain the title compound (1.1 g, 30%).
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]=3)[CH:10]=2)=CC=1.C1(OC)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[Br:15][C:14]1[C:9]([SH:8])=[CH:10][C:11]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=2)=[N:12][CH:13]=1
Reactant: COc1ccc(CSc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Sc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 75 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
4-(4-methoxybenzylthio)-5-bromo-N-(4-phenethylthiazol-2-yl)pyridine-2-amine (1.23 g, 2.4 mmol) was dissolved in TFA (10 mL):anisole (2 mL) (5:1). The reaction mixture was stirred at 75° C. overnight, then neutralized with solid NaHCO3, extracted with EtOAc, dried, and concentrated. The crude material was triturated in MeOH and filtered. The filtrate was further concentrated and triturated again with MeOH. The solids were combined and dried to give the desired product (0.68 g, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2cc(NS(C)(=O)=O)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (137 mg, 1.20 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic phase was pooled and concentrated. It was purified by prep-HPLC to give the desired product (80.5 mg, 41.0%). LCMS (ESI): RT (min)=1.181, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.17 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.38-7.34 (m, 1H), 7.15 (d, J=9.2 Hz, 2H), 3.30 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1)(=[O:38])=[O:37]>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:40][CH2:41]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(NC3CCN(S(C)(=O)=O)CC3)n2)s1
Yield: 84 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.30 g, 0.57 mmol), 1-(methylsulfonyl)-4-piperidinamine (0.3 g, 1.7 mmol) and THF (1 mL) the title compound was obtained (0.32 g, 0.48 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 8.13 (d, J=5.0 Hz, 1H), 7.71-7.44 (m, 3H), 7.45-7.32 (m, 3H), 7.29 (t, J=9.2 Hz, 1H), 6.30 (m, 1H), 3.50 (m, 2H), 3.30-3.24 (m, 1H), 2.86 (s, 3H), 2.83-2.64 (m, 2H), 1.90 (m, 2H), 1.67-1.44 (m, 2H), 1.36 (d, J=6.8 Hz, 6H). MS (ESI): 667 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17])[C:4](=[NH:8])[O:5]CC.[C:18](Cl)(Cl)=[O:19]>>[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:18](=[O:19])[NH:5][C:4]1=[O:8])[CH3:17]
Reactant: CCOC(=N)C(O)c1ccccc1OCC
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CCOc1ccccc1C1OC(=O)NC1=O
Yield: 70 %

Procedure:
Ethyl 1-hydroxy-1-(2-ethoxyphenyl)methanecarboximidate hydrochloride (20 g.) was reacted with phosgene according to the procedure of Example 3. To isolate the product, the reaction mixture was evaporated to dryness and the solid residue partitioned between 500 ml. of water and 500 ml. of chloroform. The aqueous phase was washed with two fresh portions of chloroform. The combined chloroform phase and washes was dried over anhydrous magnesium sulfate, filtered, evaporated to solids and recrystallized from toluene to yield 5-(2-ethoxyphenyl)oxazolidine-2,4-dione (11.9 g., 70%; m.p. 165°-167° C., m/e 221).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[CH3:28][N:29]([CH3:32])[CH:30]=O>>[CH3:28][N:29]([CH3:32])[CH:30]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:15]=[O:17]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 13.70 mL (146.95 mmol) of phosphorus oxychloride at 0° C. was added 13.92 mL (179.77 mmol) of anhydrous N,N-dimethylformamide dropwise. The resulting solution was stirred for 15 min at room temperature. Then, 10.00 g (48.98 mmol) of [4-(trifluoromethyl)phenyl]acetic acid in 24 mL of anhydrous N,N-dimethylformamide was added dropwise. The resulting mixture was stirred for 19 h at 70° C., and then poured onto ice. Following neutralization with potassium carbonate, 30 g of sodium hydroxide was added, and the resulting solution was heated at 50° C. for 15 min. It was then cooled to 0° C. and filtered. The filter cake was washed with water and dried under a vacuum to give 3-(dimethylamino)-2-[4-(trifluoromethyl)phenyl]-2-propenal. This dry solid was dissolved in 122 mL of methanol, 3.07 mL (97.97 mmol) of hydrazine was added, and the solution was stirred for 6 h at room temperature. It was poured into water, and the resulting mixture was filtered. The filter cake was washed with water, followed by hexanes, and dried under vacuum to give 8.35 g (80% yield) of 4-[4-(trifluoro)phenyl]-1H-pyrazole. Rf=0.26 (1:19 methanol:dichloromethane); 1H-NMR (300 MHz, DMSO-d6): δ 13.09 (br s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H); ES-LCMS m/z 213 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].NC1C=C(O)C(C)=CC=1>>[Br:33][C:34]1[CH:35]=[C:36]([NH:37][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 3-bromoaniline according to the procedure from Example 137C substituting 3-bromoaniline for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (50 mg, 38%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 3.16-3.30 (m, 1H), 3.77 (s, 3H), 7.00 (d, J=8.82 Hz, 2H), 7.40 (d, J=8.82 Hz, 2H), 7.53 (d, J=8.82 Hz, 2H), 7.64 (d, J=8.82 Hz, 1), 7.74 (d, J=8.82 Hz, 2H), 7.81 (dd, J=8.46, 1.84 Hz, 1H), 7.99 (d, J=1.47 Hz, 1H), 8.59 (s, 1H), 8.86 (d, J=8.82 Hz, 1H), 10.21 (s, 1H), 10.33 (s, 1H); MS (APCI) m/z 602 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH3:21][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([CH2:33][CH2:34][CH3:35])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc(N(C)C)nc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N(C)C)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A solution of methyl 2-(2-(dimethylamino)-4-methyl-6-phenylpyrimidin-5-yl)acetate (750 mg; 2.63 mmol) in dry DMF (13 mL) was cooled to −15° C. LHMDS (2.89 mL, 2.89 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.385 mL; 3.94 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 680 mg (79%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.46-7.40 (5H, m); 3.82 (1H, dd, J=6.1, 8.2 Hz); 3.69 (3H, s); 3.19 (6H, s); 2.31 (3H, s); 2.08-1.96 (1H, m); 1.62-1.47 (1H, m); 1.02-0.92 (2H, m); 0.65 (3H, t, J=7.1 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:10]3[CH2:11][CH2:12][NH:13][C:14]=3[CH:15]=2)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]([O:48][C:49]([C@@H:51]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])=[O:50])([CH3:47])([CH3:46])[CH3:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:44]([O:48][C:49]([C@@H:51]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:52]([N:13]1[C:14]2[CH:15]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:10]=2[CH2:11][CH2:12]1)=[O:53])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.9 %

Procedure:
To a 500 ml flask was added methyl 6-(pyridin-4-yl)indoline-4-carboxylate 54.1.C (1.98 g, 7.81 mmole), of HBTU (5.92 g, 15.6 mmole), (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid 3.11 g, 11.7 mmole, available from Aldrich) 50 ml of DMF and DIEA (4.08 ml, 23.4 mmole). The reaction was stirred at 60° C. for 6 hours, at which time the crude reaction was partitioned between 1000 ml of EtAc and 500 ml of water. The solvent was removed and the crude purified using a silica gel column (Elutent; 50/50 EtAc/Hex) to give (S)-methyl 1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylate 54.1.D as a yellow solid (2.05 g, 52.3% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[Br:37][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Alcohol 1-4 (3 g, 13.8 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. under N2 atmosphere. Triphenylphosphine (4.35 g, 16.6 mmol) was added followed by CBr4 (5.5 g, 16.6 mol) in small portions. Reaction temperature was allowed to equilibrate to 23° C. over 8 hours. 20 g of SiO2 gel was added and solvent removed in vacuo. The dried silica gel was placed in a filter and washed with 10% EtOAc/Hexanes. The filtrate was reduced to minimum volume and chromatographed with 5-10% EtOAc/Hexanes to give 3.5 g of the product 1-5 as a clear oil (90% yield). M+1=280.0/282.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (0.30 g) was heated with potassium carbonate (anhydrous, 0.46 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.16 g) in anhydrous DMF (1 mL) was added. The reaction mixture was then heated to 50° C. overnight. The reaction was quenched into water (50 mL) and extracted with ethyl acetate (50 mL, 3 times). The organic layer was combined and washed with brine (50 mL). The organic layer was separated and dried by passing through a hydrophobic frit before being evaporated under reduced pressure to give oil). This material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This material was purified by reverse phase chromatography (20-60% acetonitrile: water). This gave the title compound as a white solid (0.1279 g).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH2:19]([N:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[CH:23]=[N:22]1)[CH3:20]>>[CH2:19]([N:21]1[C:25]([NH:26][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[C:24]([CH3:27])[CH:23]=[N:22]1)[CH3:20]
Reactant: CCn1ncc(C)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C)cnn3CC)c2o1
Yield: 40 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (150 mg) and 2-ethyl-4-methyl-2H-pyrazol-3-ylamine (90 mg). Purification by column chromatography on silica eluting 2:1 ethyl acetate-heptane followed by ethyl acetate afforded the title compound as a white solid (85 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:3][CH:4]=1
Reactant: O=C(CCCCCl)N1CCOCC1
Reactant: Oc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCCSc1ccc(O)cc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 47.9 g (0.250 mole) of p-mercaptophenol, 51.4 g (0.250 mole) of 4-(5-chlorovaleryl)morpholine, 52 ml of 5N sodium hydroxide and 600 ml of water was heated to boiling and then stirred at 50°C. for 1 hour; and, thereafter, stirred at room temperature for 15 hours. The white, crystalline intermediate precipitated during this period. The dried, crude intermediate was recrystallized from benzene to give the intermediate, 4-[5-(4-hydroxyphenylthio)valeryl]morpholine, as white crystals, mp 112°-113° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[Br:34][C:35]1[N:40]=[C:39]([C:41](=[O:44])[NH:42][CH3:43])[C:38]([NH:45][C:46]2[C:51]([C:52]([F:55])([F:54])[F:53])=[CH:50][N:49]=[C:48]([NH:56][C:57]3[CH:67]=[CH:66][C:60]([CH2:61][CH2:62][PH:63](=[O:65])[OH:64])=[CH:59][C:58]=3[O:68][CH3:69])[N:47]=2)=[CH:37][CH:36]=1.[CH3:70][C:71]1([CH3:87])[C:75]([CH3:77])([CH3:76])[O:74][B:73]([C:78]2[CH:79]=[N:80][N:81]([CH2:83][CH2:84][CH2:85]O)[CH:82]=2)[O:72]1.CN1C=CN=C1>ClCCCl>[Br:34][C:35]1[N:40]=[C:39]([C:41](=[O:44])[NH:42][CH3:43])[C:38]([NH:45][C:46]2[C:51]([C:52]([F:55])([F:53])[F:54])=[CH:50][N:49]=[C:48]([NH:56][C:57]3[CH:67]=[CH:66][C:60]([CH2:61][CH2:62][PH:63](=[O:64])[O:65][CH2:85][CH2:84][CH2:83][N:81]4[CH:82]=[C:78]([B:73]5[O:74][C:75]([CH3:77])([CH3:76])[C:71]([CH3:70])([CH3:87])[O:72]5)[CH:79]=[N:80]4)=[CH:59][C:58]=3[O:68][CH3:69])[N:47]=2)=[CH:37][CH:36]=1
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: Cn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Yield: 16.5 %

Procedure:
(Benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (2.24 g, 4.30 mmol) was added to stirring suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinic acid (Compound 61B, 845 mg, 1.43 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 362 mg, 1.43 mmol), and 1-methylimidazole (1.37 ml, 17.2 mmol) in 1,2-dichloroethane (31.2 ml) at 60° C. for 16 hrs. The reaction was quenched with water and extracted with EtOAc (3×), dried over sodium sulfate, filtered, and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→10% MeOH in 1:1 EtOAc/DCM] to afford 194 mg of the title compound as a racemic mixture (16%). MS (ESI): m/z=824.65 [M+H]+. UPLC: tR=1.17 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])C=CC=CC=1>>[C:33]1([CH:31]([CH3:32])[CH2:30]/[CH:29]=[CH:1]\[C:3]2[N:4]=[C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: [I-]
Product: CC(C/C=C\c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1

Procedure:
tert-Butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.00 g) is reacted with triphenyl(3-phenylbutyl)phosphonium iodide (3.53 g) and purified as described in IV-3. This gives tert-butyl 4-{4-[(1Z)-4-phenylpent-1-en-1-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.23 g) in form of the Z isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:19]([Cl:18])(=[O:21])=[O:20])[CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:13])([F:12])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccccc1Cl)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl)C(F)(F)F
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
(R)-N-(2-Chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 74) (13.8 g, 52 mmol) was added in portions to a cooled (0° C.) solution of chlorosulphonic acid (25 ml) over 15 mins and then the mixture was heated to 85° C. After 4.5 h the reaction mixture was cooled in an ice bath and then poured very slowly onto a stirred ice-water mixture. After stirring for 15 mins, the mixture was extracted with ethyl acetate (2×100 ml) and the combined organic layer washed with brine, dried and concentrated to yield a brown oil. This oil was purified by flash column chromatography using 10:1, iso-hexane:ethyl acetate to yield the title compound as a pale yellow solid (11 g, 30 mmol). NMR: 1.6 (s, 3H), 7.55 (dd, 1H), 7.6 (d, 1H), 7.95 (d, 1H), 9.7 (brs, 1H); MS: 364.