Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([OH:20])=O)[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][C@H:46]([CH3:49])[CH2:47][OH:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:45][C@H:46]([CH3:49])[CH2:47][OH:48])=[O:20])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)O)ccc2C)c1=O
Reactant: C[C@@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)N[C@H](C)CO)ccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a cooled solution (0° C.) of 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 4) (0.25 g, 0.62 mmol) and 4-methylmorpholine (0.10 mL, 0.94 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.12 mL, 0.94 mmol). Stirred 5 min at 0° C., 30 min at ambient temperature. Added (R)-(−)-2-amino-1-propanol (0.07 mL, 0.94 mmol) and DMAP (0.02 g, 0.12 mmol) to the cooled (0° C.) reaction mixture. Stirred at ambient temperature for 3 h. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=458) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white foam (0.20 g, 70%). 1H NMR (CD3OD/400 MHz) δ8.18 (s, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.57 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.52 (q, 2H, J=12.4 Hz), 4.16 (m, 1H), 3.57 (m, 2H), 2.21 (q, 2H, J=7.6 Hz), 2.17 (s, 3H), 1.22 (m, 3H), 1.05 (t, 3H, J=7.2 Hz). ESHRMS m/z 458.1855 (M+H calculated for C24H26F2N3O4 requires 458.1886).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:9][CH2:8][CH2:7][C:6]4[S:5][CH:4]=[N:3][C:2]=4[CH3:1])=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: Cc1ncsc1CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncsc1CCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
To a solution of 4-methyl-5-thiazole-ethanol (0.375 g, 2.62 mmol) in THF (1 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (11.0M in hexanes)(1.74 ml, 1.74 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.300 g, 0.872 mmol). The reaction mixture is stirred at room temperature for 18 hours, then quenched by the addition of water (5 ml). The mixture is partitioned between water and EtOAc (40 ml each). Five ml of 1 N HCl is added, and the layers are shaken and separated. The aqueous layer is extracted with EtOAc (50 ml) and the combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (1:2 hexane:EtOAc) to give the title compound as a pale yellow solid (0.094 g, 25%). Mass (m/z): 423.1 (M++1), 421.1 (M+−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]([S:47]([C:50]1[CH:55]=[CH:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH:51]=1)(=[O:49])=[O:48])([CH3:46])[CH3:45].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:53]2[CH:52]=[CH:51][C:50]([S:47]([CH:44]([CH3:46])[CH3:45])(=[O:49])=[O:48])=[CH:55][CH:54]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(Cc1ccc(-c2nnc(-c3cc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)cc1
Temperature: 80 °C
Yield: 98 %

Procedure:
tert-Butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-bromo-3-pyridyl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (120 mg, 0.1817 mmol) was dissolved in DMF (1.2 mL) and 2-(4-isopropylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84.57 mg, 0.2726 mmol) and Pd(PPh3)2Cl2 (7.516 mg, 0.01817 mmol) were added. 2M aqueous Na2CO3 (272.6 μL, 0.5451 mmol) was added and the reaction heated at 80° C. for 1 hour in a sealed tube. The reaction mixture was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×2). The combined organic extracts were washed with water (×3), brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (ISCO Companion™, 4 g column, 0-50% EtOAc/Petroleum ether) to give the impure sub-title compound as a yellow oil (136 mg). This was used directly in the next step with no further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)nn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCO)CC4)nn3)nc2n1C1CCCC1
Yield: 12.7 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(6-piperazin-1-yl-pyridazin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-bromo ethanol (143 mg, 1.14 mmol) gave 7-cyclopentyl-2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (14 mg, 13%). MS(ESI) m/z 480.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[C:13]([CH3:15])[N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N+:11]([O-:25])[CH:12]=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 45 °C

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine at 0° C. in dioxane was added mCPBA (750 mg). The reaction mixture was heated at 45° C. for 3 h. The reaction was diluted with CH2Cl2, washed with NaHCO3, dried (MgSO4), filtered, and concentrated. It was used without purification: 1H NMR (CDCl3) δ 2.30, 2.54, 7.33, 7.42, 7.54, 8.13; 13C NMR (CDCl3) δ 14.04, 21.85, 128.10, 130.12, 131.64, 132.14, 134.07, 135.23, 136.44, 141.66, 153.87, 154.24.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)=[N+:2]=[N-:3].O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C(O)C>[O:14]=[C:10]1[C:11]2[C:6](=[CH:5][C:4]([N:1]3[C:16]([CH2:23][CH2:24][CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[N:3]=[N:2]3)=[CH:13][CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)CCNC2=O
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc2c(c1)CCNC2=O
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 6-azido-3,4-dihydroisoquinolin-1(2H)-one (0.24 g) obtained in Example 132b) and ethyl 3-keto-n-hexanoate (0.25 ml) in ethanol (7 ml) was added 28% sodium ethoxide in ethanol solution (0.60 ml) at room temperature, and the mixture was stirred for 3 hr. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The mixture was washed with ethyl acetate, 1N hydrochloric acid was added to acidify the aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (0.22 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.Cl[CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Na]>C(O)C.C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(F)Cl
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(F)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Yield: 35.3 %

Procedure:
To a stirred mixture of 2.0 g (0.0065 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.91 g (0.0065 mole) of ethyl chlorofluoroacetate in 50 mL of ethanol was added a solution of 0.15 g (0.0065 mole) of sodium in 5 mL of ethanol. The reaction mixture was heated at reflux for 34 hours. The mixture was cooled, and the solvent was removed by evaporation under reduced pressure, leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed first with water, followed by an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate, then filtered. The filtrate was evaporated under reduced pressure to yield 0.95 g of ethyl [2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]fluroacetate as an oil, Compound 51.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClCCl>CN(C=O)C.[Cu](I)I.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:6][CH:7]=1
Reactant: C#CCCn1ccnn1
Reactant: Clc1ccc(I)nn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccc(C#CCCn2ccnn2)nn1
Reaction time: 6 h

Procedure:
3-Chloro-6-iodo-pyridazine (11.56 g, 48.1 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (6.99 g, 57.7 mmol) and triethyl amine (NEt3) (94 ml) are dissolved in DMF (188 ml) and copper iodide (CuI) (0.981 g, 5.15 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium(0) (2.836 g, 2.43 mmol) is added and stirring is continued for 6 h at r.t. Dichloromethane (300 ml) is added, the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate) yielding 3-chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine as a colorless solid. Yield 9.52 g (85%).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].CS(C(CC#CC1(O)CCCCC1)CCCCCCC(O)=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Agent: CS(=O)(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC1(O)CCCCC1

Procedure:
The synthesis of this compound is carried out by the hydrogenation process described in Example 15 except that 8-methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid is replaced by an equivalent quantity of 8-methylsuflfonyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid (Example 19).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:15]([O:22][CH2:23][C@@H:24]1[NH:29][CH2:28][CH2:27][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:32])=[O:31])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].COC(C)(C)C>O.C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@H:24]1[CH2:25][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:32])[CH2:27][CH2:28][N:29]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(c1cccs1)N1CCN[C@@H](COCc2ccccc2)C1
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2ccccc2)cc1)C(F)(F)F
Temperature: 65 °C
Yield: 74 %

Procedure:
A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (43.8 g, 163 mmol, Example 27, Step 1), (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g, 136 mmol), 200 mL of toluene, and sodium tert-butoxide (32.6 g, 339 mmol). After bubbling nitrogen gas through the solution for 5 min, chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.99 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.63 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 12 h. After that time, the mixture was diluted with water and extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 60% EtOAc in hexanes) gave 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g) as a yellow foam.
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.[C:23]1([P:29](Cl)(Cl)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CC(OC)(C)C>[CH:3]([C@H:2]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C@H:12]([CH:13]([CH3:15])[CH3:14])[O:16][P:29](=[O:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:1]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CC(C)[C@@H]1OP(=O)(c2ccccc2)O[C@@H](C(C)C)c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of (S)-1-[2-((S)-1-Hydroxy-2-methylpropyl)phenyl]-2-methyl-propan-1-ol (1.0 g, 4.9 mmol) in pyridine (1.16 g 14.7 mmol) was cooled with an ice-bath. To this mixture was then added drop wise phenyl phosphonic acid dichloride (0.96 g, 4.9 mmol). After stirring for 90 minutes the reaction was complete by 31P-NMR. To the mixture was then added TBME (ca. 20 ml) and hydrochloric acid (ca. 5 ml 4N-solution). The organic layer was separated, dried (Na2SO4), and removal of the solvent left the product as an oil. Yield 1.50 g (89%). 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.965 (d, J=6.5 Hz)/20.38 (CH3); 1.075 (d, J=6.5 Hz)/19.05 (CH3); 1.106 (d, J=6.5 Hz)/17.71 (CH3); 1.112 (d, J=6.7 Hz)/20.38 (CH3); 2.37 (m)/34.58 (d, J=8.3 Hz) (CHMe2); 2.49 (m)/31.28 (d, J=7.6 Hz) (CHMe2); 5.17 (dd, J=5.6 Hz, J=7.6 Hz)/83.85 (d, J=8.9 Hz) (CH(i-Pr)); 5.53 (dd, J=3.8 Hz, J=5.9 Hz)/84.36 (d, J=7.6 Hz) (CH(i-Pr)); 7.24 (m)/127.28 (Ar CH); 7.24 (m)/127.93 (Ar CH); 7.24 (m)/127.95 (Ar CH); 7.27 (m)/128.31 (Ar CH); 7.37 (m)/128.43 (d, J=15.1 Hz) (Ph meta-CH); 129.12 (d, J=193 Hz) (Ph ipso-C); 7.47 (m)/132.38 (d, J=3.0 Hz) (Ph para-CH); 7.70 (m)/131.63 (d, J=9.8 Hz) (Ph ortho-CH); 137.23 (s), 138.48 (d, J=1.0 Hz) (2 Ar ipso-C). 31P-NMR (CDCl3) δ 18.72.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1csc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCOCC2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 4-(4-chloromethyl-1,3-thiazol-2-yl)morpholine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.33 g, 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][N:13](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:15][N:8]3[CH2:7][CH:6]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:5]23)[CH:11]=1.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:50]>>[ClH:50].[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:8]3[CH2:7][CH:6]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:5]23)[CH:11]=1
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCCCC3c3cc(Br)cc(c32)C1
Reactant: ClCCl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Product: Brc1cc2c3c(c1)C1CCCCCC1CN3CCNC2
Product: Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
The compound from Example 15 (1 g, 2.13 mmol) was dissolved in methylene chloride (2.3 mL) and cooled to 0° C. Trifluoromethane sulfonic acid (1.32 mL, 14.9 mmol) was added slowly to the solution followed by anisole (0.695 mL, 6.39 mmol). The reaction mixture was then stirred at 0° C. for 10 minutes, and then stirred at room temperature for 1 hour, at which point the reaction was complete. The pH of the reaction mixture was then adjusted with 1N NaOH until the pH was basic. The reaction mixture was then transferred to a separatory funnel and extracted with methylene chloride (3×). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated to give a yellow oil. Further purification (2-4% ammonia in 2M solution in methanol/Ethyl acetate) yielded 0.630 g of the desired free amine product (88%). The free amine product (1.85 mmol) was then dissolved in diethyl ether and isopropanol. HCl in 2M solution of diethyl ether (1.85 mmol) was added. The solution was stirred for 30 minutes and a yellow solid was filtered off.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]1[CH:41]=[CH:40][NH:39][N:38]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]3[CH:41]=[CH:40][NH:39][N:38]=3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNc2cc[nH]n2)no1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 3-aminopyrazole (249 mg, 2.97 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[O:30][N:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:31]2[O:30][N:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[CH:32]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)on1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.4 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (76 mg, 0.24 mmol) described in Example 115B in anhydrous THF (1.5 mL), was added 4-chlorophenyl 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from Example 267A (84 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (15 mg, 0.12 mmol). The mixture was stirred at rt for 6 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea (88.8 mg, 69%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.56 (d, J=9 Hz, 1H), 7.43-7.48 (m, 1H), 7.30-7.36 (m, 3H), 6.19 (s, 1H), 3.99 (s, 6H), 1.49 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([F:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[CH:11]1([CH2:16][CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[CH:39][C:40]=2[F:45])=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 80%).