Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=C(C=C(F)[CH:42]=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H:61]([NH:71][C:72]([C:74]1[CH:75]=[C:76]([CH:80]=[C:81](C)[CH:82]=1)[C:77]([OH:79])=[O:78])=[O:73])[CH2:62][C:63]1C=C(F)C=C(F)C=1)=O)(C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C)C=C(C(OC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[Li+].[OH-]>C1COCC1.O.C(OCC)C.CO>[CH2:42]([N:71]([CH2:61][CH2:62][CH3:63])[C:72]([C:74]1[CH:75]=[C:76]([CH:80]=[CH:81][CH:82]=1)[C:77]([OH:79])=[O:78])=[O:73])[CH2:2][CH3:3]
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step G (5): Preparation of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate (Step G (4), 110 mg, 0.16 mmol) in THF (2 mL) was added a solution of LiOH (18 mg, 0.8 mmol) in H2O (0.4 mL). This reaction mixture was stirred at rt for 2 h. MeOH (2 mL) was added to the reaction mixture and stirred for another 2 h at rt. Ethyl ether (100 mL) was added to the mixture and washed with 1N HCl, H2O, dried (Na2SO4), and concentrated in vacuo to give 105 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 0.05 (3H, s), 0.10 (3H, s), 0.93 (3H, m), 0.97 (9H, s), 1.47 (9H, s), 1.58 (2H, m), 2.26 (1H, m), 2.39 (3H, s), 2.47-2.52 (1H, m), 2.61 (1H, m), 3.07 (1H, m), 3.27 (1H, m), 3.37 (1H, dt, J=5, 10 Hz), 3.47 (1H, dt, J=5, 10 Hz), 3.86 (1H, dd, J=5, 10 Hz), 3.97 (1H, m), 4.12 (1H, m), 4.36 (1H, m), 4.50 (1H, m), 6.47 (1H, m), 6.89 (1H, s), 6.90 (1H, s), 7.90 (1H, s), 7.95 (1H, s), 8.26 (1H, d, J=10 Hz), 8.54 (1H, s). MS (ESI) (M−H)− 689.49.
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][NH:31][CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=O)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH2:17][CH:16]([CH2:29][CH2:30][N:31]([CH3:32])[S:34]([CH3:33])(=[O:36])=[O:35])[N:7]3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]([OH:4])=[C:6]3[C:19]2=[O:20])=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)S(C)(=O)=O)CN(Cc1ccc(F)cc1)C2=O

Procedure:
2-(4-Fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate (Example 67, Step 2, 37 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was treated with a large excess of reagents (70 μL MsCl, 270 μL triethylamine and 20 mg DMAP). Stirring the reaction at ambient temperature over night gave complete conversion to the sulfonamide with exchange of the 9-acetate to the 9-mesylate. The solvent was removed under a steady nitrogen stream at 50° C. and the residue dissolved in MeOH (1 mL) and treated with a solution of sodium methoxide in MeOH (25 wt %, 2.5 mL). After four days of stirring at ambient temperature, cleavage of the 9-mesylate to the 9-hydroxy was complete. The mixture was quenched by the addition of TFA and water and was then concentrated under a steady stream of nitrogen at 50° C. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 11.73 (s, 1 H), 7.38-7.27 (m, 2 H), 7.09-7.05 (m, 2 H), 5.22-5.15 (m, 1 H), 4.96 (d, J=14.5 Hz, 1 H), 4.78-4.76 (m, 1 H), 4.37 (d, J=14.0 Hz, 1 H), 3.72 (dd, J=1.5, 14.0 Hz, 1 H), 3.62 (dd, J=3.8, 14.0 Hz, 1 H), 2.83 (s, 3 H), 2.80-2.66 (m, 5 H), 1.90-1.83 (m, 1 H), 1.56-1.49 (m, 1 H), 1.47 (d, J=7.0 Hz, 6 H). HRMS (APCI) M+H: calcd for (C21H28FN4O6S)+ 483.1708. found 483.1729.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH3:32][N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:34].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:32][N:33]([CH3:34])[C:25]([CH:23]1[CH2:24][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:31])([F:29])[F:30])[O:14][N:13]=3)=[CH:20][CH:19]=2)[CH2:22]1)=[O:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added HATU (0.115 g, 0.304 mmol) HOBt (0.03 g, 0.223 mmol), DIPEA (0.052 g, 0.406 mmol) followed by addition of saturated solution of dimethyl amine in THF (2 mL) at 0° C. and stirred at 0° C. for 3 hours. After complete consumption of starting material, reaction mixture was quenched with water (20 mL), extracted with EtOAc (3×20 mL). Combined organic layer was washed with brine (50 mL), saturated solution of lithium chloride (50 mL), and water (50 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.6% methanol in DCM to afford white solid (0.050 g, 48%. 1H-NMR (400 MHz, CDCl3) δ: 2.94 (s, 3H), 2.97 (s, 3H), 3.61 (d, 1H, J=17.08 Hz), 3.69-3.77 (m, 1H), 4.02 (d, 1H, J=17.04 Hz), 4.11 (d, 4H, J=7.48 Hz), 6.40 (d, 2H, J=8.72 Hz), 7.46 (d, 2H, J=8.68 Hz), 7.63 (s, 2H); LC-MS (m/z): [M+H] 519.80.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH:20](B1OB(C=C)OB(C=C)O1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:5]2[N:6]=[N:7][C:2]([CH:20]=[CH2:21])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Temperature: 140 °C
Yield: 41.8 %

Procedure:
To a 5 mL microwave reaction vial was added 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (123 mg, 441 μmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (159 mg, 661 μmol, 1.5 equiv), Cl2Pd(dppf) (54 mg, 66 μmol, 0.15 equiv), potassium carbonate (182 mg, 1.32 mmol, 3 equiv), and dioxane (21 mL). The reaction was heated in a microwave reactor at 140° C. for 12 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-50% EtOAc/hexanes) to give 50 mg (46%) of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-vinylpyridazin-3-amine as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2].[O:28]=[C:29]1[NH:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]#[CH:36].CCN(CC)CC.C1(C)C=CC=CC=1>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.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([C:36]#[C:35][CH2:34][N:30]3[CH2:31][CH2:32][NH:33][C:29]3=[O:28])[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2]
Reactant: C#CCN1CCNC1=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#CCN3CCNC3=O)cc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (25.0 mg, 4.64×10−5 mol), 3-(2-oxo-1-imidazolidinyl)-1-propyne (8.6 mg, 1.5 eq.), Pd(PPh3)2Cl2 (4.88 mg, 15 mol %) and CuI (1.32 mg, 15 mol %) under a nitrogen atmosphere was added anhydrous Et3N (0.5 mL), anhydrous toluene (0.5 mL) and anhydrous THF (0.5 mL). The resulting yellow mixture was heated to 50° C. (bath temperature) and stirred at that temperature for 1 hour 20 minutes. The solvent was then removed in vacuo to give a yellow solid. Purification was carried out by column chromatography (silica gel, 6% MeOH in CHCl3) to yield the title compound (23.9 mg, 92%) as a light brown solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:18][C:19](=O)[CH3:20])[N:11]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C(OCC)(=O)C>[Cl-].[Zn+2].[Cl-].O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([C:18]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=3)[NH:31][C:19]=2[CH3:20])[N:11]=1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(C)c(-c3nc(OC)cc(OC)n3)c2c1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To 80 ml of toluene were added 8.0 g (40 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.7 g (44 m moles) of 4-metoxyphenylhydrazine hydrochloride. Thereto was added 6.0 g (44 m moles) of zinc chloride. Refluxing was made for 2 hours with heating. The reaction mixture was allowed to cool. Thereto were added ethyl acetate and water to dissolve the whole reaction mixture. The oily layer was washed with water, separated and dried over Glauber's salt. The resulting organic layer was concentrated under reduced pressure using an rotary evaporator to obtain, as an orange solid, 8.0 g (26.7 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-5-methoxy-2-methylindole. Yield: 67% Recrystallization from toluene was made.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@H]([C@@H](CS)O)O.Cl[CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(Cl)Cl.O>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CCCl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Agent: O=C([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide (200 mg, 0.46 mmol) in methanol (2.5 mL) and DCM (2.5 mL) was added dithiothreitol (71 mg, 0.46 mmol), and the mixture was stirred at room temperature for 1 h. 2-Chloroethyl-diethylamine (158 mg, 0.92 mmol), potassium carbonate (235 mg, 0.46 mmol), and potassium iodide (10 mg) were added and the reaction mixture was stirred for another 3 h at room temperature. Water (5 mL) and DCM (10 mL) were added and the organic phase was isolated and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo, and the residue was purified on a silica gel column (isocratic from 100% DMC to 100% ethyl acetate with 1% TEA) to give colourless crystals of (R)-3-cyclopentyl-N-[5-(2-diethylamino-ethylsulfanyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide. Yield: 150 mg (64%). 1H-NMR (CDCl3): δ 11.50 (broad s, 1H), 7.86 (d, 2H), 7.51 (d, 2H), 7.48 (s, 1H), 3.76 (t, 1H), 3.04 (s, 3H), 2.86 (t, 2H), 2.71 (t, 2H), 2.54 (q, 4H), 2.26 (m, 1H), 1.90 (m, 1H), 1.79-1.43 (m, 8H), 1.12 (m, 1H), 1.00 (t, 6H); HPLC-MS: m/z=510 (M+1).
Reaction SMILES: [Cl-].[Li+].[C:3]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:4]=1.[CH3:22][C:23]1[C:24](OS(C(F)(F)F)(=O)=O)=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32].C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH3:22][C:23]1[C:24]([CH:3]=[CH2:4])=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 55 °C

Procedure:
A mixture of lithium chloride (4.8 g),tris (dibenzylideneacetone)dipalladium (O) chloroform adduct (0.65 g), triphenylarsine (1.6 g) and methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (24.2 g) in N-methylpyrrolidinone (220 ml) was heated to 55° C. Vinyltributyltin (15 g) was added. After 3 hours the mixture was added to water (500 ml), potassium fluoride (16 g) and ethyl acetate. The organic solution was dried, filtered through celite and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][C@H:20]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][C@@H:23]([CH2:33][OH:34])[O:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[Si:11]([O:18][CH2:19][C@H:20]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][C@@H:23]([CH:33]=[O:34])[O:22][CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](C=O)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of oxalyl chloride (2 eq) in DCM (0.3 M) at −78° C. was added a solution of DMSO (5 eq) in DCM (0.5M). The reaction mixture was stirred at −78° C. for 30 min. A solution of tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(hydroxymethyl)morpholine-4-carboxylate (1 eq) in CH2Cl2 (0.2M) was added dropwise and stirred at −40° C. for 1.5 hours. It was then cooled to −78° C. and triethylamine (7 eq) was added and the reaction mixture was stirred at 0° C. for 1 h. Water was added and the reaction mixture was warmed to rt for 30 min. The mixture was diluted with CH2Cl2, the organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([OH:18])=O)[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([Cl:27])=[O:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)O)nnn1-c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carboxylic acid (830 mg, 3.13 mmol) in dichloromethane (3 mL) was added DMF (50 μL) followed by oxalyl chloride (546 μL, 6.26 mmol) dropwise. After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 1 h. CH2Cl2 was removed in vacuo to give 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride as a white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CO.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>O>[C:15]1([N:21]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NN(C(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 101.2 g. (0.602 mole) ethyl p-fluorobenzoate, 250 ml. methanol, 70.0 g. (0.646 mole) phenylhydrazine, and 33.6 g. (0.621 mole) sodium methoxide (mixed in that order) was heated at the reflux temperature for 16 hrs. After cooling the reaction mixture to about 25° C. It was poured into 1500 ml. water. The aqueous mixture was filtered, and the filter cake was washed with water and recrystallized from 95% aqueous ethanol. The crystals melted at 174° to 178° C. An analytical sample of p-fluorobenzoic acid phenylhydrazide melting at 177° to 179° C. was obtained by recrystallizing once from a mixture of ethyl acetate and Skellysolve B (essentially a mixture of isomeric hexanes boiling in the range of 146° to 156° F.), and once from 75% aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C1(C)C=CC=CC=1>ClCCl>[CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])=[N:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1cccs1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1cccs1
Temperature: 200 °C

Procedure:
5-Methyl-2-(methylsulfonyl)-4-(thiophen-2-yl)pyrimidine (0.1 g, 0.39 mmol) and 1-(2-aminoethyl)imidazolidin-2-one (0.06 g, 047 mmol) were added to a microwave tube along with toluene (1 mL). The tube was capped and heated to 200° C. for 10 min in a Personal Chemistry microwave. The mixture was diluted with dichloromethane and purified by flash chromatography using a gradient of 2 to 10% methanol in dichloromethane to obtain an off-white solid. Yield=0.03 g. MS (M+H)+ 304.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([Si](C)(C)[O:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][OH:27])=[CH:31][C:32]=3[F:37])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(O)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Oc2ccc(CCO)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (270 mg, 0.84 mmol) and 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-fluoro-phenol (279 mg, 0.84 mmol) in DMF (5 mL), was K2CO3 (137 mg, 0.84 mmol) added. The reaction mixture was irradiated under microwave for 1 hour at 150° C. The reaction was cooled to room temperature and treated with 1.0 M TBAF in THF (0.9 mL). After stirring for 2 hours, the reaction was poured into H2O (50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over MgSO4, and concentrated under vacuum and purified over SiO2 to afford the desired compound (321 mg, 89%) as a white solid. 1H NMR (400 Mz, DMSO-d6) δ 8.21 (s, 1H), 7.38˜7.37 (m, 1H), 7.29˜7.28 (m, 1H), 7.21˜7.17 (m, 1H), 5.30 (m, 1H), 4.75 (m, 1H), 3.67˜3.65 (m, 2H), 3.64˜3.41 (m, 2H), 3.33˜3.30 (m, 2H), 3.02 (m, 2H), 2.91 (s, 3H), 1.99˜1.93 (m, 2H), 1.66˜1.64 (m, 2H), 1.22 (d, 6H). LCMS 432.6 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[CH2:10][NH2:11].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:11][CH2:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][CH:2]=3)[F:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: NCC(F)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(F)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-fluoroethanamine (0.126 g, 0.606 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.114 g, 0.303 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.0412 g, 0.303 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0697 g, 0.363 mmol. The reaction was stirred for 16 hours at ambient temperature. It was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a linear gradient of 5-50% EtOAc in hexanes to yield 161 mg of the title compound (93.8% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(cc1CCO)COC2=O
Solvent: ClCCl
Product: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-1(3H)-one (1.20 g, 6.25 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL) was added MsCl (1.40 g, 12.5 mmol) at 0° C. The mixture was stirred at ambient temperature overnight, then was washed with water and brine. The organic layer was dried and concentrated to dryness. The collected 2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl methanesulfonate was used for the next step without any purification.