Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH3:20][NH2:21]>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:21]([CH3:20])[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Product: Cc1cc2c(n1C)C(C)CN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl-5-methyl-4-piperidone may be reacted with methylamine to give the title compound.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]([C:41]([F:44])([F:43])[F:42])=[CH:4][C:5]([NH:7][C@:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH:38]([CH3:40])[CH3:39])[CH:31]=1)([C:16]1[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1(C2C=C[N+]([O-:59])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:8]([NH:7][C:5]([CH:4]2[C:3]([C:41]([F:43])([F:44])[F:42])([C:2]([F:1])([F:45])[F:46])[O:59]2)=[O:6])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C2OC2(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
At 0° C. to a solution of (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg, 0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL, chlorine wt % 10-3%, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at rt for 1 h. The solvents were removed under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 26 min (97 mg, 74% yield). The diastereomer mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flow rate 50 mL/min
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:16][CH2:17]4)[S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(=O)(=O)C5CC5)CC4)sc3n2)cn1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 308. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s). MS (ESI+): MH+517.22 (50%)
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][C:60]1[CH:65]=[C:64](I)[CH:63]=[CH:62][C:61]=1[CH3:67]>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:64]2[CH:63]=[CH:62][C:61]([CH3:67])=[C:60]([F:59])[CH:65]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Cc1ccc(I)cc1F
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Cc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1F
Yield: 67 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 2-fluoro-4-iodo-1-methylbenzene in 67% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][CH3:21])=[CH:9][CH:10]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([N:22]=1)[C:6]1[CH:7]=[C:8]([O:20][CH3:21])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:29]2[CH:30]=[N:25][CH:26]=[N:27][CH:28]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)C1(N=C(N)N(C)C1=O)c1cc(Br)ccc1O2
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C1(N=C(N)N(C)C1=O)c1cc(-c3cncnc3)ccc1O2
Temperature: 85 °C

Procedure:
A 15 ml resealable vial was charged with 2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one (87 mg, 224 μmol), pyrimidin-5-ylboronic acid (56 mg, 448 μmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg, 22 μmol). DME (1 ml) was added to the mixture, and the vial was capped with argon. Sodium carbonate (2M aq. solution) (336 μl, 672 μmol) was added and the vial was sealed and heated at 85° C. for 16 hr. The heterogeneous mixture was cooled to RT, diluted with 5 ml EtOAc and 2 ml water, then filtered and the solids were washed with water (5 ml). The solids were redissolved in DCM/MeOH and dried with MgSO4, filtered and concentrated in vacuo to afford 2-amino-2′-methoxy-1-methyl-7′-(pyrimidin-5-yl)spiro[imidazole-4,9′-xanthen]-5(1H)-one as brownish solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1)([CH2:8][OH:9])[CH2:6][OH:7])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.C1[CH2:35][O:34][CH2:33]C1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1)([CH2:8][O:9][CH2:33][O:34][CH3:35])[CH2:6][O:7][CH2:27][O:28][CH3:29])[CH3:2]
Reactant: CCOC(=O)C(CO)(CO)c1cccc(Br)n1
Reactant: COCCl
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(COCOC)(COCOC)c1cccc(Br)n1
Temperature: 65 °C

Procedure:
To the solution of 2-(6-bromo-pyridin-2-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethyl ester (30.0 g, 98.638 mmol) in dry THF (250 ml) was added tetrabutyl ammonium bromide (15.8 g, 49.319 mmol) and di-isopropyl ethyl amine (127.47 g, 163.0 ml) followed by methoxymethyl chloride was added drop wise at rt. Resultant reaction contents were refluxed at 65° C. for 3 h and cooled to rt. Reaction mixture was concentrated under reduced pressure and purified by column chromatography over silica gel using 10% ethyl acetate in hexane to furnish title compound as a brown liquid. Yield=20.4 g (52%). TLC (30% ethyl acetate in hexane) Rf=0.55; LCMS: RtH7=1.639, [M+1]+=392.0 and 394.0; 1H NMR (400 MHz, CDCl3): δ 7.49 (t, 1H), 7.35 (d, 1H), 7.22 (d, 1H), 4.62-4.47 (m, 4H), 4.24-4.16 (m, 6H), 3.25 (s, 6H), 1.23 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]([CH3:32])[C@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C@H:25]([N:24]([CH3:32])[C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:29]([CH3:31])[CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)N(C)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol), (R)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutanoic acid (116 mg, 0.501 mmol), HOBT (77 mg, 0.501 mmol), EDC (96 mg, 0.501 mmol) and triethylamine (0.116 mL, 0.834 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc) to obtain tert-butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl(methyl)carbamate (190 mg, 0.417 mmol, 100% yield) as a white glass. MS found: (M+H)+=453.15.
Reaction SMILES: [C:1]([Cl:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH2:28])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[ClH:11].[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH:28][C:1](=[O:10])[CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)CCc1ccccc1
Product: Cl
Yield: 63.1 %

Procedure:
Using the general method of Example 92, hydrocinnamoyl chloride (0.1 g, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol). After one hour the reaction mixture was poured directly onto a silica gel column and eluted with dichloromethane at first, then 15% methanol/dichloromethane to provide 0.2 g of a solid. This solid was recrystallized from toluene to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]([1,5]naphthyridin-1-yl)ethyl]-3-phenylpropanamide hydrochloride as a white powder, m.p. 183-185° C. Analysis: Calculated for C24H28N6O HCl: %C, 63.64; %H, 6.45; %N, 18.55; Found: %C, 63.68; %H, 6.43; %N, 18.55.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:7].CO>O1CCCC1.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH:6]([CH3:7])[C:5]([OH:15])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.17 g, 7.10 mmol) was added to a stirred solution of 2-(4-chloro-phenyl)-propionic acid methyl ester (0.47 g, 2.366 mmol) in tetrahydrofuran, water and:methanol (4:1:1, 12 ml). The mixture was stirred overnight and the volatiles evaporated in vacuo. The mixture was basified by addition of aqueous sodium hydrogencarbonate and washed with ethyl acetate. The aqueous was then acidified with 2M HCl and the product extracted into ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.4 g, 91%. NMR 1H (300 MHz, DMSO): 1.36 (d, 3H), 3.72 (q, 1H), 7.23-7.38 (m, 4ArH), 12.48 (bs, 1H).
Reaction SMILES: [Na+].[C:2]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[S:14]([O-:17])(=O)=[O:15])(O)=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:19].[ClH:24]>P(Cl)(Cl)(Cl)=O>[Cl:24][C:2]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[S:14]([Cl:19])(=[O:17])=[O:15])=[O:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cl
Reactant: O=C(O)c1sc2ccccc2c1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1sc2ccccc2c1S(=O)(=O)Cl
Temperature: 100 °C

Procedure:
44.0 gm (0.157 mol) of the above 2-carboxy-benzo[b]thiophene-3-sulfonic acid mono sodium salt were suspended in 200 cc of phosphorus oxychloride and admixed with 65.4 gm (0.314 mol) of phosphorus-(V)-chloride. To complete the reaction which was exothermic in the beginning accompanied by evolution of hydrogen chloride, the reaction mixture was heated to 100° C. for 2 hours, cooled and the inorganic salts were filtered off. After evaporation in vacuo, the residue was taken up in 300 cc of dry chloroform, the solution was filtered and again evaporated. The oily residue, consisting of 27 gm (58% of theory) of raw 2-chlorocarbonyl-benzo[b]thiophene-3-sulfonic acid chloride, crystallized upon cooling (m.p. 45°-47° C.) and was used without further purification in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[N:7]12[CH2:14][CH2:13][C:10]([C:15]([O:17]CC)=O)([CH2:11][CH2:12]1)[CH2:9][CH2:8]2>C1COCC1>[N:7]12[CH2:8][CH2:9][C:10]([C:15]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[OH:17])([CH2:11][CH2:12]1)[CH2:13][CH2:14]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 2-thienyllithium (1.0M in THF, 9.10 mL, 9.10 mmol) was chilled down to −30° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.4196 g, 2.289 mmol) in THF (8 mL) was slowly added to the reaction mixture over 20 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with water and then evaporated to dryness. H2O and DCM were added, causing a light brown solid to crash out. This solid was filtered off to give the title compound (0.4161 g, 59.5%). EI-MS m/z 306(M+H+) Rt (1.35 min).
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1Cl)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][OH:22])[CH3:19]>C1COCC1>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:22][P:6]1[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:8][O:7]1)[CH3:19]
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: CCCCC(CC)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(CC)COP1OCCN1C(C)(C)C
Yield: 81 %

Procedure:
The procedure of Example 3 is repeated using 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 115 ml of THF and 13.16 ml (0.10 mol) of triethylamine and 13.2 g (0.10 mol) of 2-ethylhexanol in 115 ml of THF to give 22.3 g (81.0%) of a clear liquid: b.p. 89°-92° C. (0.05 mm Hg).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].CN1CCOCC1.Br[CH2:36][C:37](=[O:40])[CH2:38][CH3:39]>CN(C=O)C>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[N:17]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)c[nH]1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(=O)Cn1cc(-c2ccccc2)nc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-phenylethyl]4-phenyl-1H-imidazole (100 mg, 1 eq) in DMF (2 mL) were successively added morpholinomethyl polystyrene resin (Novabiochem, loading: 3.51 mmol/g, 159 mg, 2 eq) and 1-bromo-2-butanone (28 mL, 2 eq). After about 18 hours of stirring at about 20° C., 2 mL DMF were added to the reaction mixture followed by aminomethylpolystyrene resin (Novabiochem, loading: 1.73 mmol/g, 319 mg). The mixture was stirred overnight at 20° C. and filtered. The filtrate was concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to yield 107 mg (90% yield) of the title compound. NMR (1H, 400 MHz, CDCl3) δ: 7.80-6.98 (m, 11H, arom. H), 5.45 (d, 1H, NH), 4.80 (m, 1H, CH), 4.40 (AB, J=18 Hz, NCH2CO), 3.33 (m, 2H, CH2Ph), 2.25 (m, 2H, CH2CH3), 1.0 (t, 3H, CH3). LC/MS: calculated MW=433.5, m/z=434.2 (M+H), m/z=432.2 (M−H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1)(=[O:18])=[O:17]
Reactant: OCc1csnn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1csnn1
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 mL) was cooled to 5° C. under a nitrogen atmosphere and treated with triethylamine (1.018 mL, 7.3 mmol) and methanesulfonyl chloride (0.565 mL, 7.3 mmol). After 15 min, the ice-bath was removed and the reaction mixture was stirred for 2 h. The solution was washed with 1N hydrochloric acid solution (2×2 mL) and water, dried (MgSO4 +MgO) and concentrated. The residue was purified by chromatography (silica gel column 1.5×21 cm) with ether as eluting solvent to give 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 59 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (54 mg, 59%) was obtained as a pale brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH2:44][CH2:43]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:53][C:51]2[N:52]=[C:48]([N:45]3[CH2:46][CH2:47][O:42][CH2:43][CH2:44]3)[S:49][CH:50]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)[O:9][C:5]=2[CH:4]=1
Reactant: OCc1csc(N2CCOCC2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2csc(N3CCOCC3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.10 g, 0.315 mmol), triphenylphosphine (0.124 g, 0.473 mmol) and (2-morpholinothiazol-4-yl)methanol (Example 5B, 0.086 g, 0.429 mmol) were added in a 25 mL round-bottom flask and purged under vacuum and nitrogen. Tetrahydrofuran (8 mL) was then added and the mixture was treated with DIAD (0.083 g, 0.410 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 22° C. for 1 hour and diluted with ethyl acetate. This was washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column chromatography (2.5×10 cm, 40% ethyl acetate in CH2Cl2) and the residue obtained after concentration was crystallized in ethyl acetate to give the title material as crystals (0.083 g, 53%) and as an amorphous impure solid from the mother liquor (0.169 g). LC (Method F): 2.466 min. HRMS (ESI) calcd for C22H22N5O5S2 [M+H]+ m/z 500.1057. found 500.1075. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.82 (s, 1H) 7.07 (s, 1H) 6.67 (d, J=2 Hz, 1H) 6.62 (s, 1H) 6.40 (d, J=1.5 Hz, 1H) 5.10 (s, 2H) 4.19 (s, 3H) 3.82 (s, 3H) 3.81 (m, 4H) 3.46 (m, 4H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].C1C=CC=CC=1.C1CCCCC1.[N+:16]([C:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:27][O:28][C:23]=2[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1>[CH2:1]([C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:25][C:24]2[C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=[CH:22][C:23]=2[O:28][CH2:27]1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc2c1N=C(c1ccccn1)CO2
Reactant: [Li]CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.5 M Ethyl lithium in benzene-cyclohexane (1.8 mL, 0.88 mmol) was added drop-wise to a solution of 5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine (0.025 g, 0.88 mmol) in tetrahydrofuran (4 mL), cooled to −78° C. The reaction was stirred for 1 h at −78° C. and was then quenched with methanol. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 3-ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine as a solid (0.021 g. 84%). LCMS calculated for C15H16N3O3 (M+H)+: m/z=286.1. found: 286.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.Cl.[CH3:15][NH:16][CH3:17].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:11]([C:6]1[C:5]2[CH2:4][CH2:3][C:2](=[O:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 5 (300 mg, 1.70 mmol) in N,N-dimethylformamide (3 mL) was added dimethyl amine hydrochloride (139 mg, 1.70 mmol), 1-hydroxybenzotriazole hydrate (253 mg, 1.87 mmol), triethylamine (0.48 mL, 3.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (358 mg, 1.87 mmol). The reaction mixture was stirred at room temperature overnight, quenched by addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (20:1) as the mobile phase to provide the desired product. MS (APCI): m/z 204 (M+H)+.