Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][CH2:33][NH:32][C:31]=2[CH:36]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:32]3[C:31]4[CH:36]=[C:27]([CH3:26])[CH:28]=[CH:29][C:30]=4[O:35][CH2:34][CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: Cc1ccc2c(c1)NCCO2
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)CCO2

Procedure:
6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.099 min; MS m/z: 546.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:53](=[O:56])[CH:54]=[CH2:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:59][C:60]1[CH2:64][CH2:63][CH2:62][CH:61]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:53](=[O:56])[CH2:54][CH2:55][CH:61]3[CH2:62][CH2:63][CH2:64][C:60]3=[O:59])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Reactant: C[Si](C)(C)OC1=CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc2ccc(C(=O)CCC3CCCC3=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.201 g of the product of Example 3 in 4.5 ml of methylene chloride, cooled to -78° C., is added dropwise 0.549 ml of 1.0M TiCl4 in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and 0.098 ml of 1-(trimethylsilyloxy)-cyclopentene added dropwise. The reaction mixture is stirred at -78° C., for 0.5 hours and quenched with saturated potassium carbonate, diluted with chloroform, filtered through magnesium sulfate and concentrated in vacuo to give a residue which is purified by chromatography on silica gel by elution with 1:3 ethyl acetatehexane to give 0.079 g of the desired product as a white solid.
Reaction SMILES: O[C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(S(F)(F)[F:19])CC)C>ClCCl.O>[F:19][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(C#N)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzonitrile (1.00 g, 6.20 mmol; obtained from 4-(propan-2-yl)benzonitrile according to literature procedure: Synth. Comm. 2006, 36, 2145-2155) in dichloromethane (20 mL) was added diethylamino sulfur trifluoride (DAST; 1.20 g, 7.44 mmol) at a temperature of 0° C. The reaction mixture was allowed to stirr at rt for 2 h, whereupon it was diluted with water and extracted with dichloromethane. The organic extract was washed with water, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 95:5) to afford the title compound (675 mg, 67%): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 163, HPLC RT (Method F) 2.12 min.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.N[C:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=C[NH:17][N:16]=1>C(O)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[CH:15]=[N:16][N:17]2[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 17.5 g. of 3-dimethylaminoacrylophenone and 15.52 g. of 3-amino-4-carbethoxypyrazole in 50 ml. of glacial acetic acid is refluxed for 4 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 129°-130° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O.O.[OH-].[Na+]>[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:40]=1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Reactant: NCCCCCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3ccc(C(=O)NCCCCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To an ice-cold suspension of 16.15 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 15.75 g of diphenylphosphorylazide, and 10.2 g of 6-(3-pyridyl)-hexanamine in 100 ml of dry dimethylformamide was added 8.0 ml of triethylamine. The reaction mixture was held at 0° C. for 2 hours and allowed to warm to room temperature over night. The resulting clear, yellow solution was diluted with water and 5M sodium hydroxide solution and was extracted with 3×300 ml of dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated to a yellow semi-solid which was recrystallized from ethyl acetate-hexane to give 21.22 g (84%) of N-[6-(3-pyridyl)hexyl]-2-(1-methylethyl)-11-oxo-pyrido[2,1-b]-quinazoline-8-carboxamide, mp 94°-96° C. Recrystallization gave mp 100°-103° C. Conversion to the dihydrochloride salt gave 22.12 g, mp 230°-236° C. (dec.) and recrystallization from ethanol-ether gave 21.06 g, mp 234°-240° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].C(N(CC)CC)C.Cl.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CO>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N[C@@H]2CCCC[C@H]2O)c([N+](=O)[O-])c1

Procedure:
Compound 9 (689 mg, 3 mmol) was suspended in acetonitrile (5 mL) and then triethylamine was added (1.3 mL, 9 mmol). trans-2-aminocyclohexanol hydrochloride (682 mg, 4.5 mmol) was then added and the reaction refluxed for 12 hours, 2 mL methanol was then added and the reaction further refluxed for another 24 hours. Water (100 mL) was added and the resulting precipitate filtered, washed 3 times with water and air-dried. The product was used without further characterization in the next step. MS: 309.3 (M+H+)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:7][CH:8]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26]>>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][N:7]=3)[CH2:16]2)[CH2:12]1)=[O:26]
Reactant: Cc1ccoc1C(=O)O
Reactant: FC(F)(F)c1ccc(N2CC3CNCC3C2)nc1
Product: Cc1ccoc1C(=O)N1CC2CN(c3ccc(C(F)(F)F)cn3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing 2-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. C18H18F3N3O2, 365.36; m/z found 366.0 [M+H]+. 1H NMR (CDCl3): 8.39 (s, 1H), 7.62 (d, J=9.1 Hz, 1H), 7.32 (d, J=1.4 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 6.32 (d, J=1.4 Hz, 1H), 4.17 (brs, 1H), 3.94 (brs, 1H), 3.81 (brs, 3H), 3.71-3.67 (m, 1H), 3.50 (brs, 2H), 3.11 (brs, 2H), 2.37 (s, 3H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)C.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(#N)C>[N:7]1([CH2:6][CH2:5][CH2:4][NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CC(C)(N)CO
Reactant: CCOC(CCn1ccnc1)OCC
Solvent: CC#N
Product: CC(C)(CO)NCCCn1ccnc1

Procedure:
3-(Imidazol-1-yl)propionaldehyde diethyl acetal (8.1 g) was converted into the free aldehyde, as described in Example 24, and then added to a mixture of 2-amino-2-methylpropanol (1.83 g) in acetonitrile (40 ml) and 4A molecular sieves (6.0 g). The mixture was reacted following the procedure of Example 24 to give 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol, m.p. 81-85° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[I-].[K+].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:39])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1.C(O)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH:17]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:39])[CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 2.36 g of p-t-butylphenol in 3 ml of tetrahydrofuran is added 0.625 g of sodium hydride (60% dispersion in oil). After stirring under argon for 1 hour and heating at 50° C. for 20 minutes, 2.4 g of potassium iodide and 6.0 g of methyl bromo{p-[2-(p-chlorophenoxy)-1-methylethoxy]phenyl}acetate in 30 ml of tetrahydrofuran is added. The mixture is stirred and refluxed for 18 hours and poured into 300 ml of ice-water containing 3 ml of acetic acid. The mixture is extracted with dichloromethane and the extracts washed with saturated NaHCO3, 10% sodium thiosulfate and saturated sodium chloride solution. The dichloromethane extract is dried (MgSO4) and the solvent removed under reduced pressure to give 6.7 g of product as a gum. Chromatography over silica gel with dichloromethane as eluent gives 5.7 g of yellow gum.
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([Cl:25])[C:19]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:12]3[C:13]=2[C:8](=[CH:9][C:10]([N+:26]([O-:28])=[O:27])=[CH:11]3)[C:7]1=[O:29])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:25][C:18]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:12]2[CH:11]=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=[C:8]3[C:13]2=[C:14]([CH:17]=1)[C:15](=[O:16])[N:6]([OH:5])[C:7]3=[O:29]
Reactant: CC(C)(C)ON1C(=O)c2cc([N+](=O)[O-])cc3c(N4CCCC4)c(Cl)cc(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cc([N+](=O)[O-])cc3c(N4CCCC4)c(Cl)cc(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A mixture of 2-tert-butyloxy-5-chloro-8-nitro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.2 g, 0.47 mmol, from Example M3-A) and TFA (1.6 mL) was stirred at room temperature for 2 hours and poured into ice water. The solid was collected, washed with water and ether, and dried to give 0.12 g of the title compound, mp 209-210° C.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 80.6 %

Procedure:
Cis-2-diphenylmethylpyran-4-yl methanesulfonate 4b (0.38 g, 1.10 mmol) was reacted with sodium azide (0.29 g, 4.4 mmol) in dry DMF (Procedure B) to yield compound 5b (0.26 g, 80%) as a liquid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:8]=2[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[O:17])[CH2:12][CH2:11]2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:8]=2[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:21])([F:22])[F:23])=[O:17])[CH2:14][CH2:15]2)[CH2:3]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A 4 mL vial was charged with (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (28 mg, 0.057 mmol), a magnetic stirbar, CH2Cl2 (2 mL), and DIPEA (30 μL, 0.172 mmol). The reaction was cooled to 0° C. and an acetyl chloride solution (7 mg, 0.086 mmol, in 1 mL CH2Cl2) was added dropwise. After stirring for 30 min at 0° C., the reaction was quenched with sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% to 10% MeOH in CH2Cl2) and yielded (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (30 mg, 35%). 1H NMR 400 MHz (CDCl3) δ 7.31 (d, J=8.2 Hz, 1H), 6.91 (dd, J=8.1, 1.8 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 5.84-5.70 (m, 2H), 4.62-4.50 (m, 1H), 3.59-3.53 (m, 4H), 3.50 (s, 2H), 3.48-3.44 (m, 1H), 3.43-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.50-2.42 (m, 4H), 2.34 (td, J=13.4, 7.6 Hz, 1H), 2.01 (s, 3H), 1.91-1.79 (m, 1H). LCMS (ESI, m/z): 531 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29](=O)[CH2:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH3:25].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:24]([O:26][C:27]([C:28]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:39])[CH3:25]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCCn1ccnc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (453 mg), 6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (320 mg) and acetic acid (5 ml), concentrated sulfuric acid (0.03 ml) was added, followed by stirring at 100° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured over water, alkalinized with 2 N sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1-imidazolyl)propyl]quinoline-3-carboxylic acid ethyl ester (310.0 mg, 43%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 164 to 165° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH3:21])[N:19]=2)=[CH:11][C:10]=1[CH2:22][CH2:23][CH3:24])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO>[CH2:20]([C:18]1[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:22][CH2:23][CH3:24])[CH:11]=2)[S:16][CH:17]=1)[CH3:21]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, palladium on charcoal (0.10 g) was added to a solution of 2-[4-benzyloxy)-3-propylphenyl]-4-ethyl-1,3-thiazole (0.86 g, 2.53 mmol) (Example 32) and ammonium formate (1.28 g, 20.3 mmol) in EtOH (45 mL). The mixture was stirred at 40° C. for 2 h, and then cooled to rt. The solvent was evaporated and the material was suspended in EtOAc. This suspension was filtered through a small plug of silica gel and then concentrated to give a crude solid. The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.56 (d, 1H), 6.77-6.66 (m, 2H), 5.70-5.42 (br, 1H), 2.88-2.76 (m, 2H), 2.64-2.55 (m, 2H), 1.72-1.57 (q, 2H), 1.31 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: [P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].Br[CH2:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28]>>[P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2]
Reactant: CCC(C)(C)C(=O)CBr
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)n[nH]c2c1
Product: CCC(C)(C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared from 1-(6-methoxy-1H-indazol-3-yl)-2-methylprop-1-en-1-yl dimethyl phosphate from Method I Step B of Example 1 and 1-bromo-3,3-dimethylpentan-2-one from the above using a procedure similar to described in Method I Step C of Example 1. It was purified on RP-HPLC using 30-100% MeCN gradient without TFA to give colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) δ 7.70 (d, 9.0 Hz, 1H), 6.86 (dd, 2.1 & 8.9 Hz, 1H), 6.48 (d, 2.1 Hz, 1H), 5.29 (s, 2H), 3.86 (s, 3H), 3.56 (d, 11.3 Hz, 6H), 2.02 (d, 2.5 Hz, 3H), 1.82 (d, 3.5 Hz, 3H), 1.74 (q, 7.5 Hz, 2H), 1.28 (s, 6H), 0.94 (t, 7.6 Hz, 3H). NOE difference spectrum from irradiating 5.29 ppm singlet showed positive NOE at 6.48 ppm doublet and 1.28 ppm singlet. LC-MS: 3.48 min. (m/Z=313.2, 461.2, 439.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:25][C:26]3[CH:27]=[C:28]([C:33]4[N:37]=[C:36]([CH:38]5[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]5)[O:35][N:34]=4)[CH:29]=[CH:30][C:31]=3[CH3:32])=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(Br)ccn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (24f) (400 mg, 1.67 mmol), in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (325 μL, 3.72 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hour. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (429 mg, 1.49 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred to room temperature under Argon for 30 minutes. Then, the reaction was quenched with water. The solvent was concentrated and the crude product was purified by silica chromatography to yield methyl 3-(3-(3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (42). MS m/z 511.1 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:23]=O>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:9][CH:4]([CH2:3][CH2:2][NH:1][CH3:23])[C:5]([O:7][CH3:8])=[O:6])[C:11]([O:13][CH3:14])=[O:12])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(CCN)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CNCCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.4 %

Procedure:
The crude (4S)-dimethyl 2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (5.00 g, 15.7 mmol) was dissolved in methanol (100 mL) and 40% formaldehyde (1.0 g, 14 mmol) and Pd/C (0.8 g) were added. The mixture was stirred under H2 atmosphere (20 psi) for 8 h at ambient temperature. The mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to afford (2S)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(2-(methylamino)ethyl)pentane dioate (5.0 g, crude) as a dark brown oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([NH2:26])=[N:25][C:17]=2[Cl:16])([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOP(=O)(COC/C=C\CCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COC/C=C\Cn1cnc2c(Cl)nc(N)nc21)OCC
Temperature: 20 °C
Reaction time: 48 h
Yield: 54.5 %

Procedure:
A mixture of Z-(4-chloro-2-butenyloxy)methyl phosphonic acid diethylester (1.05 g, 4 mmol), 6-chloro-2-aminopurine (1 g, 6 mmol) and potassium carbonate (0.92 g, 6 mmol) in anhydrous dimethylformamide (10 ml) is stirred 2 days at 20° C. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography on silica gel to give the title product (0.85 g, 55%).