Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:9])=[O:7].Cl[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1>CCOC(C)=O>[CH3:9][O:8][C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
(S)-Methyl pyrrolidine-2-carboxylate (6.56 g, 50.8 mmol) was added to methyl 6-chloro-5-nitronicotinate (5.00 g, 23.1 mmol) and the reaction mixture was stirred at 90° C. for 10 min (exothermic reaction). It as cooled to room temperature, diluted with EtOAc (10 mL) and purified using flash column chromatography on silica gel (20-30% EtOAc in hexanes) to afford the title compound as a yellow oil (6.70 g, 94%). [M+H] calc'd for C13H15N3O6, 310; found, 310.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[O:18][CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:20]
Reactant: COC(=O)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
From 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and methyl chlorocarbonate in a mixture of dioxan and toluene, 5,11-dihydro-11-methoxycarbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one was obtained, m.p. 266°-267° C. (D) (from 1,2-dichloroethane);
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.C(#N)C>[CH:19]([N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1])([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)C)c(=O)c1
Temperature: 60 °C
Yield: 25.8 %

Procedure:
To methyl 2-oxo-1H-pyridine-4-carboxylate (700 mg, 4.57 mmol) in dry DMF (4.4 mL) was added finely ground K2CO3 (2.53 g, 18.3 mmol) followed by 2-iodopropane (914 μL, 9.14 mmol). The mixture was heated at 60° C. (external) for 1 h. The mixture was diluted with acetonitrile (10 mL) and was filtered. The filtrate was evaporated onto Celite and was purified by column chromatography (0-100% EtOAc/DCM) to give methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (230 mg). ESI-MS m/z calc 195.1, found 196.3 (M−1)−. Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.O.NN>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[NH2:8]
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCN(c3ccc(N)cc3F)CC2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirred suspension of compound 3 (0.2 g, 0.6 mmol) and palladium catalyst (10% Pd on carbon 0.04 g) in ethanol (6 mL), hydrazine monohydrate (0.29 mL, 5.7 mmol) was added slowly and the reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to obtain amine 4 (0.17 g, 93%).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (less polar isomer) (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19](=[O:27])[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C(O)CCCC>>[C:14]([O:18][C:19](=[O:27])[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COc1ccc2nccc(Br)c2n1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CCCC(NC(=O)OC(C)(C)C)C3)c2n1

Procedure:
According to procedure F and starting from 8-bromo-2-methoxy-[1,5]naphthyridine and (RS)-piperidin-3-yl-carbamic acid tert-butyl ester (commercial) and using 1-pentanol instead of NMP as reaction solvent, the title compound was isolated as an orange oil (2.44 g, 68%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[Cl:32][C:33]1[C:34]([OH:40])=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[N:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[N:47][CH:48]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:32][C:33]1[C:34]([O:40][CH:52]2[CH2:53][CH2:54][N:49]([C:46]3[N:45]=[CH:44][C:43]([C:42]([F:41])([F:56])[F:57])=[CH:48][N:47]=3)[CH2:50][CH2:51]2)=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OC2CCN(c3ncc(C(F)(F)F)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 100 mL recovery flask under nitrogen was added triphenylphosphine (1285 mg, 4.90 mmol), DMF (10 mL), and then (E)-diethyl diazene-1,2-dicarboxylate (0.67 mL, 4.20 mmol). The mixture was stirred at room temperature for 5 minutes at which point 5-chloro-4-hydroxypyridin-2(1H)-one (509 mg, 3.50 mmol) was added. After stirring for an additional 5 minutes, 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (1865 mg, 3.50 mmol) was added. The reaction was placed in a 100° C. oil bath under a nitrogen atmosphere with a vent line for two hours. The clear amber reaction mixture was cooled to room temperature and added to 600 mL of ethyl acetate. After washing the ethyl acetate with water (2×200 mL), the solvent was removed in vacuo from the slightly cloudy, pale pink solution to provide 3.06 g of a red, oily foam. This material was purified using a 65 mm id×120 mm silica gel column and eluting as follows:
Reaction SMILES: [NH2:1][CH2:2][S:3]([OH:6])(=[O:5])=[O:4].[Cl:7][C:8]1[C:9]([F:33])=[N:10][C:11](NCC(OC)=O)=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1>>[Cl:7][C:8]1[C:9]([F:33])=[N:10][C:11]([NH:1][CH2:2][S:3]([OH:6])(=[O:5])=[O:4])=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1
Reactant: NCS(=O)(=O)O
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCS(=O)(=O)O)c2Cl)ccc1O

Procedure:
By use of aminomethanesulfonic acid in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [F:1][C:2]([C:5]1[NH:9][N:8]=[N:7][N:6]=1)([F:4])[F:3].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25]Cl>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25][N:6]1[C:5]([C:2]([F:4])([F:3])[F:1])=[N:9][N:8]=[N:7]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1C(F)(F)F)c1ccc(Cl)cc1Cl

Procedure:
Trifluoromethyl tetrazole was made according to the procedure published in Tetrahedron Letters 38(7):1257-1260. A mixture of tetrachlorosilane (5 mmol) and sodium azide (15 mmol) in dry acetonitrile (10 ml) and trifluoromethyl acetamide (5 mmol) was refluxed and stirred with the exclusion of moisture. The reaction mixture was poured into ice cold sodium carbonate solution and extracted with chloroform (3×20 ml). The solvent was distilled off under reduced pressure to yield trifluoromethyl tetrazole (MS: MH−=136.7) which was used without further purification. Trifluromethyl tetrazole (1 mmol), Cs2CO3 (1.3 mmol) and 1-(2,4-dichlorophenyl)-2-chloroethan-1-one (1 mmol) were refluxed in DMF (2 ml) overnight. The reaction mixture was cooled and concentrated in vacuo, and then extracted into ethyl acetate and dried over sodium sulfate. The extract was further purified by column chromatography on silica gel to yield 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one. 1 mmol of 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one was heated to 80° C. in neat DMF-DMA for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether. 1 mmol of the above enaminone, 1 mmol of amino{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 were dissolved in DMF and heated to 90° C. for fourteen hours. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the residue after solvent evaporation was purified by column chromatography eluting with 5-10% methanol in methylene chloride to yield {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}{4-(2,4-dichlorophenyl)-5-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]pyrimidin-2-yl}amine as a yellow powder after lyophilization.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[NH:5].P(=[S:20])([O-])([O-])[O-].[Na+].[Na+].[Na+]>O>[ClH:2].[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH:7]1[NH:6][C:4](=[NH:5])[CH2:3][SH:20]
Reactant: [O-]P([O-])([O-])=S
Reactant: N=C(CCl)NC1Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)NC1Cc2ccccc2C1

Procedure:
The procedures described above in Example 1 were carried out on 4.0 g. (0.0149 mole) of the product of Step A above and 2.68 g. (0.0149mole) of trisodiumphosphorothioate in 25 ml. of water. The product was recrystallized from ethanol: ether [m.p. 102-103° C. (decomposition)].
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(NC(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=1[N+:38]([O-:40])=[O:39]>ClCCl>[CH2:1]([N:3]1[CH2:20][CH2:19][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[C:30]([N+:38]([O-:40])=[O:39])[CH:31]=4)=[CH:16][CH:17]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN1CCC2(CCN(CCc3ccc(N)cc3)C2)C1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(F)c([N+](=O)[O-])c4)cc3)C2)C1
Reaction time: 1 h

Procedure:
4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenylamine from above was dissolved in dichloromethane to which was added diisopropylamine (1 ml) and the reaction was cooled in an ice bath. A solution of 4-Fluoro-3-nitro-benzoyl chloride (0.5 N, 8 ml) was added and the reaction stirred for 1 h then evaporated under reduced pressure to a yellow foam which was used as is in the next step.
Reaction SMILES: CCOCC.C1COCC1.[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[CH3:16].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>[Cu]I.CCOCC>[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH2:14][C:15]([C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 M ether/THF solution of 1,1,1-trifluoro-4-methylpent-3-en-2-one was added 3.8 g of copper (I) iodide and 10 mL of a 2 M ether solution of 4-fluorophenylmagnesium bromide at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, and extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield 460 mg of 1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][S:32]([CH2:35][C:36]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:37])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 88.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), (methylsulfonyl)acetic acid (75 mg, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 377, the title compound (171 mg, 88%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:37]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[Cl:37])=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 85 %

Procedure:
A solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (74) (7.0 g, 18.79 mmol) and triethylamine (5.2 mL, 37.58 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 6.2 g (85%) of 4-chloro-6-fluoro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (76) as yellow waxy solids. 1H-NMR (DMSO-d6): δ 1.31 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 4.37 (q, J=7.2 Hz, 2H), 5.51 (s, 2H), 6.84 (m, 2H), 7.24 (m, 2H), 8.37 (dd, J=2.8, 8.0 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 391 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]1=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[F:25])[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1F
Yield: 36 %

Procedure:
A solution (5 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (131 mg, 0.40 mmol), 1-(2-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (119 mg, 0.48 mmol), HATU (183 mg, 0.48 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol) in N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was divided into two layers with tetrahydrofuran and sodium hydrogen carbonate saturated aqueous solution and the aqueous layer was subjected to extraction (3 times) with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica) and recrystallized from ethanol to give the title compound (80 mg, 36%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccn(CCN2CCOCC2)n1

Procedure:
Into an 8-dram vial, 3-Nitro-1H-pyrazole (0.50 g, 4.4 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.23 g, 6.63 mmol), Potassium carbonate (1.83 g, 13.3 mmol), and Acetonitrile (30 mL, 600 mmol) were added. The reaction mixture was heated. The reaction was poured over ice. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (1 to 3% methanol). The collected fractions afforded 4-[2-(3-Nitro-pyrazol-1-yl)-ethyl]-morpholine a yellow solid (0.75 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9]2
Reactant: [H][H]
Reactant: O=C1Cc2cccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-nitroindoline-2-one in methanol (1.0 gm/60 mL), added Pd/C (300 mg, 30 wt %). H2 gas maintained with pressure using hydrogen gas balloon, solution stirred for 4 hours at RT. The catalyst was removed by filtration over celite. The filtrate was concentrated in vacuo to give crude product, which was washed with diethyl ether to afford compound 7-aminoindolin-2-one; YD: 76.77%; mp: 248-251° C.; Rf: 0.6 (CHCl3:MeOH: 9.0:1.0). 1H NMR (DMSO-d6) 200 MHz, δ: 3.382 (s, 2H), 4.794 (s, 2H), 6.453-6.498 (m, 2H), 6.673 (t, J=8.0 Hz, 1H), 9.906 (s, 1H). MS (ESI): m/z 146.8 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C@H:27]([OH:36])[CH2:26]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CC(O)C.C([O-])(O)=O.[Na+].[NH4+].[Cl-].C([O-])(=O)C.[NH4+]>O.C(#N)C.CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:27](=[O:36])[CH2:26]1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)C(=O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4 ml vial was loaded with methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (Example 328) (31 mg, 0.061 mmol) and Dess-Martin Periodinane (52 mg, 0.123 mmol). DMSO (1 ml) was added (complete dissolution of starting material). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by addition of 2-Propanol (0.10 ml, 1.298 mmol). The reaction mixture was poured into a dilute solution of NaHCO3 and NH4Cl in water. The product precipitated as an off-white solid, which was collected by filtration, washed with water and dried in an air-stream. An analytically pure sample was obtained via purification by prep HPLC with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-80% B over 20 minutes, then a 0-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R)-methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (4.2 mg). The product exists as a mixture of ketone and hydrate (and if analyzed in MeOH solution also mono- and dimethyl-acetal)