Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@@H:8]([NH:63][C:64]([C@@H:66]1[C:70]([CH3:72])([CH3:71])[S:69][CH2:68][N:67]1[S:73]([C:76]1[CH:81]=[CH:80][C:79]([CH3:82])=[CH:78][CH:77]=1)(=[O:75])=[O:74])=[O:65])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C@@H:35]([C:56]([O:58]C(C)(C)C)=[O:57])[NH:36][C:37]([C@@H:39]4[C:43]([CH3:45])([CH3:44])[S:42][CH2:41][N:40]4[S:46]([C:49]4[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=4)(=[O:48])=[O:47])=[O:38])=[CH:30][CH:29]=3)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[CH:12][CH:11]=1)=[O:7])(C)(C)C>C(O)=O>[C:56]([C@@H:35]([NH:36][C:37]([C@@H:39]1[C:43]([CH3:44])([CH3:45])[S:42][CH2:41][N:40]1[S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=1)(=[O:48])=[O:47])=[O:38])[CH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([C:6]([OH:7])=[O:5])[NH:63][C:64]([C@@H:66]4[C:70]([CH3:72])([CH3:71])[S:69][CH2:68][N:67]4[S:73]([C:76]4[CH:81]=[CH:80][C:79]([CH3:82])=[CH:78][CH:77]=4)(=[O:75])=[O:74])=[O:65])=[CH:15][CH:14]=3)=[O:18])[CH2:24][CH2:23]2)=[O:26])=[CH:29][CH:30]=1)([OH:58])=[O:57]
Reactant: Cc1ccc(S(=O)(=O)N2CSC(C)(C)[C@H]2C(=O)N[C@@H](Cc2ccc(OC(=O)N3CCN(C(=O)Oc4ccc(C[C@H](NC(=O)[C@H]5N(S(=O)(=O)c6ccc(C)cc6)CSC5(C)C)C(=O)OC(C)(C)C)cc4)CC3)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=CO
Product: Cc1ccc(S(=O)(=O)N2CSC(C)(C)[C@H]2C(=O)N[C@@H](Cc2ccc(OC(=O)N3CCN(C(=O)Oc4ccc(C[C@H](NC(=O)[C@H]5N(S(=O)(=O)c6ccc(C)cc6)CSC5(C)C)C(=O)O)cc4)CC3)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared by hydrolysis of the di-t-butyl ester from Example 299 with formic acid to give a white foam (300 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClN1C(=[O:25])CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-n2ccc3ccccc32)cc1F
Solvent: ClCCl
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Fluoro-4-methoxyphenyl)indole (7.0 g, 0.029 mole), N-chlorosuccinimide (98%, 4.14 g, 0.0304 mole) and CH2Cl2 (200 ml) were combined and stirred 2 hours at 25° C., producing a solution which was evaporated in vacuo to a semisolid. The latter was diluted with 120 ml CH3CO2H and warmed to 70°. H3PO4 (85%, 31.3 ml) was added in one portion, the mixture was refluxed 1 hour, cooled, basified with saturated Na2CO3 and extracted 4×100 ml ethyl acetate. The organic layers were combined, dried over MgSO4, and evaporated in vacuo to solids (7.9 g). Chromatography on silica gel, (7.5×15 cm) eluting with CH2Cl2 in 1 liter fractions gave, on evaporation of combined fractions 4-13, purified title product, 3.8 g, m.p. 133°-136°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:20]=[N:19][CH:18]=[CH:17][C:9]=1[C:10]([OH:16])=[N:11]2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1.C(OCC)(=O)C>CC(N(C)C)=O>[F:38][C:37]([F:40])([F:39])[S:34]([O:16][C:10]1[C:9]2[CH:17]=[CH:18][N:19]=[CH:20][C:8]=2[C:7]2[C:12](=[CH:13][CH:14]=[N:15][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CCCCOc1nccc2nc(O)c3ccncc3c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
To a mixture of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-ol (2 g, 7.43 mmol) and cesium carbonate (4.84 g, 14.85 mmol) in DMA (75 ml), N-phenyltrifluoromethanesulfonamide (5.31 g, 14.85 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 7 min. The reaction was then cooled to room temperature and added to ethyl acetate. The organic mixture was washed with aqueous sodium hydrogen carbonate (saturated), aqueous sodium carbonate (saturated), and brine. The organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.68 (s, 1H), 9.08 (d, 1H), 8.52 (d, 1H), 8.14 (d, 1H), 7.62 (d, 1H), 4.70 (t, 2H), 1.96 (m, 2H), 1.57 (m, 2H), 1.00 (t, 3H). LRMS (APCI) calc'd for (C16H15F3N3O4S) [M+H]+, 402.1; found 402.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:18](=[O:34])[CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:17][C:18](=[O:34])[CH2:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2c(c1)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M144) (170 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (84 mg, 65%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.CC(C)=[O:18].C(OCC)(=O)C>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: [O-][n+]1ccccc1Cc1ccccc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A stirred solution of 3.0 g (18 mmol) 2-benzylpyridine and 1.65 mL of 30% aqueous hydrogen peroxide in 5.0 mL of acetic acid was heated at 100° C. for 3 hr (S. Hibino and E. Sugino, J. Heterocycl Chem., 1990, 27, 175). After cooling to room temperature, the reaction was diluted with 30 mL ethyl acetate and neutralized with sodium carbonate. The sodium acetate was separated by filtration and the filtrate was dried (sodium carbonate) and concentrated to give a yellow oil. Flash column chromatography on 125 g of silica gel using 7 of L 20% acetone/ethyl acetate furnished 2,58 g (79% yield) of 2-benzylpyridine N-oxide as an amber syrup.
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].[NH2:6][C@@H:7]([CH3:10])[CH2:8][OH:9].O>C(Cl)Cl>[OH:9][CH2:8][C@@H:7]([NH:6][CH2:2][C:3](=[O:5])[CH3:4])[CH3:10]
Reactant: CC(=O)CBr
Reactant: C[C@H](N)CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)CN[C@@H](C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 145.7 %

Procedure:
A solution of 1-bromopropan-2-one (7.8 mL, 102 mmol) in DCM (15 mL) was added dropwise to a solution of (S)-2-aminopropan-1-ol (18.2 g, 0.243 mol) and anhydrous DCM (150 mL) at 0° C. The reaction stirred at 0° C. for 2 h. Water (150 mL) was added, and the organic phase was separated. The aqueous was extracted with DCM (3×40 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product 19.5 g, which was used directly in the following step. LCMS: 132 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]([F:12])([F:13])[F:14])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Cl)c1C(F)(F)F
Solvent: C1CCOC1
Product: OCc1cccc(Cl)c1C(F)(F)F
Temperature: 75 °C
Yield: 85.3 %

Procedure:
To a solution of 3-chloro-2-(trifluoromethyl)benzoic acid (0.15 g, 0.668 mmol) in THF (5 mL) was added dropwise a solution of borane dimethyl sulfide complex in THF (2 M, 0.70 mL, 1.40 mmol) at 0° C. to 5° C. The resulting solution was heated at 75° C. for 2 h under nitrogen atmosphere. The reaction was quenched with MeOH (1 mL) at 0° C. and concentrated under vacuum to give the crude title product (0.12 g). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.66-7.64 (m, 1H), 7.48-7.44 (m, 2H), 4.90 (d, J=2.0 Hz, 2H), 3.70 (t, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19](O)[CH:20]=3)[NH:15][CH:14]=1)[CH2:6]2.OC1C=C2C(=CC=1)NC=C2.N12CCC(CC1)C(=O)C2>CN(C=O)C.O=[Mn]=O>[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]([C:13]1[C:21]3[C:20]4[N:3]=[CH:2][CH:1]=[N:4][C:19]=4[CH:18]=[CH:17][C:16]=3[NH:15][CH:14]=1)[CH2:6]2
Reactant: NCCN
Reactant: Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Agent: O=[Mn]=O
Agent: O=C1CN2CCC1CC2
Agent: Oc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: c1cnc2c(ccc3[nH]cc(C4CN5CCC4CC5)c32)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.2 mmol of ethane-1,2-diamine and 1 mmol of MnO2 are added to a solution of 0.1 mmol of 3-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indol-5-ol (prepared analogously to Example 1.1 to 1.2 by reaction of 5-hydroxy-1H-indole with 3-quinuclidinone followed by hydrogenation) in 2 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The suspension is filtered through Celite and subjected to conventional work-up, giving 9-(1-azabicyclo[2.2.2]oct-3-yl)-7H-pyrrolo[3,2-f]quinoxaline; ESI 279.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:11]([C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[H-].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[CH:24][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ccc(OCCO)cc1
Reactant: COc1c(Cl)ccnc1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1c(OCCOc2ccc(C(C)(C)C)cc2)ccnc1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 1.57 g (10 mmol) of 2-methyl-3-methoxy-4-chloropyridine, 2.52 g (13 mmol) of 2-(4-tert-butylphenoxy)ethanol and 15 ml of DMSO is added dropwise at 25° C. to 0.36 g (12 mmol) of NaH (80% strength) in 25 ml of DMSO. The mixture is then stirred at 60° C. for 5 hours. For working up, saturated ammonium chloride solution is added at 20° to 25° C. and the mixture is extracted with ethyl acetate. The reaction product is purified by chromatography (SiO2 ; EtOAc). Yield: 2.63 g (74.9%); m.p.: 84° to 87° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(Cl)Cl.O[CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17].C(N(CC)CC)C>O>[CH3:1][S:2]([CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17])(=[O:4])=[O:3]
Reactant: Cc1ncsc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (5.4 mmol) was added to a methylene chloride (0.2 M) solution of 5-(2-hydroxyethyl)-4-methyl-thiazole (4.5 mmol) and triethylamine (23 mmol), and stirred at room temperature overnight. The mixture was poured into water and extracted with methylene chloride. The organic extracts were washed with NaHCO3 (sat), and the product was extracted with 1M aq. HCl. The aqueous extracts were neutralized with NaHCO3 (sat) and then extracted with methylene chloride. The organic extracts were dried (MgSO4) and filtered. Solvent removal afforded product (5).
Reaction SMILES: O=[C:2]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:4][CH2:3]1.C1COCC1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[N:7]1([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH:2]=[CH:3][CH2:4][CH2:5][C@@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CCC=CN1C(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of (R)-1-tert-butyl 2-ethyl 6-oxopiperidine-1,2-dicarboxylate (D19) (0.5 g, 1.84 mmol) in toluene (5 ml) was cooled at −50° C. LiEt3BH 1M solution in THF (1.93 ml, 1.93 mmol) was added dropwise in a manner that the reaction temperature did not exceed −45° C. After complete addition the mixture was stirred at −45° C. for 30 minutes. DIPEA (1.38 ml, 7.92 mmol) was added to the reaction maintaining the temperature below −45° C. followed by the addition of DMAP (3.4 mg, 0.027 mmol). The reaction mixture was then charged with TFAA (0.3 ml, 2.11 mmol) keeping the temperature below −45° C. After complete addition, the reaction mixture was warmed to 20-25° C. within one hour and kept for an additional 4 hrs at this temperature. Reaction mixture was quenched by slow addition of water. Phases were separated and the organics washed with water, dried over Na2SO4 and concentrated to obtain a clear oil, which was used as such to be subjected to the same procedure once again to afford the title compound (D20) (260 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Al+3].[Li+].[Cl-].[Cl-].[Cl-].[NH2:11][C:12]1[S:13][C:14]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=O)[CH2:18][CH2:17][C:15]=2[N:16]=1>C(OCC)C.O1CCCC1>[C:29]1([C:26]2[CH2:27][CH2:28][N:23]([CH2:21][CH:19]3[CH2:18][CH2:17][C:15]4[N:16]=[C:12]([NH2:11])[S:13][C:14]=4[CH2:20]3)[CH2:24][CH:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1nc2c(s1)CC(C(=O)N1CC=C(c3ccccc3)CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CC(CN1CC=C(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An ice-cold solution of aluminum chloride (0.80 g) in 20 ml of diethyl ether is added dropwise to a suspension of lithium aluminum chloride (0.65 g) in 30 ml of tetrahydrofuran and 30 ml of diethyl ether under nitrogen. The mixture is stirred at room temperature for 15 minutes and a solution of (±)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)-carbonyl]-1,2,3,6-tetrahydro-4-phenylpyridine (3.5 g) (Example 6a) in 50 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at 40° C. for 30 minutes. After cooling in an ice bath, the reaction is quenched by careful addition of 4 ml of a 10% solution of hydrochloric acid, 4 ml of a 30% solution of sodium hydroxide and 4 ml of water. The salts that precipitate are filtered through Celite and the filtrate evaporated and purified by MPLC (silica; 5% methanol, 95% dichloromethane). The title compound is obtained as a beige solid; mp 187° -190° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:45](=[O:48])[CH2:46][CH3:47])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ncnn2c(CCCN3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCN(CCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 50 °C
Yield: 42.5 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with EtN(iPr)2 (44 μL, 0.32 mmol) followed by the addition of propionyl chloride (22 μL, 0.24 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (35.5 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.88 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.28 (m, 5H), 7.13 (dd, 1H), 6.60 (s, 1H), 5.63 (s, 2H), 3.41-3.31 (m, 4H), 2.89 (t, 2H), 2.38 to 2.24 (m, 8H), 1.90 to 1.84 (m, 2H), 0.93 (t, 3H); ES-MS m/z 523.3 [M+H]+, RT (min) 2.15.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:20]2[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21]2)[CH2:9][C:10]([F:19])([F:18])[C:11](=[O:17])C(OCC)=O)[C:5]([N+:26]([O-])=O)=[CH:4][N:3]=1.Cl.CCOC(C)=O.CCOCC>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:26][C:11](=[O:17])[C:10]([F:19])([F:18])[CH2:9][N:8]([CH:20]3[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CC[C@@H](C)C1
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H]1CCC(N2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Compound ethyl 4-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-3,3-difluoro-2-oxobutanoate was dissolved in AcOH and then cooled in an ice bath (sometimes this crystallizes out upon cooling). Iron powder (2 equivalents) was added followed by the slow addition of HCl (15 mL, conc.). After 10 minutes the reaction was transferred to a heat bath and left to stir at 60° C. for 5 hours. The reaction was then cooled, the stir bar and unreacted iron removed with a magnet (or by filtration through paper), and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water (150 mL) and EtOAc (1500 mL), the layers separated, the aqueous layer washed with EtOAc (2×150 mL), the organic extracts combined, washed with sat. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to yield a brown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) to coax out a tannish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91-2.29 (m, 10 H) 3.80-4.20 (m, 2 H) 4.81-5.07 (m, 1 H) 8.12 (s, 1 H) 11.07 (br. s., 1 H). m/z 317.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:9])/[CH2:4][O:5][CH2:6][CH2:7][CH3:8].Cl[C:11](=O)[C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH2:6]([O:5][CH2:4][C:3]1[N:9]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[O:1][N:2]=1)[CH2:7][CH3:8]
Reactant: CCCOC/C(N)=N/O
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: CCCOCc1noc(C(=O)OC)n1
Reaction time: 0.17 h

Procedure:
To a solution of (1Z)—N′-hydroxy-2-propoxyethanimidamide (3.1 g) in absolute THF under Ar atmosphere is added CaH2 (1.09 g) and molecular sieves (4 A°). The mixture is stirred for 10 min and subsequently methyl chloro(oxo)acetate (3.16 g) is added and the reaction mixture is stirred for 3 h under reflux conditions. The mixture is filtered through celite and the filtrate is evaporated to dryness under vacuo. The resulting residue is purified by flash column chromatography (silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)) to give the title compound as an oil.
Reaction SMILES: C(C1([SiH2][C:12]([O:28]C(C2C=NC(CC)=CC=2)([SiH2]C2C=CC=CC=2)[SiH2]C2(C(C)(C)C)C=CC=CC2)([C:20]2[CH:21]=[N:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=2)[SiH2]C2C=CC=CC=2)C=CC=CC1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:26]([C:23]1[N:22]=[CH:21][C:20]([CH2:12][OH:28])=[CH:25][CH:24]=1)[CH3:27]
Reactant: CCc1ccc(C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(CC)nc2)([SiH2]c2ccccc2)[SiH2]C2(C(C)(C)C)C=CC=CC2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
After dissolving the 1-(tert-butyl)-1,1-diphenylsilyl [(6-ethyl-3-pyridyl)methyl]ether (7.81 g, 20.8 mmol) in tetrahydrofuran (80 ml), TBAF (31.2 ml, 31.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and was extracted with ethyl acetate. After washing the extract with brine, it was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.25 g) as a colorless oil. (78.8% yield)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2].Br[CH2:42][CH:43]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:44][CH:43]([O:45][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:47])[CH3:48])[CH3:42])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(CBr)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(C)O[Si](C)(C)C(C)(C)C)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (500 mg, 0.86 mmol) in dry DMF (10 mL), was added (1-bromopropan-2-yloxy)(tert-butyl)dimethylsilane (327 mg, 1.3 mmol) and cesium carbonate (847 mg, 2.6 mmol). The reaction mixture was was stirred at 60° C. for 14 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (350 mg, 53.8%) as white solid.