Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C12CCNCC2
Reaction time: 3 h

Procedure:
A solution of 1′-tert-butoxycarbonyl-spiro[3H-indole-3,4′-piperidin]-2(1H)-one, as described above in Step A, (551 mg, 1.70 mmol) in ethyl acetate saturated with HCl (5 mL) was stirred at ambient temp. for 3 hours as the product salt slowly crystallized out. This salt was collected by filtration and partitioned between methylene chloride and aqueous sat'd. sodium carbonate. The organic layer was separated off, dried (anhyd. sodium sulfate) filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether to give the title compound as a white solid, mp: 184-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]([O:12][CH3:13])=[O:11])=[N:3]1>CO.[Pd]>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate (351.2, 0.48 g, 2.60 mmol) in MeOH (15 ml) under nitrogen was added palladium on carbon (10%, 0.25 g). The flask was further degassed with nitrogen and filled with H2 through a balloon. The mixture was stirred at room temperature for 1.5 hours. After purging the system with nitrogen, the reaction mixture was filtered through a Celite cake and concentrated to give 363 mg (90%) of a white solid. m/z (ES+) 156 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:6]([NH:11][C:12]([O:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:13])[C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.C1COCC1>O>[CH:1]1([C@H:6]([NH:11][C:12]([O:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:13])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)O)C1CCCC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A mixture of methyl (2S)-cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amino]acetate (1.97 g, 5.84 mmol) and LiOH.H2O (0.74 g, 17.51 mmol) in a 1:1 mixture of THF:H2O (60 mL) was heated to 40° C. The solution was stirred for 4 hours, then cooled to 20° C. The THF was removed under reduced pressure, and the residual aqueous solution was extracted with EtOAc. The organic phase was washed with H2O and brine, then dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (1.85 g, 98%) as an oil that was used directly in subsequent steps. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 7.28 (d, J=8.1 Hz, 1H), 5.84-5.71 (m, 1H), 4.98 (d, J=17.4 Hz, 1H), 4.92 (d, J=10.1 Hz, 1H), 4.60-4.52 (m, 1H), 3.78 (t, J=8.0 Hz, 1H), 2.18-2.05 (m, 1H), 2.04-1.94 (m, 3H), 1.91-1.74 (m, 3H), 1.70-1.06 (m, 15H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[C:24]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3CC[C@H]2C1
Reaction time: 66 h

Procedure:
3α-Hydroxy-5α-pregn-9(11)-en-20-one (3.7 g.) was dissolved in pyridine (37 ml.) and acetic anhydride (18.5 ml.) added; the reaction was allowed to stand at room temperature for 66 hr. It was then poured into water (4 l.) and stored at 2° for 2 hr., the white solid was filtered off and dried to give the title compound (3.8 g.) m.p. 163°-165°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16](O)=[O:17].C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[NH4+:2].[OH-:17].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH2:26])=[O:17]
Reactant: On1nnc2ccccc21
Reactant: Cn1c(-c2cncc(C(=O)O)c2)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2cncc(C(N)=O)c2)cc2ccccc21
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 5-(1-methyl-1H-indol-2-yl)-nicotinic acid (0.037 g, 0.146 mmol), HOBT (0.024 g, 0.175 mmol), EDCI (0.034 g, 0.175 mmol), DIPEA (0.076 mL, 0.439 mmol) and DMF (3 mL). Ammonium chloride (0.012 g, 0.219 mmol) is added and the reaction is stirred at room temperature overnight. Purification by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradient gives 5-(1-methyl-1H-indol-2-yl)-nicotinamide. 1H NMR (400 MHz, MeOD) δ ppm 3.85 (s, 3H), 6.77 (d, J=0.6 Hz, 1H), 7.08-7.19 (m, 1H), 7.29 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.50 (dd, J=8.3, 0.7 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.49 (t, J=2.1 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 9.09 (d, J=2.1 Hz, 1H). HRMS (ESI) m/z 252.1145 [(M+H)+ Calcd for C15H14N3O: 252.1137].
Reaction SMILES: [N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+]>CC(O)C.CCOC(C)=O>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[N:18][OH:19])[NH2:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (5.08 g, 23.5 mmol) and hydroxylamine hydrochloride (3.27 g, 47.0 mmol) were mixed in 2-propanol (94.0 mL). To this suspension was added sodium bicarbonate (7.90 g, 94.0 mmol) and the resulting mixture was heated at reflux for 2 h. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc (250 mL) and washed with water and brine. The combined aqueous layers were extracted again with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide Int-2-D (5.71 g, 22.9 mmol, 97.5% yield): LCMS=250.08 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4](OC)=[O:5].[NH3:15]>[OH-].[NH4+]>[NH2:1][C@@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([CH3:8])[C:4]([NH2:15])=[O:5]
Reactant: N
Reactant: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: C[C@H](C(N)=O)[C@@H](N)c1ccccc1
Reaction time: 96 h

Procedure:
A solution of methyl (2S,3R)-3-amino-2-methyl-3-phenylpropionate (6.3 g, 33 mmol) in 2N methanolic ammonia (20 ml) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After 4 d, concentration followed by chromatography on a short column of silica gel (dichloromethane-methanol-conc. ammonium hydroxide=93:7:0.7; 90:10:0.8) provided the amide as a white solid. MS (m/z): 179.2 (M+H)+; C10H14N2O requir. 178.2.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C[CH2:32][N:33](CC)[CH2:34]C.CNC.C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:30][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:33]([CH3:34])[CH3:32])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (0.30 g, 0.28 mmol, 1.00 eq) in DCM (15.00 ml, 50.00 V) were added Et3N (0.09 g, 0.84 mmol, 3.00 eq) and dimethylamine solution 2.0 M in THF (0.70 mL, 1.40 mmol, 5.00 eq) at 0° C., and warmed to room temperature. The reaction mixture was stirred at RT for 1 h and sodium triacetoxyborohydride (0.09 g, 0.42 mmol, 1.50 eq) was added and the reaction mixture was stirred at RT for 16 h and the solvent was removed under vacuum. The crude product was purified by prep HPLC to provide 6-chloro-2-(3-dimethylaminocyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexyl methyl)-amide (0.03 g, 0.06 mmol, 22.3%, Brown solid). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (t, J=5.82 Hz, 1H), 8.01-7.96 (m, 2H), 7.76-7.74 (m, 1H), 7.60-7.56 (m, 1H), 7.56-3.28 (m, 1H), 3.27-3.25 (m, 2H), 2.68-2.57 (m, 1H), 2.56-2.48 (m, 1H), 2.25-2.16 (m, 1H), 2.15-2.07 (m, 6H), 2.06-1.96 (m, 5H), 1.96-1.90 (m, 4H), 1.88-1.83 (m, 2H), 1.78-1.72 (m, 1H), 1.30-1.24 (m, 2H). m/z: 450.2 [M+H]+
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>C1C=CC=CC=1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: C[Si](C)(C)N1CCCC1=O
Solvent: c1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 4-fluorophenyl chloroformate (3.55 g, 20.0 mmol) in anhydrous benzene (10 ml ) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from 2-propanol afforded 2.24 g of colorless prisms. Yield 46.9%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([Li])(C)(C)C.CN([CH:37]=[O:38])C>C(OCC)C>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([S:7]([N:5]2[CH:6]=[C:2]([CH:37]=[O:38])[CH:3]=[C:4]2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1cc(-c2cc(Br)cn2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(-c2cc(C=O)cn2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-bromo-1-(p-toluenesulfonyl)-2-(3,4,5-trimethoxyphenyl)-pyrrole (2.33 g, 5.0 mmol) in dry ethyl ether (20 ml), a tert-butyl lithium solution (3.82 ml, 1.3 equiv., 1.7 M in pentane) is added at −78° C. The reaction mixture is stirred for 15 min at −78° C. DMF (1.93 ml, 5 equiv.) is added, and stirring continued at −78° C. for 2 h. The reaction mixture is slowly brought to 4° C., quenched with cooled aqueous 1 N HCl solution and ethyl acetate. The organic layer is extracted with brine, dried over MgSO4, the solvents evaporated and the residue chromatographed with gradients of hexane/ethyl acetate (2:1 to 1:1) to yield the title compound as a greenish solid. 1H-NMR (300 MHz, CDCl3): 9.9 (s, 1H); 8.13 (d, J=2.0 Hz, 1H); 7.3-7.1 (m, 4H); 6.57 (d, J=2.0 Hz, 1H); 3.36 (s, 2H); 6.36 (s, 2H); 3.92 (s, 3H); 3.76 (s, 6H); 2.39 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[OH:6][C:7]1[C:20]2[CH2:19][CH2:18][C@H:17]3[C@H:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>ClCCl>[ClH:5].[CH3:1][S:2]([O:6][C:7]1[C:20]2[CH2:19][CH2:18][C@H:17]3[C@H:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: O=C(NCCCCN1CCC[C@@H]2c3cccc(O)c3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCCN1CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Product: Cl
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (0.04 ml, 0.5 mmol) was added to stirred solution of cis-7-hydroxy-4-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4,4a,5 ,6,10b-octahydrobenzo[f]quinoline (E4, 200 mg, 0.4 mmol) and triethylamine (0.07 ml, 0.5 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 2 h and then poured onto saturated aqueous K2CO3 (10 ml) and extracted into dichloromethane (3×10 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give a solid which was chromatographed on silica using 50-100% ethyl acetate/pentane as elution gradient to give the free base of the title compound (156 mg, 73%). The free base was treated with 1M ethereal HCl in dichloromethane to afford after evaporation the title compound as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[N:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1cnc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cnc(N)cc1C
Reaction time: 2 h

Procedure:
A mixture of ethyl (4-methyl-6-nitropyridin-3-yl)acetate (1.65 g, 7.36 mmol) and palladium on carbon (10%, 1.57 g, 1.47 mmol) in Ethanol (10 mL) was evacuated and refilled with nitrogen (3×), then stirred under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through Celite® and concentrated in vacuo to provide ethyl (4-methyl-6-aminopyridin-3-yl)acetate which was used directly in the next reaction without further purification. LC-MS (IE, m/z): 195 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.Cl.[NH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([O:26]CC)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]2[CH2:20][CH2:21][O:22][CH2:23][C:24]2=[O:26])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCOCC1=O)CCCN2
Reaction time: 1 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.50 g, 5.40 mmol), ethyl 2-(2-aminoethoxyl)acetate hydrochloride (intermediate 105, 1.24 g, 6.75 mmol) and triethylamine (0.97 ml, 7.02 mmol) in 1,2-dichloroethane (25 ml) at room temperature was stirred for 1 h and then sodium triacetoxyborohydride (1.83 g, 8.63 mmol) was added. The reaction mixture was stirred for 18 h at room temperature and additional sodium triacetoxyborohydride (0.92 g, 4.32 mmol) was added. After a further 5 h stirring at room temperature the reaction mixture was partitioned between saturated aqueous NaHCO3 solution and DCM, the mixture extracted with DCM (3×), the combined organic layers dried over Na2SO4 and evaporated. The residue was applied to a 80 g RediSep® silica and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an yellow solid. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=[CH2:24])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1([CH2:22][CH:23]2[CH2:24][O:33]2)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC(CC2CO2)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
(3S)-3-Allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.9 g, 14.9 mmol) was dissolved in methylene chloride, and mCPBA (10.3 g, 59.5 mmol) was added. The mixture was stirred at room temperature for 15 hours and then heated to reflux for three hours. The solvent was evaporated under reduced pressure, and then the residue was blended with a mixture of ethyl acetate and a saturated sodium thiosulfate solution. The organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4:1→1:1) to give 4.33 g (84%) of the colorless oil title compound as a diastereomer mixture. The diastereomers were used for the next step without separation and purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:52]([C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=1)([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:1]([N:9]([CH2:60][C:59]1[CH:62]=[CH:63][C:56]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:57][CH:58]=1)[C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N(Cc5ccc(C(C)(C)C)cc5)C(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To N6 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine (658 mg, 1.0 mmole) was added DMF (anhydrous, 10 ml) and evaporated to dryness. This was repeated. Fresh DMF (10 ml) was added under an Argon atmosphere. Sodium hydride (44 mg, 60% in oil, 1.1 mmole) was added and the mixture was stirred for 0.5 hour at room temperature. 4-(tert-butyl)benzyl bromide (272 mg, 1.2 mmole) was added dropwise and stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was partitioned between ethyl acetate and water (20 ml each). The organic phase was washed with water (3 times, 20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (100 g), using methylene chloride:methanol:triethylamine 96.5:3:0.5 to yield N -benzoyl-N -(p-tert-butylbenzyl)-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine, (229 mg, 28.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]2)=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:15]=2)[CH:11]=1)[NH2:5].[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([OH:47])=[O:46])[C:40]2=[O:48])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:45]([C:41]2[C:40](=[O:48])[N:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)[CH:44]=[CH:43][CH:42]=2)=[O:46])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]1)[NH:15][N:14]=[CH:13]2.[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:45]([C:41]2[C:40](=[O:48])[N:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)[CH:44]=[CH:43][CH:42]=2)=[O:47])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]2)=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:15]=2)[CH:11]=1
Reactant: CC1CN(c2cc3nn(C4CCCCO4)cc3cc2Oc2ccc(N)cc2F)CCO1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2cc3[nH]ncc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Product: CC1CN(c2cc3nn(C4CCCCO4)cc3cc2Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 211.5 %

Procedure:
To a 10 mL screw-cap vial is added 3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yloxy)aniline (44 mg, 103.17 μmol), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (42 mg, 0.18 mmol), EDCI (45.177 mg, 232.13 μmol), HOBT (23.699 mg, 154.75 μmol) followed by DMF (5 mL, 64.66 mmol) and DIPEA (44.980 μL, 257.92 μmol). The reaction mixture is stirred at RT overnight. The reaction is diluted into EtOAc (50 mL) and washed with saturated aqueous sodium chloride (5×25 mL). Organic layers are dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 80% (A): 20% (B) to 30% (A): 70% (B) over 40 min, hold at 30:70 ratio for 15 min to give a yellow solid as desired product N-(3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (70 mg, 99% yield). MS (m/z): 641.8 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[O:7][C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:23]([CH3:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=3)=[CH:13][CH:12]=2)[N:10]=1.[Li+].[OH-].ClCCl.C(O)C>O1CCCC1>[CH3:24][N:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])[O:7][C:8]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1nc(-c2ccc(OCc3nc4ccccc4n3C)cc2)c(-c2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(COc2ccc(-c3nc(CCC(=O)O)oc3-c3ccccc3)cc2)nc2ccccc21

Procedure:
A solution of the ester (1 g, 2.14 mmole) of Step A, in tetrahydrofuran (13 mL) containing 1N-LiOH (6.42 mL) is stirred under nitrogen at room temperature for 1 hour (TLC, dichloromethane-ethanol 9:1 ). The solvent is evaporated, water added and the pH adjusted to 6.5 with 10% acetic acid. The fight yellow precipitate is collected, washed with water and dried in vacuo. It is redissolved in hot ethyl acetate (containing enough methanol to obtain a clear solution), concentrated to a smaller volume and cooled in an ice bath. The crystals are collected and dried (0.642 g, 66.2%, m.p. 222°-224° C.).