Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=O>CO.Cl>[CH3:20][C:18]1([CH2:17][C:16]([O:22][CH3:23])=[O:21])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: COC(=O)CC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cl
Solvent: CO
Product: COC(=O)CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 55 °C
Yield: 47.3 %

Procedure:
To a mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.11 g, 0.50 mmol) and methyl acetoacetate (0.54 mL, 5.0 mmol) in methanol (15 mL) was added 1 drop of concentrated hydrochloric acid, and the reaction was heated at 55° C. for 15 h and with reflux for 24 h. Then, the reaction mixture was cooled, and concentrated with NaHCO3 (0.5 g) and silica gel (5 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.075 g, 47%) as a yellow solid:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[CH2:11]([O:18]/[C:19](=[C:24](/O)\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])/[C:20](OC)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+].Cl>CO>[CH2:11]([O:18][C:19]1[C:20](=[O:21])[NH:9][C:8]([O:7][CH3:6])=[N:10][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=N)N
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 40 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl methyl oxalate (5.8 g, 36 mmol) and methyl 2-(benzyloxy)acetate (6.5 g, 36 mmol) in THF (80 mL) at −78° C. was added a dropwise a solution of LDA (prepared by dropwise addition of nBuLi (20 mL, 50 mmol) to diisopropylamine (7.1 mL, 50 mmol) in THF (20 mL) at 0° C. then stirring for 10 min. After the addition, the reaction mixture was stirred at −78° C. for 2 h then allowed to warm to rt over the course of 1 h. The reaction mixture was cooled to 0° C. then cold 1 N HCl (ca. 70 mL) was added. The resulting solution was extracted with EtOAc (3×), and the combined organic portions dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to give 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 49% yield) as tan viscous oil. O-Methylisourea hydrogensulfate (2.5 g, 14 mmol) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 17 mmol) were stirred in anhydrous MeOH (15 mL) at 0° C. under argon. Sodium methoxide (10 g, 46 mmol) in MeOH (25% wt) was added and the reaction mixture was stirred at room temperature for 40 h. MeOH (3 mL) was added and the mixture cooled in an ice bath. 1 N HCl (11 mL) was added to acidify the mixture and the resulting precipitate was collected and rinsed with cold H2O:MeOH (10:1). The filtrate was concentrated under reduced pressure and the residue was extracted with CH2Cl2 (2×). The organic extracts and the precipitate were combined, concentrated under reduced pressure, then purified by silica gel chromatography eluting with EtOAc/hexanes to give Compound 46d (2.8 g, 58% yield) as a white solid. LCMS ESI 333.2 (M+H-tBu), RT=2.02 min (Method Q). 1H NMR (400 MHz, DMSO-d6) δ 13.48-12.16 (m, 1H), 7.91-6.79 (m, 5H), 5.02 (s, 2H), 3.86 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]([OH:14])[CH2:12][CH3:13])[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:16]([N:23]1[CH:31]=[C:30]2[C:25]([CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:29]2)=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:28]=[CH:29][C:30]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:31]=4)[CH:9]=[C:10]([CH:11]([OH:14])[CH2:12][CH3:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCC(O)c1cc(Br)c2c(N)ncnn12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CCC(O)c1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 80 °C
Reaction time: 17 h
Yield: 56.6 %

Procedure:
1-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (355 mg, 1.31 mmol) and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (656.4 mg, 1.96 mmol, 1.5 eq) were dissolved in 1:1 EtOH-toluene (11 mL each) and degassed with nitrogen. After 30 minutes [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with dichloromethane (95.8 mg, 0.13 mmol, 0.1 eq) followed by 2M sodium carbonate solution (1.31 mL, 2.62 mmol, 2.0 eq) were added. The reaction mixture was stirred at 80° C. for 17 h and cooled to rt. The reaction mixture was partitioned between EtOAc and water and filtered through a pad of Celite® to rid of excess palladium salts. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 1 to 100% [20% MeOH/DCM+1% Et3N]/DCM) and the product containing fractions were concentrated. Trituration with DCM-hexane gave 295.3 mg (57%) of the title compound as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.88 (s, 1 H), 7.80 (d, 1 H), 7.57 (s, 1 H), 7.34-7.28 (m, 5 H), 7.13 (dd, 1 H), 6.66 (s, 1 H), 5.65 (s, 2 H), 5.23 (d, 1H), 5.04 to 4.99 (m, 1H), 1.89 to 1.83 (m, 1H), 1.78 to 1.70 (m, 1H), 0.90 (t, 3H); ES-MS m/z 399.3 [M+H]+, RT (min) 2.55.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)COCCO>[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1ccccc1N
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 81.6 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 2-methylaniline (267 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of saline and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried with anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 237 mg of a desired compound as solid in 82 % of yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](=O)[NH:9][CH:10]=1)=[O:4].P(Cl)([Cl:25])(OC1C=CC=CC=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([Cl:25])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C)c12
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Product: COC(=O)c1cnc(Cl)c2ccn(C)c12

Procedure:
1-Methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.25 g) and phenyl dichlorophosphate (12 ml) were heated at 180° C. under argon for 30 minutes. The reaction was allowed to cool at which point a precipitate formed. This was filtered off and washed with diethyl ether to yield the title compound as a grey solid (1.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: c1csc(N2CCNCC2)n1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3nccs3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(thiazol-2-yl)piperazine obtained in Example 81(1) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=136-137° C.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>C(O)(C)(C)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.O>[CH3:16][O:15][C:11](=[O:14])[CH2:12][CH2:13][CH:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N+:1]([O-:3])=[O:2]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])CC1CCCCC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CO
Product: COC(=O)CCC(C1CCCCC1)[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 3.18 g (22.2 mmol) nitromethyl-cyclohexane (CAS: 2625-30-1) in 1 ml tert-butanol and 0.12 ml 35% benzyltrimethylammonium hydroxide in methanol warmed to 40° C. were added 1.99 ml (22.2 mmol) methyl acrylate. The yellow mixture was stirred at 40° C. for 2 hours then diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The title compound was obtained in as slightly yellow oil: MS (EI): 198 (M.+−MeO), 183 (M.+−NO2), 151 (M−(MeO+NO2+H)).+ (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[OH:9])[NH2:5].[C:13](Cl)(Cl)=[O:14]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[C:13]=[O:14])[CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[OH:9]
Reactant: CCCc1cc(N)cc(C)c1O
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCc1cc(N=C=O)cc(C)c1O
Temperature: 25 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5-n-propylaniline (1.65 g) and ethyl acetate (20 ml) was added to an ethyl acetate solution containing 10 g of phosgene at 0° to 5° C. The resulting mixture was gradually heated and, after the solution became clear, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-methyl-4-hydroxy-5-n-propylphenyl isocyanate. the thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g). Sodium hydride (0.28 g, 60% dispersion in mineral oil) was added to dimethylformamide (50 ml). To the resulting mixture was added isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and (chloromethyl)methylsulfide (0.67 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-methylthiomethyloxy-5-n-propylphenyl)carbamate (Compound No. 14) (1.90 g) in a yield of 61.0%. nD21.4
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 78.5 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.088 mL (0.78 mMol) butyl isocyanate, 0.168 gm (78%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. MS(m/e): 329(M+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cc(F)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(F)cnc1N
Yield: 73.9 %

Procedure:
A solution of 5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.2 g, 15.4 mmol) in MeOH (77 mL) and K2CO3 (11 g, 7.7 mmol) is stirred at rt for 0.5 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 15%-55% EtOAc in heptane to afford 3-ethynyl-5-fluoro-pyridin-2-ylamine (1.55 g, 74%). MS: 137 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.94 (d, 1H), 7.35 (m, 1H), 4.91 (s, NH2, 2H), 3.44 (s, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:19])[CH:13]=1.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=1[Cl:31]>C1COCC1.Cl.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=2[Cl:31])=[C:14]([Cl:19])[CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Cl
Reactant: Nc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
LiHMDS (1.0 M solution in hexanes, 53.0 mL, 53.0 mmol) was added dropwise to a stirred solution of 4-bromo-2-chlorophenylamine (7.10 g, 35.0 mmol) in THF (15 mL) cooled to −78° C. After one hour, 4,5,6-trichloronicotinic acid (3.73 g, 16.5 mmol) was added dropwise as a solution in THF (12 mL). The reaction was allowed to warm to room temperature slowly while stirring overnight. The suspension was diluted with 1 M HCl and ethyl acetate, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4 and concentrated to a tan solid. The solid was triturated with diethyl ether overnight and the solids were isolated by filtration to provide the desired product (25) as a tan-colored solid (4.85 g, 75%). MS APCI (−) m/z 395, 397 (M-, Cl, Br pattern) detected.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23](O)=[O:24])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]1=2.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])=[N:12][N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:15])[C:3]1=2
Reactant: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Reactant: C1CCNC1
Product: Cn1c2ccccc2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21

Procedure:
The preparation is carried out as in Example 3.2, from 1 g (3 mmol) of 5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and from excess pyrrolidine. The product is recrystallized from propan-2-ol. 0.5 g (1.3 mmol) of solid is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24].[BH4-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C@H:9]([OH:22])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@@](C)(O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@@](C)(O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.8 %

Procedure:
8 g of (8S,9R)-2,3,8-trimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 160 ml of anhydrous methanol, and the suspension is treated with 2 g of sodium borohydride using a spatula and stirred at room temperature for 24 h, a solution being formed. It is then concentrated to dryness on a vacuum rotary evaporator, the residue is partitioned between water and dichloromethane (50 ml each), and the aqueous phase is adjusted to pH 8 using dilute hydrochloric acid and extracted twice with 200 ml of dichloromethane each time. The organic phases are combined, washed with a little water and dried over anhydrous sodium sulfate, the solvent is stripped off in vacuo and the residue obtained is washed with stirring in acetone. 5.3 g of the title compound are obtained as colorless crystals of melting point 180° C.
Reaction SMILES: C([O:9][C:10]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:14]3[CH2:13][C:12]=2[CH:11]=1)(=O)C1C=CC=CC=1.CC[O-].[Na+]>C(O)C>[OH:9][C:10]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:14]3[CH2:13][C:12]=2[CH:11]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OC(=O)c4ccccc4)ccc3[C@@H]21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@@H]2Cc3cc(O)ccc3[C@@H]21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The benzoyl ester from Step E (30 g, 93.168 mmol) was dissolved in anhydrous ethanol (300 mL) and cooled to 0° C. under nitrogen. A solution of EtONa in EtOH (46.6 mL, 93.200 mmol) was slowly added. The resulting solution was stirred at room temperature for 4 hr. Most of the solvent was removed and the residue was carefully partitioned between ethyl acetate (200 mL) and HCl (aq, 0.5 M, 300 mL) and extracted with ethyl acetate (200 mL). The combined organic solution was washed with brine (200 mL), dried with sodium sulfate, and evaporated. The crude product was purified on silica gel column (EtOAc/PE=1:20) and then chiral prep-HPLC to obtain the pure title compound (enantiomeric excess: >95%). 1H-NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.4 Hz, 1H), 6.60-6.65 (m, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.19-3.25 (m, 1H), 2.87-2.99 (m, 2H), 2.39-2.43 (m, 1H), 1.26 (t, J=7.2 Hz, 3H), 1.17-1.19 (m, 1H) ppm. MS: m/e 219.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1>FC(F)(F)C(O)=O.CO>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2c(Br)n[nH]c12
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 4-((1-(3,5-dibromo-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (99 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 6 mL) and stirred for 30 min. The reaction was concentated and the resulting residue loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 82 mg (94%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.62 (d, J=1.5 Hz, 1H), 7.25 (dd, J=9.5, 5.8 Hz, 2H), 7.12 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8.6, 8.6 Hz, 2H), 4.46 (q, J=6.7 Hz, 1H), 3.44 (s, 2H), 3.36 (d, J=8.9 Hz, 1H), 3.24 (d, J=9.2 Hz, 1H), 2.87 (m, 2H), 2.68 (m, 2H), 2.14 (m, 1H), 2.03 (m, 1H), 1.84 (m, 2H), 1.41 (d, J=6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 139.3, 137.3, 128.7, 128.61, 128.57, 127.7, 125.3, 121.7, 121.6, 115.6, 115.5, 114.3, 79.0, 77.8, 50.5, 42.5, 42.4, 41.4, 33.7, 33.4, 22.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33](=[O:40])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH2:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:14]1[CH:13]=[C:12]([NH:16][C:17]([C:19]2([C:22](=[O:23])[NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[C:11]([F:32])=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3 g, 6.5 mmol) (as prepared in Example 1), tert-butyl carbamate (2.3 g, 19.5 mmol), Xantphos (0.37 g, 0.65 mmol), and cesium carbonate (4.2 g, 13 mmol) were dissolved in dry dioxane (50 mL) and argon was bubbled through the mixture for 10 minutes. Pd2(dba)3 (0.3 g, 0.33 mmol) was then added, and the solution was sparged with argon for an additional 10 minutes. The flask was fitted with a reflux condenser and a balloon of argon and slowly heated to 100° C. and stirred overnight. The reaction mixture was cooled to RT. It was diluted with ethyl acetate (100 mL) and water (80 mL). The organic layer was separated and washed with brine. The aqueous layer was back extracted with the ethyl acetate, which was then washed with brine. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give tert-butyl 4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamate (1.8 g, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 9.88 (s, 1H), 9.78 (s, 1H), 8.13-8.05 (m, 2H), 7.59-7.53 (m, 3H), 7.33 (d, J=2.4 Hz, 1H), 7.18-7.13 (m, 2H), 6.63 (d, J=2.4 Hz, 1H), 1.63-1.62 (m, 2H), 1.58-1.56 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[OH-].[Na+].[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH3:1][O:20][C:19](=[O:21])[C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:10]
Reactant: Cc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
A 0.2 molar solution phenylalanine methyl ester in 10 milliliters of water was prepared. Toluene was added and the pH of the system adjusted to 7.0 with sodium hydroxide. Chymotrypsin in the amount of 1 milligram was added. The concentration of phenylalanine in the aqueous phase was monitored. The initial concentration was 0.05 molar and the final concentration at the end of the hydrolysis was 0.15 molar, consistent with only one isomer being extracted.