Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C(Cl)Cl>[C:28]1([NH:27][C:2]2[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: CCC(=O)c1cccnc1Cl
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(=O)c1cccnc1Nc1ccccc1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
A solution of 1-(2-chloro-pyridin-3-yl)-propan-1-one (6.0 g, 35.4 mmol) in 1,4-dioxane (59.0 mL) in a high pressure reaction tube was treated with (1S)-(+)-10-camphorsulfonic acid (20.5 g, 88.4 mmol). The resulting mixture was heated to 70° C. until all of the solids went into solution. The reaction was raised out of the heating bath, opened and treated with aniline (4.94 g, 4.84 mL, 53.1 mmol). The vessel was then re-sealed and heated at 95° C. overnight. After cooling to room temperature, the reaction was diluted with methylene chloride (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL). The organics were then dried over sodium sulfate, filtered, concentrated in vacuo and dried under high vacuum. The residue was then recrystallized from methanol. Collection by filtration (washing with 10 mL of methanol and 30 mL of hexanes) afforded 1-(2-phenylamino-pyridin-3-yl)-propan-1-one (5.64 g) of the desired product as a yellow, crystalline solid. The mother liquor was dry loaded onto silica gel. Flash chromatography (40 g, 10-25% ethyl acetate-hexanes) afforded an additional amount (1.28 g, 86% total yield) of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)=[O:4].Br[CH2:36][C:37]1[N:42]=[C:41]([N:43]2[C:51](=[O:52])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]2=[O:53])[CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([O:14][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([N:43]3[C:44](=[O:53])[C:45]4[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:51]3=[O:52])[N:42]=1)[CH:10]=[CH:9]2)=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(N4C(=O)c5ccccc5C4=O)n3)ccn2c1C(=O)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A suspension of methyl 3-[1-(2,2-dimethylpropanoyl)-7-hydroxy-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate (350 mg, 0.75 mmol), 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 0.90 mmol), and potassium carbonate (416 mg, 3.0 mmol) in DMF (4 mL) is stirred for 6 h at 70° C. The mixture is partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) gives methyl 3-[1-(2,2-dimethylpropanoyl)-7-{[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pyridin-2-yl]methoxy}-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate that is dissolved in EtOH (5 mL) and treated with a 50% aqueous hydrazine (wt/wt) solution (0.75 mL). The mixture is heated at 70° C. for 2 h then cooled to 23° C. and filtered. The volatile components from the filtrate are removed in vacuo. The residue is purified by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) giving methyl 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoate (342 mg, 78%) that is dissolved in MeOH (2 mL), THF (2 mL), and aqueous 5M sodium hydroxide (1 mL). The solution is heated at 70° C. for 3 h then cooled and acidified with AcOH. The mixture is partitioned between CH2Cl2 and brine then organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoic acid (310 mg, 98%) that is dissolved in DMF (3 mL). This solution is treated with ammonium carbonate (57 mg, 0.73 mmol), Boc-anhydride (136 mg, 0.62 mmol), and pyridine (0.1 mL, 1.5 mmol) and stirred for 30 min. The mixture is directly purified by reverse phase HPLC to give the title compound (115 mg, 40%).
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)C1)CO>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:43][CH:44]=1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Cc3ccc(F)cc3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21](Cl)([Cl:23])=[O:22].N1C=CC=CC=1>C1COCC1>[Cl:23][C:21]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH2:18][N:17]=[CH:16][NH:15]1)=[O:22]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(OC(=O)Cl)C(Oc1ccc(Cl)cc1)N1CN=CN1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 29.6 g (0.1 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 250 ml of THF was added 20 ml of liquid phosgene, followed by 9 ml of pyridine. The mixture was stirred at ambient temperature for about 21 hours. White solid (water-soluble) was filtered off and the THF filtrate concentrated in vacuum to a residual oil, the intermediate chloroformate. Further purification of the chloroformate was accomplished by dissolving it in about 300 ml of 1-chlorobutane, washing the butyl chloride solution with 0.5 N HCl (twice), water and saturated brine, drying (MgSO4), filtration, and evaporation of the filtrate in vacuum to leave, as a residual oil, 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-2-yl)-2-butyl chloroformate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]>S(Cl)(Cl)=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]
Yield: 141.3 %

Procedure:
A mixture of 2-nitrobenzoic acid (25.0 g.) and thionyl chloride (50 ml.) was refluxed for an hour and then evaporated. To the residue was added benzene (125 ml.) followed by removal of benzene. To the residue were added benzene (125 ml.), pyridine (23.7 g.) tert-butyl alcohol (22.2 g.) under ice-cooling and then the resulting solution was refluxed under heating for 2 hours. The reaction mixture was poured into ice water. The benzene layer was separated, washed successively with water, 1N aqueous solution of sodium hydroxide (twice), water 1M aqueous solution of citric acid (twice), water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. Thus obtained organic layer was chromatographed on silica gel (150 g.) eluting with a mixture of benzene and n-hexane (1:1) to give a yellowish oil of the title compound (23.6 g.)
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21].Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21]
Reactant: COc1cc(-n2ccc(CO)cc2=O)ccc1OCC(C)(C)O
Reactant: Clc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-n2ccc(COc3ccccn3)cc2=O)ccc1OCC(C)(C)O
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(hydroxymethyl)pyridin-2(1H)-one Part B (50 mg, 0.16 mmol) and 2-chloropyridine (0.059 mL, 0.63 mmol) in DMF (0.6 mL) was added to a mixture of Pd(OAc)2 (7.0 mg, 0.03 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (19 mg, 0.05 mmol), and Cs2CO3 (128 mg, 0.39 mmol) in 0.4 ml DMF. The mixture was stirred 15 min prior to heating at 80° C. for 6 h. After cooling to RT, the mixture was diluted with EtOAc and was filtered. The filtrate was concentrated and the residue was purified by Prep-HPLC (MeOH/H2O/TFA) to afford the title compound A-4 as a white solid (24 mg, 37% yield). LC-MS, [M+H]+=397. 1H NMR (CDCl3, 400 MHz) δ 8.16 (m, 1H), 7.62 (m, 1H), 7.31 (d, J=7.1 Hz, 1H), 6.91 (m, 5H), 6.72 (s, 1H), 6.28 (dd, J=7.1 and 2.2 Hz, 1H), 5.29 (s, 2H), 3.85 (s, 5H), 1.33 (s, 6H), HPLC-Method 6; 3.07 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-]>[Br:24][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=2)[N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(C(F)(F)F)cnc32)cc1
Yield: 89.1 %

Procedure:
To a stirred solution of 5-trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (53.7 g, 158 mmol) in DCM (250 mL) was added a solution of bromine (16 mL, 316 mmol) in DCM (50 mL) dropwise. No significant exotherm was observed. After an hour at room temperature, the reaction mixture had thickened and stirring ceased. The reaction was deemed complete by tic and was diluted with 1.2 litres of DCM and 50:50 saturated bicarbonate: saturated sodium thiosulfate aqueous solution. The organic layer was separated and further washed with the 50:50 aqueous mixture, dried over magnesium sulfate and evaporated. The crude yellow solid was triturated with diethyl ether and solid isolated and dried to give the product as a yellow powder (59 g, 59% yield)
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.CI>O1CCCC1.O>[CH3:1][C:20]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a 500 mL round-bottomed flask was added diisopropylamine (7.98 mL) in tetrahydrofuran (233 mL) to give a colorless solution. The mixture was cooled to −78° C. under N2 and n-BuLi (2.5 M in hexanes, 22.40 mL) was added. The reaction was stirred for 30 minutes and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g) was added. The reaction was allowed to stir for 1.5 hours upon which time CH3I (4.38 mL) was added. The reaction was allowed to warm to room temperature overnight with stirring. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by normal phase flash column chromatography (Analogix, 0-50% hexanes/ethyl acetate).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:46])[C:10]([CH3:45])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH:17]=[C:16]4[CH2:30][N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][C@H:32]3[CH3:44])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CC(O)C>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])[CH:17]=[C:16]4[CH2:30][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][C@H:32]3[CH3:44])[C:10]([CH3:45])=[C:9]([F:46])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@H]3C)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
(3R)-tert-Butyl 4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate (27 g) was dissolved in 2-propanol (200 mL) and HCl (54.1 mL of a 5-6 N solution in 2-propanol) was added. The reaction was heated at 50° C. for 4 h, cooled to room temperature and stirred overnight. The volatiles were evaporated in vacuo and excess HCl removed by addition of toluene followed by solvent removal in vacuo. Water (300 mL) was added followed by the portionwise addition of sodium bicarbonate (7.15 g) until pH 7. Further sodium bicarbonate (7.15 g) was added portionwise and the mixture extracted with DCM (500 mL+200 mL). The combined organics were washed with brine (250 mL), dried (Na2SO4), filtered and the volatiles evaporated in vacuo to give the title product (22 g).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([OH:10])[N:3]=1.[OH-].[Na+].[CH3:13]I>>[CH3:9][C:5]1[C:4]([OH:10])=[N:3][C:2]([S:1][CH3:13])=[N:7][C:6]=1[OH:8]
Reactant: CI
Reactant: Cc1c(O)nc(S)nc1O
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-mercapto-5-methylpyrimidine-4,6-diol (2.08 g, 13.14 mmol) in 2 N aq. NaOH-solution (19.7 mL, 39.41 mmol) was cooled to 0° C., then MeI (2.07 mL, 32.84 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 1 h 40 and at rt for 2 h. The reaction mixture was concentrated to yield 5-methyl-2-(methylthio)pyrimidine-4,6-diol as a white solid which was used in the next step without further purification. LC-MS conditions
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:4]=1[O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O)=O>O1CCOCC1.C(O)C.[Ni]>[CH3:25][O:24][C:20]1[C:4]2[O:5][C:6]3[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=3[NH:17][CH2:1][C:3]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(Oc2c(C=O)cccc2OC)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)NCc1cccc(OC)c1O2
Yield: 76.4 %

Procedure:
A solution of ethyl 4-(2-formyl-6-methoxyphenoxy)-3-nitrobenzoate (145 g) in dioxane (1.2 l) and ethanol (150 ml) was hydrogenated over Raney nickel catalyst (60 ml) at room temperature under atmospheric pressure. After a pre-calculated amount of hydrogen was absorbed, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was treated with ethanol (20 ml) to crystallize and then the separated crystals were collected by filtration. Recrystallization from ethanol gave ethyl 10,11-dihydro-4-methoxydibenz[b,f][1,4]oxazepine-8-caboxylate (96 g) as colorless needles. (Yield: 77%, m.p. 121°-122° C.)
Reaction SMILES: [CH2:1]([N:4]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C@:14](N=[N+]=[N-])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[C:32]([O:36][C:37](=[O:80])[CH2:38][C@@]1(C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@@H](C(N(C(OC(C)(C)C)=O)C2C=CC=CC=2)=O)C1)([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([N:4]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C@:14]([CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:80])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)C[C@@]2(C)N=[N+]=[N-]
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)O)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
According to the procedure for the preparation of 18f, intermediate 38b (413.9 mg, 0.62 mmol) was deprotected to afford 273.9 mg (89%) of intermediate 38c. MS (ESI) 498.4 (M+H+), 496.2 (M−H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:18]=[N+:19]=[N-:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 95 °C
Yield: 78 %

Procedure:
The compound (3R)-1-benzyl-3-[(methylsulfonyl) oxy]pyrrolidine (1.3 g, 5.8 mM) was dissolved in dimethylformamide (25.0 ml) and sodium azide (1.5 g, 23.3 mM) was added to it. The reaction mixture was maintained at 90-100° C. for about 12 hours followed by cooling at room temperature. The reaction mixture was poured into cold water (150.0 ml) with constant stirring. The organic compound was extracted with ethyl acetate and washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated to give the title compound. Yield=78% (0.9 g, 4.5 m. This material was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].N#N.[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of ((S)-5-benzyloxycarbonylamino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (0.68 g, 1.27 mmol) in EtOH (20 mL) under an inert atmosphere of N2 is treated with activated palladium on charcoal (10%). The reaction mixture is then placed under a positive pressure of hydrogen and stirred at RT. After 3 h, the catalyst is removed by filtration through Celite® (filter material). The filtrate is concentrated in vacuo and the resulting colourless oil is dissolved in MeOH (10 mL) and allowed to stand at RT overnight. A cream precipitate forms which is removed by filtration and the solution is concentrated in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% NH3) affords the title compound. [M+H]+ 402.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[CH3:11].[C:17](O)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[CH3:11])(=[O:19])[CH3:18]
Reactant: CCOC(=O)c1cc2c(N)cccc2n1C
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(NC(C)=O)cccc2n1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
In 20 ml of pyridine was dissolved 1.2 g (5.52 mmol) of ethyl 4-amino-1-methyl-2-indolecarboxylate. While stirring at room temperature, 10 ml of anhydrous acetic acid was added to the solution. After stirring for 2 hours at room temperature, the reaction mixture was poured onto ice water. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with 1N hydrochloric acid and then with saturated sodium hydrogencarbonate solution. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 1.40 g (97.9%) of ethyl 4-acetamido-1-methyl-2-indolecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.S([O-])([O-])=O.[NH4+:17].[NH4+]>N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH2:17])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: [NH4+]
Agent: N
Agent: O=S([O-])[O-]
Product: Nc1ccc2cc(Br)ccc2c1
Temperature: 190 °C
Yield: 33.5 %

Procedure:
6-Bromo-2-naphthol (2.0 g, 9 mmol), ammonium sulfite (10.4 g, 90 mmol) and 10 mL of ammonia solution were sealed in a tube. The reaction mixture was heated at 190° C. for 24 hrs and allowed to cool to room temperature, the reaction mixture was extracted with EtOAc. HCl (10%) was added to the organic layer to give a precipitate. After filtration, the solid was dissolved in 10% of Na2CO3 and extracted with EtOAc, the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the product as yellow solid (0.67 g, 33%). MS [M++43]=265, LC-MS: tR=2.14 min.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]1[C:9]2=[C:10]([S:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:11]3[C:12]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:10]2[C:11]3[C:12]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:32])=[O:2])[C:9]=23)=[CH:26][CH:27]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)C)cc(S(C)(=O)=O)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)c1cc(S(C)(=O)=O)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of the ester of Step 4 (140 mg) in THF/MeOH (3/1) mixture at r.t. was added 1 M LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 hours and AcOH was added and the solvent was evaporated. The residue was taken up in EtOAc/H2O and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 1% AcOH in EtOAc to give 100 mg of the title compound.