Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:30][C:31]1[Se:32][C:33]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=2[N:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:30][C:31]1[Se:32][C:33]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=2[N+:35]=1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc2[se]c(C)nc2c1
Product: CCCCCCCCCCCCCCCCCC[n+]1c(C)[se]c2ccc(C)cc21
Product: O=S(=O)([O-])c1ccc(Cl)cc1
Temperature: 130 °C
Yield: 60.1 %

Procedure:
Octadecyl parachlorobenzenesulfonate (11.5 g) was added to 3.96 g of 2,5-dimethylbenzoselenazole, and the mixture was heated at 130° C. for 6 hours. The crystals yielded by the reaction were washed with ether and then recrystallized from ethyl acetate. Drying of the crystals gave 7.42 g of 2,5-dimethyl-3-octadecylbenzoselenazolium parachlorobenzenesulfonate (yield 61%).
Reaction SMILES: C[Si](C#C)(C)C.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([C:17]#[C:18][Si](C)(C)C)[C:12]([CH:13]=O)=[CH:11][N:10]=1.[OH-].[NH4+:24]>C(O)C>[CH3:7][O:8][C:9]1[N:10]=[CH:11][C:12]2[C:15]([CH:16]=1)=[CH:17][CH:18]=[N:24][CH:13]=2
Reactant: [NH4+]
Reactant: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Agent: C#C[Si](C)(C)C
Agent: [OH-]
Solvent: CCO
Product: COc1cc2ccncc2cn1

Procedure:
Preferably the 1,2,3,4-tetrahydro-2,7-naphthyridine intermediate (VIIb) can be synthesised as shown in Schemes 3 and 4. In Route B, commercially available 6-methoxynicotinaldehyde is treated successively with the lithium salt of N,N,N′-trimethylethylenediamine, then n-BuLi in hexanes and finally iodine to afford the 4-iodo-6-methoxynicotinaldehyde (cf. Tetrahedron Lett. 1993, 34(39), 6173-6176). The iodo compound is coupled with trimethylsilylacetylene under usual Sonagashira-Hagihara conditions (Synthesis 1980, 627-630) and the resulting 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde is condensed with ammonium hydroxide in ethanol to give 3-methoxy-2,7-naphthyridine (Synthesis 1999, 2, 306-311). Regioselective catalytical reduction (cf. Eur. J. Med. Chem. Ther. 1996, 31(11), 875-888) affords 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Demethylation and N-protection with BOC-anhydride and finally treatment of the resulting tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate with triflic anhydride in a two-phase system gives (VIIb).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([F:27])[CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl.Cl.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([F:27])[CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl{1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193, 0.21 g) in dioxane (3 mL) and water (1 mL) was added 4 M HCl in dioxane (1 mL). After 30 minutes, additional 4 M HCl/dioxane (3 mL) was added. After 1 hour, the reaction was diluted with chloroform and poured into a saturated solution of Na2CO3. The organic solution was collected, dried (Na2SO4), filtered and concentrated yielding 0.158 g of crude titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:22][CH2:21][CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCOCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCCOCc1ccccc1)c1ccc(Br)cc1
Yield: 94.3 %

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (5.5 g, 21.7 mmol) dissolved in dichloromethane (15 ml) was added dropwise to a solution of 2-benzyloxyethanol (3.0 g, 19.7 mmol) in triethylamine (3 g, 29.6 mmol) at 0° C. under nitrogen. The resultant mixture was stirred for 16 h at room temperature. To the reaction mixture was added water (3 ml) and then the combined mixture was poured onto water (100 ml) and the product was extracted with dichloromethane. The organic layer was washed repeatedly with water and then saturated aqueous sodium hydrogen carbonate solution, before drying (Na2SO4) and concentrating in vacuo to give the title compound as a white solid (6.9 g, 94%).
Reaction SMILES: [O:1]=[C:2]1[CH:14]=[C:13]2[C@:5]([CH2:25][CH2:26][CH3:27])([CH:6]([Cl:24])[C:7]3[C:12]2=[C:11]([Cl:15])[C:10]([Cl:16])=[C:9]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:8]=3)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[ClH:15].[O:1]=[C:2]1[CH:14]=[C:13]2[C@:5]([CH2:25][CH2:26][CH3:27])([CH:6]([Cl:24])[C:7]3[C:12]2=[C:11]([Cl:15])[C:10]([Cl:16])=[C:9]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=3)[CH2:4][CH2:3]1
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2Cl
Product: Cl

Procedure:
Ethyl [(3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-5,6,9-trichloro-1H-fluoren-7-yl)oxy]acetate (4.31 g, 0.01 mole) was stirred with ethanol (50 ml) and 1N sodium hydroxide (15 ml) for 12 hours at 25° C. The solution was evaporated in vacuo and the residue dissolved in water. Acidification with hydrochloric acid gave [(3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-5,6,9-trichloro-1H-fluoren-7-yl)oxy]acetic acid which was purified by column chromatography on silica gel (400 g) eluting with methylene chloride/tetrahydrofuran/acetic acid, 50/2/1 (v/v/v).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.IC.[C:31]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:31])[C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: O=C(CN1CCC2(CC1)C(=O)Nc1ccccc12)N1CCN(C2CCC2)CC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)c2ccccc21
Temperature: 65 °C

Procedure:
A mixture of 1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]spiro[indole-3,4′-piperidin]-2(1H)-one (0.136 mmol), iodomethane (0.544 mmol) and Cs2CO3 (177 mg, 0.544 mmol) in DMF (3 ml) is heated in a sealed tube at 65° C. overnight. DMF is removed in vacuo and the residue is partitioned between water (5 ml) and EtOAc (10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. Purification of the residue with PTLC gives the title compound as a white solid. LC-MS (M+1): 396.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=CC=[CH:7]2)([O-:3])=[O:2].F[C:15](F)(F)[C:16]([OH:18])=O.[OH:21]O>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:21])=[C:16]([OH:18])[CH:15]=[CH:7]2.[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:21])=[C:16]([OH:18])[CH:15]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Reactant: OO
Solvent: O
Product: Nc1ccc2c(ccc(O)[n+]2[O-])c1
Product: O=[N+]([O-])c1ccc2c(ccc(O)[n+]2[O-])c1
Yield: 37 %

Procedure:
6-amino-2-hydroxyquinoline-N-oxide was prepared as follows. A solution of 25 g 6-nitroquinoline, 560 g of trifluoroacetic acid, and 60 g of 30% hydrogen peroxide was heated at reflux for 6 hr. After checking for the absence of peroxides, the mixture was cooled and poured into 3750 mL of water. The product was collected by filtration, washed with water and dried under vacuum at 60° C., to give 6-nitro-2-hydroxyquinoline-N-oxide (5.48 g, 19% yield). 1HNMR data for this compound (DMSO) was as follows: δ 8.8 (s, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 6.9 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2cccc(OC(F)(F)F)c2)c1

Procedure:
2.61 g (12.09 mmol) of methyl 5-bromonicotinate and 2.49 g (12.09 mmol) of 3-(trifluoromethoxy)phenylboronic acid were reacted according to the General Method 1A. Yield: 2.44 g (68% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>C(OCC)C>[C:16]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A suspension of 0.5 g (2.87 mmol) of 5-bromo-2-pyridinol in 10 ml of ethyl ether is prepared and 1 ml (7.1 mmol) of triethylamine and then 1 ml (14 mmol) of acetyl chloride are added at ambient temperature. The mixture is stirred at ambient temperature for 24 hours and then the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel, elution being carried out using a toluene/2-propanol mixture (9/1; v/v). The expected product is obtained in the form of a pale yellow powder with a yield of 52%.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6]C)=[O:5].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>C(Cl)Cl.C1COCC1.O>[CH:9]1([NH:15][C:2](=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: COC(=O)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (2.2 g, 16.1 mmol) in dry DCM (30 ml) at 0° C. was added cyclohexylamine (4.0 g, 40.3 mmol). The reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was washed with diluted HCl, saturated NaHCO3 then brine well. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated. The resultant crude amide was used directly in the next step with no additional purification (3.2 g, 100%). To a solution of this material (500 mg, 2.51 mmol) in THF/water (1:1, 20 ml) was added NaOH (200 mg, 5.02 mmol) and the mixture was stirred for 3 hrs at room temperature. The mixture was extracted with Et2O then the aqueous phase was acidified to pH 1 and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated to afford the title compound 58 as a beige solid (450 mg, 97% yield). MS (m/z): 186.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].CO>C1COCC1>[Cl:13][CH2:14][CH2:15][NH:16][C:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:18]
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 4-amino-2-methylquinoline (12.6 g, 80 mmol) in THF (480 mL) is added 2-chloroethylisocyanate (10.2 mL, 120 mmol) at rt. The reaction mixture is stirred for 40 h at rt. MeOH (100 mL) is added, and stirring is continued an additional hour. The reaction mixture is evaporated and the residue is taken up in CH2Cl2. The organic layer is shaken with 1 N HCl (250 mL), and the resulting precipitate is collected by filtration. The solid is washed with CH2Cl2 (100 mL), saturated NaHCO3 (2×100 mL), and with water (4×100 mL). The resulting solid is dried under HV at rt for 14 h to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15](OCC)=[O:16])=[C:7]2[OH:20].Cl.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[C:3]([OH:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:16])=[C:7]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 105.4 %

Procedure:
A mixture of ethyl 8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.4 g, 1 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.3 g, 2 mmol) in 2 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (0.5 g, 4 mmol). The resulting mixture was warmed to 85° C. and stirred for 4 hours, M+Na=402, M+1=380. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.4 g of the title compound as a pale white solid. MS (m/z)=378 (M−1)−.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#N.[O:15]1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:5][C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:4])[CH:1]=[O:15]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (8.60 g, 45.5 mmol) produced in Example C6(ii) in toluene (60 mL)/tetrahydrofuran (40 mL) was added dropwise a 1.0M solution (100 mL, 100 mmol) of diisobutylaluminum hydride in hexane at −78° C. for 1 hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr and at 0° C. for 1 hr. The reaction mixture was poured into a mixture of ethyl acetate (200 mL) and 3N hydrochloric acid (300 mL), the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (6.39 g, 73%) as colorless crystals.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17](OCC)=O)=[CH:13][CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:42].[O:43]1[CH2:47]C[CH2:45][CH2:44]1>>[CH2:44]([O:43][C:47]([CH2:17][CH:16]=[CH:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:1])=[CH:23][CH:22]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)C=Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reactant: O
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)CC=Cc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.9 g) in tetrahydrofuran (6 ml) was added dropwise tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 6.0 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was treated according to C. J. Kowalski's method described in J. Am. Chem. Soc., Vol.107, No.5, 1429-1430 (1985) to give 2-[4-(3-ethoxycarbonyl-1-propenyl)phenyl]ethyl alcohol (0.42 g) as colorless powder.
Reaction SMILES: [ClH:1].[C:2]1(=[O:32])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](=[NH:24])OC)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:5](=[O:27])[C:4]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:3]12.[NH3:33].CCOCC>CO>[ClH:1].[C:5]1(=[O:27])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH2:33])=[NH:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:2](=[O:32])[C:3]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:4]12
Reactant: COC(=N)c1ccc(CCc2ccc(C(C)N3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: N
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(c1ccc(CCc2ccc(C(=N)N)cc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.8 g of methyl 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzimidate hydrochloride in 30 ml of anhydrous methanol, was added 2.3 ml of a solution of anhydrous ammonia in anhydrous methanol (0.036 g/ml). The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzamidine hydrochloride; m.p. 110°-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]3[NH:19][N:18]=[N:17][N:12]=3)=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2oc(C#N)cc(=O)c2c(C)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2oc(-c3nnn[nH]3)cc(=O)c2c(C)c1Cl

Procedure:
A mixture of 23.4 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, 7.8 parts of sodium azide, 6.4 parts of ammonium chloride and 200 parts of N,N-dimethylformamide was stirred and heated on the steam bath for 18 hours. Most of the solvent was then removed by distillation under reduced pressure. A solution of the residue in 400 parts of water was acidified with 20% hydrochloric acid. The precipitated solid was filtered off, washed with water and crystallized from dioxan to give 15.5 parts of 5-(6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-yl) tetrazole as a colourless solid, melting point 246-247°C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][CH2:20][C@H:21]2[C@@H:25]([F:26])[CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:22]2)[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[N:10]=1.C(N(CC)CC)C.C(Cl)(Cl)=[O:53].C1(C)C=CC=CC=1.C(N1C([C@H:75]([N:80]([CH2:84][C@H:85]2[C@@H:89](F)CN(C(OCC3C=CC=CC=3)=O)C2)[C:81](Cl)=[O:82])[C:76](C)(C)[CH3:77])=NC(C2C=C(F)C=CC=2F)=N1)C1C=CC=CC=1.CC1OC(C)CNC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:20][C@H:21]2[C@@H:25]([F:26])[CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:22]2)[C:81]([N:80]2[CH2:84][C@@H:85]([CH3:89])[O:53][C@@H:76]([CH3:77])[CH2:75]2)=[O:82])[C:15]([CH3:18])([CH3:16])[CH3:17])[N:11]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[N:10]=1
Reactant: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)Cl
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1
Reactant: O=C(Cl)Cl
Agent: CC1CNCC(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)N(C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2cccc(F)c2)C(C)(C)C)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 0.049 mmol) in dichloromethane (450 μL, 0.1 M solution) was added triethylamine (20.6 μL, 0.148 mmol) followed by addition of 20% phosgene in toluene (6.2 μL, 0.059 mmol) at room temperature. After the resulting solution was stirred at room temperature for 15 min (LC/MS (uplc): MH+ 654.3, 1.37 min for (3S,4R)-benzyl 3-((((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)(chlorocarbonyl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate), 2,6-dimethylmorpholine (64 mg, 0.558 mmol) was added and stirred for 15 min at room temperature. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. After the volatile organic materials were removed in vacuo, the crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 81%, over 2 steps). LC/MS (uplc): MH+ 751.5, 1.39 min.
Reaction SMILES: ClCCl.[OH:4][C@H:5]([CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C:27]2=[O:32])=[CH:22][CH:21]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:33](=O)([O-])[O-:34].[K+].[K+]>O1CCCC1>[O:34]=[C:33]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:18][C@H:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[O:4]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In a four neck round bottom flask, charged dichloromethane (150 ml), 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (15 g), N,N′-dicarbonyldiimidazole (9.22 g), and powdered potassium carbonate (5.24 g) at 25 to 30° C. The obtained reaction mass then stirred for 5 h at 25 to 30° C. Reaction mass then filtered and obtained solid is washed the by dichloromethane. Separated filtrate is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (30 ml) to residue. The obtained mixture is heated to 40 to 45° C. for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran. Yield 90%