Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([CH:34]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[CH3:35])([F:33])[C:29]([F:32])([F:31])[F:30].[F:45][C:46]([F:55])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][NH2:48]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]([C:28]([F:27])([F:33])[C:29]([F:30])([F:31])[F:32])[CH3:35])=[CH:44][CH:43]=1.[F:45][C:46]([F:55])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][NH2:48]
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)C(F)(F)F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: NCC(F)(F)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (9 g, 21.1 mmol) with 4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 2 (11.4 g, 42.3 mmol) in anhydrous toluene (270 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine isomer 2 (9.5 g, 83%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>O.C(OCC)C>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Oc1cccc(F)c1
Reactant: CC(Br)CCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OCCCCCCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6](O)[C:3]=1[C:4]#[N:5].P(Cl)(Cl)([Cl:14])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:14][C:6]1[C:3]([C:4]#[N:5])=[C:2]([OH:1])[N:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(O)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc(Cl)c(C#N)c(O)n1
Temperature: 40 °C
Yield: 47.5 %

Procedure:
To a solution of 2,4-dihydroxy-6-methylnicotinonitrile (1.5 g, 10 mmol) in acetonitrile (50 mL) were added benzyltriethylammonium chloride (9.1 g, 40 mmol) and phosphoryl chloride (6.13 g, 40 mmol). The reaction mixture was heated to 40° C. for 4 hours at the same temperature. LC-MS showed that 2,4-dihydroxy-6-methylnicotinonitrile was consumed completely. The solvent was removed by rotary evaporation. To the residue was added dichloromethane (100 mL) and water (50 mL). The organic phase was separated, and it was washed with brine (50 mL) once, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product, which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 4-chloro-2-hydroxy-6-methylnicotinonitrile (800 mg, 24%) as a brown solid.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[Cs].[C:34]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[I-].[Na+]>O.C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:49][C:47](=[O:48])[C@@H:42]([NH:41][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@@H:43]([CH3:44])[CH2:45][CH3:46])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Yield: 79 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (1.00 g, 2.04 mmol), the cesium salt of N-BOC-L-isoleucine (15f) (1.48 g, 4.07 mmol), sodium iodide (0.31 g, 2.07 mmol) and acetonitrile (50 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 30 minutes) to afford the title compound. Isolated yield: 79%. 1H NMR (400 MHz, CDCl3): δ 7.48-7.42 (m, 1H), 7.22-7.17 (m, 1H), 7.14-7.10 (m, 1H), 6.91-6.85 (m, 1H), 5.08 (d, 0.5H), 4.94 (d, 0.5H), 4.81-4.74 (m, 1H), 4.24-3.98 (m, 4H), 3.71-3.64 (m, 1H), 3.13-3.04 (m, 5H), 2.51 (d, 3H), 2.42-2.31 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.81 (br m, 1H), 1.57 (dd, 3H), 1.52 (s, 1H), 1.38 (d, 9H), 1.21-1.09 (m, 1H), 0.93-0.85 (m, 6H); MS-APCI (m/z+): 341, 385, 586, 686.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:30])[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=2)(O)[C:16]([F:19])([F:18])[F:17])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].O=S(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:30])[CH:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=2)[C:16]([F:19])([F:18])[F:17])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1sc(C(=O)CC(O)(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sc(C(=O)C=C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Yield: 99.6 %

Procedure:
Stir a mixture of 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxyl-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (26 g, 53.7 mmol), SOCl2 (12.7 g, 7.8 mL, 0.107 mmol) and pyridine (42.3 g, 0.537 mmol) in anhydrous DCM (300 mL) at room temperature for 3 hours. Concentrate the mixture under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 12:1) to afford 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as a pale yellow solid (25 g, 100%). (m/z): 467 (M+1).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2C=C[C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[S:28]1C=CC=C1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[S:28][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1cccs1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccs2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and thiophene-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-thiophen-2-yloxazole.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24](F)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]>N1C=CC=CC=1>[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24]([N:13]3[CH2:12][CH2:11][NH:10][CH:9]([CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14]3)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]
Reactant: CCCCCCOCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 3 g portion of 2-[(hexyloxy)methyl]piperazine was added to 20 ml of pyridine in a pressure bottle, under argon. A 1.26 g portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added, the bottle sealed and the mixture heated at 80°-90° C. for 4 hours, then evaporated. The residue was evaporated twice from toluene, the residue triturated with ether and the solid collected, giving 2.03 g of the desired product, mp 121°-124° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20](OC3C=CC=CC=3)[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20]([NH2:5])[C:19]=2[N:18]=[C:17]1[CH2:33][O:34][CH2:35][CH3:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc(C)cc2n1CCOCc1ccccc1
Yield: 51.4 %

Procedure:
Ammonium acetate (25 g, 0.32 mol) and 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.5 g, 6.0 mmol) were heated at 150° C. in a sealed tube for 22 hours. The resulting solution was adjusted to pH 14 with the addition of 20% sodium hydroxide, and water (50 mL) was added. The mixture was stirred for several hours to provide a yellow precipitate, which was isolated by filtration. The precipitate (1.75 g) was recrystallized from a 50:50 mixture of hexane:ethyl acetate (29 mL/g), and the crystals were isolated by filtration and dried under vacuum for 23 hours at 60° C. to provide 1.05 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine as small white crystals, mp. 127-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-Methoxy-4-(1-Boc-4-piperidyloxy)benzoic acid (3.2 g, 9.1 mmol) was dissolved in THF (35 ml). Thionyl chloride (1 ml, 1.63 g, 13.7 mmol) was added dropwise, followed by 2 drops of pyridine. The mixture was stirred at ambient temperature under nitrogen for 4.5 hours, then concentrated in vacuo. The residue was reconcentrated from ether to give 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[OH:23][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:17]([N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:18][CH:19]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: OCCc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: OCCc1ccc(N2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 29.8 %

Procedure:
A mixture of 8.7 g (45 mmol) of 5H-dibenz[b,f]azepine, 12.4 g (50 mmol) of p-iodophenethyl alcohol, 2.8 g (50 mmol) of potassium hydroxide, 4. 8 g (75 mmol) of copper powder, and 20 ml of decalin was heated at an external temperature of 200° C. while stirring in a nitrogen stream for 40 hours. The reaction mixture was cooled nearly to room temperature, chloroform was added thereto, followed by filtration using Celite to remove any insoluble matter. The filtrate was concentrated. To remove decalin, n-hexane was added to the residue, followed by filtration. The filter cake was reprecipitated in methanol, and the resulting crude product was purified by silica gel column chromatography to give 4.2 g (30%) of 5-(4-(2-hydroxyethyl)phenyl)-5H-dibenz[b,f]azepine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[I:12].[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[I:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCc1nc2ccccn2c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1OCc1nc2ccccn2c1I
Yield: 45.7 %

Procedure:
4 g (13.68 mmol) of 2-(chloromethyl)-3-iodoimidazo[1,2-a]pyridine were dissolved in dimethylformamide with magnetic stirring and then 2.71 ml (20.51 mmol) of methyl 2-hydroxybenzoate and 6.68 g (20.51 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2 h before being poured into 200 ml of water. The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of a saturated NaHCO3 aqueous solution, 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was triturated in 50 ml of diisopropyl ether, the obtained solid was isolated by filtration. 2.55 g of expected product were isolated. On the other hand, an aqueous phase suspension was isolated by filtration and washed with 2×30 ml of water. The analyses confirmed that this was also the expected product. Both batches were therefore collected and 5.58 g (yield=76%) of methyl 2-((3-iodoimidazo[1,2-a]pyridin-2-yl) methoxy)benzoate were obtained as a white powder. LC-MS: m/z=409 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.33 (d, J=6.9 Hz, 1H), 7.69-7.44 (m, 3H), 7.45-7.28 (m, 2H), 7.16-6.93 (m, 2H), 5.23 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([OH:29])[C@H:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:15]([CH3:20])[CH2:16][N:17]=[N+:18]=[N-:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([O:29][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@H:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C@@H:15]([CH3:20])[CH2:16][N:17]=[N+:18]=[N-:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN=[N+]=[N-])cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
To a solution of (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-2-hydroxy-4-methylpentyl 4-methylbenzenesulfonate (1.0 equiv.) and 2,6-lutidine (3.4 equiv.) was added TBDMSOTf (1.7 equiv.) at 0° C. The solution was stirred for 7 hours as it warmed to rt. The solution was diluted with EtOAc, washed with 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (2.5-5-10-20% EtOAc/n-heptanes) yielding (2R,3R,4S)-5-azido-2,3-bis(tert-butyldimethylsilyloxy)-4-methylpentyl 4-methylbenzenesulfonate (75%).
Reaction SMILES: C(OC(C1[C:12]2[NH:13][C:14]3C=CC=CC=3C=2CCNC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[C:31]2[NH:32][C:33]3[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][C:38]=3[C:30]=2[C:29]([CH3:41])([CH3:40])[CH2:28][N:27]([C:42](=[O:51])[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[C:45](F)[CH:44]=2)[CH:26]=1)=[O:24])[CH3:21].C(N(CC)CC)C.C(N=[C:63]=[O:64])CC>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[C:31]2[NH:32][C:33]3[CH:34]=[C:35]([O:39][C:63](=[O:64])[N:13]([CH3:12])[CH3:14])[CH:36]=[CH:37][C:38]=3[C:30]=2[C:29]([CH3:40])([CH3:41])[CH2:28][N:27]([C:42](=[O:51])[C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)N(C)C)ccc21
Temperature: 60 °C

Procedure:
To prepare 3-(3,4-difluoro-benzoyl)-1,1-dimethyl-8-propylcarbamoyloxy)-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester, a mixture of 3-(3,4-difluoro-benzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]-indole-5-carboxylic acid ethyl ester (45 mg, 0.1 mmol), triethylamine (0.1 mL), and propylisocyanate (0.2 mL) in dry DCM (5 mL) was refluxed at 60° C. for 20 hours. The solvent was removed in vacuo, and the residue was purified by preparative reverse-phase HPLC to give the title compound, which was then acylated in the manner described in Example 2A; 1H-NMR (CDCl3): δ 10.62 (1H, s), 7.76-7.73 (2H, m), 7.52-7.47 (1H, m), 7.36-7.31 (1H, m), 7.24-7.19 (1H, m), 7.16 (1H, d), 6.86 (1H, m), 5.04 (1H, t), 4.26 (2H, q), 4.09 (2H, brs), 3.25 (2H, q), 1.66-1.54 (8H, m), 1.25 (3H, t), 0.99 (3H, t). MS (ES): 526 (MH+).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:53])[CH:24]([CH2:27][C:28]3[N:29]=[CH:30][N:31]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]=3[CH3:33])[CH2:25][CH2:26][C:15]=12.C(Br)C=C>O1CCCC1.CCCCCC>[CH2:3]([C:24]1([CH2:27][C:28]2[N:29]=[CH:30][N:31]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:32]=2[CH3:33])[C:23](=[O:53])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:1]=[CH2:2]
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CCc2c(C)c3ccccc3n2C1=O
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
To a solution of diisopropylamine (395 mg) in tetrahydrofuran (5 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (2.62 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.61 g) in tetrahydrofuran (5 ml) over 15 minutes. The mixture was stirred at -65° C. for 30 minutes and at -30°~-40° C. for 30 minutes and a solution of allyl bromide (363 mg) in tetrahydrofuran (5 ml) was added dropwise at -65° C. over 10 minutes. After the mixture was stirred at -65° C. for 1 hour, at -20° C. for 1 hour and at ambient temperature for 1 hour. The resultant mixture was washed with water (10 ml×2) and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Purification of the residue with silica gel column chromatography (5% ethyl acetate-chloroform) gave 7-allyl-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.15 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:15]([C:14]3[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=3)[O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cc1O
Product: Fc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-fluorobenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4,5-difluorobenzoic acid (5.37 g, 31.0 mmol) in THF(50 mL) was dropwise added to the suspension on LAH (1.65 g, 43.5 mmol) in THF (15 mL) at room temperature under N2 over 10 min. The resulting suspension was stirred at room temperature for 1 hr. Then the mixture was cooled down to 0° C., quenched with saturated Na2SO4 (100 mL), and extracted with Et2O (2×100 mL), the combined organic layers were washed with brine (60 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected crude product as a brown solid, which was pure enough to be used in next step without further purification. 1H NMR (400 MHz, CDCl3) δppm 4.07 (s, 1H), 4.56 (s, 2H), 6.46 (dd, J=11.71, 6.92 Hz, 1H), 6.87 (dd, J=10.58, 8.56 Hz, 1H); Mass spec. 160.04 (MH+), Calc. for C7H7F2NO 159.05.