Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:3]([CH2:2][CH:1]=[O:7])[C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COC(CC=O)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL). The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g. 88% yield) as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)=[NH:9])[CH:4]([CH3:6])[CH3:5].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>N1C=CC=CC=1>[ClH:18].[CH2:3]([NH:7][C:8](=[NH:9])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[O:27])[CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)CNC(=N)Nc1cccc(N)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)CNC(=N)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 16 h

Procedure:
To a solution of 1-isobutyl-3-m-aminophenylguanidine dihydrochloride (19.6 g.) in pyridine (100 ml.) is added dropwise a solution of p-chlorophenyl isocyanate (11.5 g.) in pyridine (25 ml.) at room temperature. The mixture is stirred for 16 hours, and the pyridine is removed by distillation under reduced pressure. The residual gum is shaken with a mixture of ether (100 ml.) and 1% aqueous sodium hydroxide solution (10 ml.) to remove pyridine hydrochloride whereafter the product crystallizes. The solid is filtered off, washed with water and ether and dried, and recrystallized from ethanol/petroleum ether b.p. 40°-60° C. to give 1-(3-isobutylguanidino)-3-(3-p-chlorophenylureido)benzene hydrochloride, m.p. 215°-216° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[N:26][N:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:35][C:36]([C:44]#[N:45])([CH2:40][CH2:41][CH2:42][CH3:43])[C:37](O)=[O:38]>ClCCl>[C:44]([C:36]([CH3:35])([CH2:40][CH2:41][CH2:42][CH3:43])[C:37]([O:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[S:24][C:23]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:27][N:26]=2)=[CH:33][CH:32]=1)=[O:38])#[N:45]
Reactant: CCCCCCCc1nnc(-c2ccc(O)cc2)s1
Reactant: CCCCC(C)(C#N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCc1nnc(-c2ccc(OC(=O)C(C)(C#N)CCCC)cc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
With exclusion of moisture, 0.1 mol of dicyclohexylcarbodiimide in dichloromethane is added to a mixture of 0.1 mol of 2-heptyl-5-p-hydroxyphenyl-1,3,4-thiadiazole and 0.1 mol of optically active 2-methyl-2-butylcyanoacetic acid in 200 mL of dichloromethane, while cooling with ice. The mixture is stirred for a further 12 hours at room temperature, the dicyclohexyl urea is filtered off and 2-[4-(2-cyano-2-methylhexanoyloxy)-phenyl]-5-n-heptyl-1,3,4-thiadiazole is isolated by working up in the usual way.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:8](=[O:9])([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14](=[O:17])[CH:15]=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: CC(Cl)OC(=O)Cl
Reactant: C=CC(=O)OCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 2.26 g (90%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.80 (4 H, m, CH2 --CH2), 1.86 (3 H, d, J=5 Hz, CH3), 4.24 (4 H, m, 2×CH2 --O), 5.7-6.6 (4 H, m, CH=CH2 and CH).
Reaction SMILES: [C:1]([N:18]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OCC)(=O)C>[C:1]([N:18]1[CH2:23][C:24](=[O:26])[O:22][C:20](=[O:21])[CH2:19]1)([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CC(=O)O1
Reaction time: 1 h

Procedure:
N-FMOC-Iminodiacetic acid (0.40 g, 1.13 mmol) was suspended in 30 ml ethyl acetate and treated with 1 ml of trifluoracetic anhydride. After stirring for one hour, most of the solvent was evaporated. Petroleum ether was added, followed by evaporation, resulting in a solid residue was dried in vacuo at room temperature. The yield was 0.37 g (97%) mp 180°-185° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 1-methyl-1,4-diazepane (1 g, 8.8 mmol) in DMSO (20 mL) were added K2CO3 (2.4 g, 18 mmol) and 5-bromo-2-nitropyridine (51-7) (1.78 g, 8.8 mmol). The mixture was stirred at 65° C. for overnight. It was allowed to cool to room temperature and poured into water. The resulting solid was collected and dried under vacuum. The solid was further purified by flash column eluting with 3:1 petroleum ether/ethyl acetate and then methylene chloride to give 338a as a yellow solid (800 mg, 69%). MS: [M+H]+ 236.
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: CC(Br)CCCCO
Reactant: Oc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
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: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:10]=[N:9][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1N
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: Brc1ccc2nc[nH]c2n1
Temperature: 100 °C
Yield: 18 %

Procedure:
A stirred mixture of 6-bromopyridine-2,3-diamine (1.30 g, 6.91 mmol) from Step 1 of this Example, formic acid (0.7 mL), and triethylorthoformate (28 mL) was heated at 100° C. for 1.5 h. After the reaction mixture was cooled to rt, the mixture was concentrated under reduced pressure. The residue was triturated with a mixture of 5% MeOH in DCM. The solid was collected by filtration and dried to afford 5-bromo-3H-imidazo[4,5-b]pyridine (245 mg, 18%) as a tan solid which did not require further purification. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluting with 100% DCM to 10% MeOH in DCM) to afford additional 5-bromo-3H-imidazo[4,5-b]pyridine (756 mg, 55%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 13.08 (br s, 1H), 8.50 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:38])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:38])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.4 %

Procedure:
A suspension of (S)-9-chloro-5-(p-tert-butoxycarbonylaminomethyl-o-carboxyphenylcarbamoylmethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]-quinoxaline-2,3-dione (430 mg) in 2N hydrogen chloride in 1,4-dioxane (14 mL) was stirred overnight at room temperature and diluted with diethyl ether. The precipitates were collected by filtration and recrystallized from water to give 350 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O1CCOCC1.[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14].Cl>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
1 g of each isotope labeled alanine (11.2 mmol) were dissolved in 15 mL of purified water and 1.2 g of sodium carbonate (see Figure GP2). 15 mL of 1,4-Dioxane was added slowly to each and stirred. Over the period of two and a half hours, 3.8 g of Fmoc-OSu (9-Fluorenylmethyl-N-hydroxysuccinimide) was added to each (see Figure GP3 for scheme). Additional saturated sodium carbonate in water was added to maintain a pH=10. Solutions were allowed to stir overnight. 6M HCl was slowly added to the solution until the pH was approximately 2. Extraction of the compound was completed using two times 150 mL of ethyl acetate, washing four times with 300 mL of acidified/purified water. Magnesium sulfate was added to remove any excess water. Samples were filtered and concentrated using a RotoVap until the final volume was approximately one-third the original volume. Crystallization was completed using Hexane. Hexane was decanted and compound allowed to dry.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]3[CH2:28][C:27]4[C:26]5[C:21](=[CH:22]C=[C:24](OC)[CH:25]=5)[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.[CH3:34][OH:35]>>[C:5]1([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]3[CH2:28][C:27]4[C:26]5[C:21](=[CH:22][C:34]([OH:35])=[CH:24][CH:25]=5)[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH2:10]2)[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: COc1cccc(C2CCCN(CC3CCc4[nH]c5ccc(OC)cc5c4C3)C2)c1
Solvent: ClCCl
Product: Oc1ccc2c3c([nH]c2c1)CCC(CN1CCCC(c2ccccc2)C1)C3

Procedure:
3-(3-m-methoxyphenylpiperidinomethyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole, Rf 0.7 (CH2Cl2 /methanol 9:1)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C:19]3[N:24]([CH3:25])[C:23](=[O:26])[CH:22]=[C:21]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[F:33])[N:20]=3)[CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[F:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[C:21]1[N:20]=[C:19]([N:15]2[CH2:16][CH2:17][O:18][C@@H:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[N:24]([CH3:25])[C:23](=[O:26])[CH:22]=1
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2F)cc1=O
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Methyl chloroformate (0.13 g, 1.38 mmol) was added to a solution of 2-((2S)-2-(4-aminophenyl)morpholine-4-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one obtained in Example 13 (0.35 g, 0.92 mmol) and triethylamine (0.25 g, 2.47 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at room temperature for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish methyl (4-((2S)-4-(6-(3-fluoropyridin-4-yl)-3-methyl-4-oxo-3H-pyrimidin-2-yl)morpholin-2-yl)phenyl)carbamate (0.17 g, 42%) as white crystals.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:31])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoic acid (880 mg, 2.70 mmol) obtained from Example 22-(5) in dichloromethane (15 ml) was cooled to 0° C., and then N,N-dimethylformamide (15 μl) and oxalyl chloride (1.71 g, 13.5 mmol) were added thereto. After the mixture was stirred at room temperature for 30 minutes, crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoyl chloride was obtained according to a similar procedure to that described in Example 1-(12).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[CH2:32]([NH:34][C:35](=[O:36])[O:14][C:12]1[C:11]([CH3:15])=[C:10]2[N:9]([CH:13]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=1[F:1])[CH3:33]
Reactant: CCN=C=O
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (25 mg, 0.082 mmol, Compound F of Example 1), DIEA (0.017 mL, 0.1 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.078 mL, 0.1 mL) and stirred at room temperature for 2 h. The reaction was quenched with water (5 mL). The organic layer was separated, dried and concentrated in vacuo. The mixture was purified by flash chromatography (1-5% Methanol/CH2Cl2) to give the title compound (12.5 mg, 32%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:32][O:33][C:34]1[C:35]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:44]=2[CH2:53]Br)=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:53][C:44]3[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:43]=3[C:35]3[CH:36]=[C:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one) (46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3 mL) was added. NaHMDS (296 μL of a 1M solution in THF, 0.296 mmol) was added and the reaction was stirred for 5 min. At this time, 2′-(bromomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl methyl ether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2 mL). After 30 min, the reaction was quenched with saturated NH4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The organic layer was washed with water (15 mL), and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}4-methyl-1,3-oxazolidin-2-one. Rf=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H), 3.25-3.74 (m, 4H), 2.88 (m, 1H), 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C=O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:14][CH:15]=1
Reactant: Clc1ccnc2ccccc12
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc2c(c1)ccn2-c1ccnc2ccccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
9 g (76.3 mmol) of 1H-pyrrolo[2,3-b]pyridine were added with stirring to 100 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C., and 2.7 g of 75% sodium hydride (84 mmol) were gradually added. After stirring at a temperature in the region of 20° C. for 10 minutes, a solution of 12.5 g (76.4 mmol) of 4-chloroquinoline in 100 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kPa), the residue was taken up in 300 cm3 of water. A first precipitate formed and then a second, which were filtered off. The 2 batches were combined and dissolved in 300 cm3 of dichloromethane. After separating by settling, the organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture. The fractions comprising the expected product were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.6 g of 1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of a white solid. Mass spectrum: EI: m/z=245 M+; base peak m/z=244 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(=O)(=O)(O)O.[CH2:22](O)[CH2:23][CH3:24]>C1C=CC=CC=1.O>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1)[CH2:23][CH3:24]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Into a 50 l enamelled double-walled apparatus equipped with a stirrer and adjusted to azeotropic distillation 7.5 kg (0.125 kmole) of n-propanol, 19 kg of benzene, 25 kg (0.1 kmole) of 4-chloro-3,5-dinitro-benzoic acid and 1 kg of concentrated sulfuric acid are weighed in. The reactor is closed and the content thereof is heated to boiling by means of steam heating. The reaction mixture is heated to boiling (86°-90° C. until no more water leaves the system while the organic phase (a mixture of benzene and n-propanol) is continuously reintroduced into the reactor. Once the distillation of water is completed (5-7 hours) the mixture is cooled below 20° C., the precipitated crystals are isolated by centrifugation, washed with cold benzene and dried. Thus 25.4 kg of the desired compound are obtained, yield 88%, purity 97%.