Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].C(OC(C)C)(=O)C.II>O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Agent: II
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 77.1 %

Procedure:
Into a reactor, equipped with a reflux condenser and under inert gas, 8-fluoro-2H-chromene-5-carboxylic acid amide (4.94 g; 25.6 mmoles), sodium nitrite (4.4 g; 64 mmoles) and isopropyl acetate (40 ml) were charged. The mixture was kept under mechanic stirring and heated at 50° C. In one portion iodine (1.9 g; 7.5 mmoles) and then, in 3 hours, Oxistrong 15® (6 ml) were added. At the end of the addition the reaction mixture was kept under stirring for 1 hour and cooled to 20° C. After addition of water (30 ml), the mixture was further cooled at 5° C. for 1 hour. The solid was filtered and washed with isopropyl acetate (3×10 ml), pre-cooled at 0° C., and with water (2×10 ml). After drying in oven under vacuum at 50° C. overnight, 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (4.7 g; HPLC titre 90%; 70% yield) was obtained. The mother liquors of the reaction were treated with a 15% solution of sodium metabisulphite (20 ml) up to decoloration. The phases were separated, the organic phase was dried and the organic solvent was removed under reduced pressure obtaining a solid (0.8 g) containing 49% of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide. Overall yield: 76.4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:30][CH:31]=[C:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[N:42][C:37]=3[CH2:36][O:35][C:34]3[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]2=3)[CH2:13][CH2:12]1
Reactant: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzoic acid methyl ester (0.23 g, 0.916 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% Methanol) to yield the title compound.
Reaction SMILES: O[C@H:2]([CH2:35][CH3:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C@@H:2]1[O:6][C:5]([C:7]2[NH:8][C:9]([C:12]3[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=3)=[CH:10][CH:11]=2)=[N:4][CH2:3]1)[CH3:36]
Reactant: CC[C@@H](O)CNC(=O)c1ccc(-c2cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2)[nH]1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H]1CN=C(c2ccc(-c3cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c3)[nH]2)O1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
N-[(2R)-2-Hydroxybutyl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.01 g, 1.95 mmol) synthesized in Example (106d) was dissolved in tetrahydrofuran (40 mL), and anhydrous methanesulfonic acid (600 mg, 3.44 mmol) and triethylamine (1.60 mL, 11.48 mmol) were added, followed by stirring at 50° C. for 8 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-70%) to afford the desired compound (980 mg, yield 100%) as a yellow solid.
Reaction SMILES: C1COCC1.[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH:9][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)=[O:25]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1I
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To a 100 mL of anhydrous THF in a 250 mL round bottom flask containing a stirring bar, 2-iodo-4-bromoaniline (2.00 g, 6.70 mmol) was added along with 3-trifluoromethylphenylisocyanate (1.51 g, 7.00 mmol) and 52 mg of pyridine. The resulting solution was heated at 65° C. overnight. THF was removed by rotary evaporation and the product was recrystallized from ethyl acetate to give 3.0 g (92%) of 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: C([O-])C.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](#[N:18])[CH:16]=[CH2:17].Cl>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH2:17][CH2:16][C:15]([NH2:18])=[N:8]2)[CH:10]=1
Reactant: NNc1cccnc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NN(c2cccnc2)CC1
Temperature: 20 °C
Yield: 73.5 %

Procedure:
To a 4-neck, round bottomed flask (250 mL) was charged sodium ethanolate (21 wt % in ethanol, 32 mL). 3-Hydrazinopyridine-dihydrochloride (5.00 g, 27.5 mmol) was added, causing an exotherm from 20° C. to 58° C. The mixture was allowed to cool to 20° C. and acrylonitrile (2.91 g, 54.9 mmol) was added. The reaction was heated at 60° C. for 5 hours and cooled to 20° C. The excess sodium ethanolate was quenched with hydrochloric acid (4 M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at <20° C. The mixture was adsorbed on silica gel (10 g) and the crude product was purified by flash column chromatography using 0-10% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to dryness to afford the title compound as a yellow solid (3.28 g, 74%): mp 156-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=2.8, 0.8 Hz, 1H), 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.22 (ddd, J=8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.20 (s, 2H), 3.70 (t, J=9.3 Hz, 2H), 2.92 (t, J=9.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74; ESIMS m/z 163 ([M+H]+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(O)C>[N+:36](=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:6])=[N-:37]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of O-acetoacetyl-N-trifluoroacetyl-L-serine (232 mg) and triethylamine (0.41 ml) in ethanol (7 ml) was added p-toluenesulfonyl azide (193 mg) at 0° C. The mixture was stirred for an hour at 0° C. and for 4 hours at room temperature. The solvent was distilled off in vacuo and the residue was diluted with chloroform and washed successively with aqueous acetic acid, water and brine. After drying over sodium sulfate, the chloroform extract was filtered and concentrated. The residue was flash chromatographed on silica gel (10 g) eluting successively with chloroform and a 1:9 mixture of methanol and chloroform to give O-(2-diazo-1,3-dioxobutyl)-N-trifloroacetyl-L-serine (193 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4]Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]>COCCOC.C(O)C>[Cl:1][CH2:2][C:3]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Solvent: CCO
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1,3-dichloropropan-2-one (1.40 g, 11 mmol) in 1,2-dimethoxyethane (5 mL), pyridin-2-amine (0.94 g 10 mmol) was added. The solid dissolved immediately and a white precipitate was observed. The mixture was stirred at room temperature for 1 h, and then was cooled to 0° C. for 20 min. The resulting mixture was filtered to give a white solid. The precipitate was suspended in ethanol (EtOH) (40 mL) and heated at reflux to render a clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous NaHCO3 solution was added to adjust the pH to ˜7.0. A white suspension formed during the course of addition. The resulting mixture was stirred for 20 min and then filtered to give the title compound as a white solid (0.5 g, 30% yield). ESI MS: m/z 167 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=6.8 Hz, 1H), 7.97 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 6.88 (t, J=6.4 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[N:25]=2)([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:38]=[CH:39][C:40]([NH:41][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:42][CH:43]=3)[N:25]=2)([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Phenyl chloroformate (0.482 mL, 3.83 mmol) was added dropwise to 4-[4-[2-(4-fluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.8 g, 3.83 mmol) and sodium bicarbonate (0.482 g, 5.74 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired material as a white solid (2.26 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(OCC)(=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>[Cl-].[Na+].O>[O:21]1[CH2:22][CH2:23][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccnc(N2CCOCC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Methyl 2-chloroisonicotinate (320 mg, 1.89 mmol) was dissolved in morpholine (5 mL) and stirred at 90° C. for 4 hours. The reaction mixture was added with saturated brine and ethyl acetate, and the organic layer was separated, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain methyl 2-morpholinoisonicotinate (50 mg, 98%).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CN1C(=O)CCC1>[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(5-hydroxy-2-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (290 mg), pyridine (1 mL), and NMP (3 mL) at 50 C, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 3 hours. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) and then further fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (210 mg).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:46][CH2:47][C@H:42]([C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:43][CH2:44]3)[C:50]=2[C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH3:74])=[CH:68][CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@]4(C)COC(=O)N4)ccc23)cc1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@@](C)(N)CO)ccc23)cc1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 35% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS; m/z=459.45 [M−16]+. 1H NMR (MeOD) δ: 7.91-7.95 (m, 1H), 7.83-7.88 (m, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.44-7.49 (m, 1H), 7.37 (s, 1H), 7.19-7.26 (m, 2H), 7.01-7.07 (m, 2H), 4.10-4.19 (m, 2H), 3.98-4.07 (m, 1H), 3.73 (d, J=10.8 Hz, 1H), 3.69 (d, J=11.0 Hz, 1H), 1.97-2.04 (m, 2H), 1.75-1.82 (m, 2H), 1.52 (s, 3H), 1.48 (t, J=6.9 Hz, 3H), 1.14-1.23 (m, 2H), 0.96-1.12 (m, 3H), 0.87 (s, 9H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:19]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH2:35][CH2:36]OS(C)(=O)=O)[CH:26]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:19]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH2:35][CH2:36][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:26]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCn1cc(C2=C(c3cc(OCc4ccccc4)cc4ccoc34)C(=O)NC2=O)c2ccccc21
Reactant: C1CCNC1
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2cc(OCc3ccccc3)cc3ccoc23)=C1c1cn(CCCN2CCCC2)c2ccccc12
Temperature: 55 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Dissolve methanesulfonic acid 3-{3-[4-(5-benzyloxybenzofur-7-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]indol-1-yl}propyl ester (220 mg, 0.39 mmol) and pyrrolidine (411 mg, 5.78 mmol) in 1-methylpyrrolidine (6 ml) and heat to 55° C. for 5 hours. Allow the reaction to cool to room temperature and stir overnight. Dilute the reaction in ethyl acetate, wash with water and brine, and dry with magnesium sulfate. Purification by flash chromatography gives the title compound (200 mg, 95%). MS(ES+): 546.13.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 21.73 mmol), triethylamine (4.39 g, 43.38 mmol), 3-phenylpropanoyl chloride (3.67 g, 21.76 mmol) in dichloromethane (50 mL). The resulting mixture was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with 3×50 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH2:13]1CCN2C(=NCCC2)C[CH2:14]1.[Br-].C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=C>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:7]=1[CH:8]=[CH:13][CH2:14][O:10]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(F)c(C=O)c1O
Agent: C=C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)c2c1OCC=C2
Yield: 35.1 %

Procedure:
6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32 g, 19 mmol) was dissolved in acetonitrile (20 ml) and DBU (2.97 ml, 19 mmol) was added followed by vinyltriphenylphosphine bromide (7.2 g, 19 mmol). The reaction mixture was heated under reflux for 48 h, diluted with water and extracted with ether (3×50 ml). The organic phase was washed with water, 10% sodium hydroxide, water and brine and evaporated in vacuo. The residue was submitted to column chromatography (silica gel, EA:Hex, 1:20) yielding 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: Fc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Ferric chloride (0.5 g) was added to a mixture of 4-bromo-3-fluoro-benzenesulfonyl chloride (2.5 g) and fluorobenzene (3 ml) and then stirred at reflux for 18 hours. The flask was cooled to room temperature and the residue was partitioned between aqueous NaHCO3 and DCM. The DCM layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from ethanol to give buff coloured crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=2[CH:45]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:3][CH:2]2[O:1][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=3[CH:45]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21

Procedure:
Analogously to Method D, 5.25 g of benzyl 3-hydroxy-4-(4-methoxycarbonylphenyl)piperidine-1-carboxylate and 0.572 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.28 (2:1 EtOAc-heptane). Rt=5.06.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25](O)=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:15])[N:2]([NH:1][C:25](=[O:26])[CH2:24][C:19]3[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=3)[N:11]=2)[CH2:13][CH2:14]1
Reactant: Nn1nc(C2CC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CC2)c2ccccc2c1=O

Procedure:
The product from Example 22B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.94 (m, 2H) 0.93-1.09 (m, 2H) 2.42-2.55 (m, 1H) 3.73 (s, 2H) 6.95-7.29 (m, 3H) 7.92 (t, J=7.63 Hz, 1H) 7.98-8.13 (m, 1H) 8.32 (d, J=7.93 Hz, 2H) 11.56 (s, 1H); MS (ESI) m/z 356 (M+H)+.