Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].Cl[CH:4]([O:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[CH3:5]>CC#N>[I:1][CH:4]([O:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[CH3:5]
Reactant: [I-]
Reactant: CC(Cl)OC(=O)C(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)C(C)C
Reaction time: 6.5 h
Yield: 45.8 %

Procedure:
Sodium iodide (4.5 g, 29.43 mmol) was dissolved in CH3CN (13 mL). Compound 13 (2.16 g, 14.4 mmol) and CH3CN (5 mL) were added and stirred for 6.5 hours. After filtering and concentrating, the reaction solution was diluted with ether (10 mL) and then re-concentrated to give 1.597 g of isobutyric acid 1-iodo-ethyl ester 14 (Yield: 46%). 1HNMR (CDCl3, 500 MHz) δ1.16-1.21 (m, 6H), 2.20 (d, J=5.5 Hz, 3H), 2.45-2.61 (m, 1H), 6.86 (q, J=6.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC1c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 7 (390 mg, 2.0 mmol) in MeOH (5 mL) was added 2N NaOH (5 mL) slowly. The reaction solution was stirred at room temperature for 2 h then diluted with H2O (25 mL). After extraction with ether (20 mL), the aqueous layer was acidified with 2N HCl (2.1 mL). The resulting solution was extracted with ether (3×40 mL). The combined organic layers were dried over MgSO4 and concentrated to give 8 (325 mg, 1.8 mmol, 99%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.87-0.91 (dd, J=6.0, 13.5 Hz, 1H), 1.21-1.29 (m, 1H), 1.39-1.43 (ddd, J=5.0, 6.5, 8.0 Hz, 1H), 1.67-1.72 (m, 1H), 1.90-1.94 (m, 1H), 2.58-2.63 (m, 1H), 6.79-6.82 (dd, J=2.0, 5.5 Hz, 1H), 6.90-6.95 (m, 2H), 7.24-7.28 (m, 1H), 8.90-11.00 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 17.8, 24.4, 26.9, 31.8, 113.3, 113.5, 113.8, 114.0, 122.30, 122.32, 130.2, 130.3, 142.4, 142.5, 162.2, 164.2, 179.8; LCQ-MS (M−H+) calcd for C10H8FO2 179. found 179.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[CH:17]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:22][C:23](/[N:10]=[C:8]2\[S:9][C:5]3[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=3[N:7]\2[CH2:11][CH2:12][O:13][CH3:14])=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Agent: Br
Product: COCCn1/c(=N/C(=O)CC2CCCC2)sc2cc(F)ccc21

Procedure:
The product from Example 113A and cyclopentylacetyl chloride were processed as described for example 11 to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.54 (d, J=5.76 Hz, 2H) 7.65 (t, J=8.14 Hz, 1H) 7.75 (dd, J=8.81, 2.71 Hz, 1H) 7.83 (dd, J=7.97, 1.53 Hz, 2H) 7.97 (dd, J=8.14, 1.36 Hz, 1H) 8.41 (d, J=3.05 Hz, 1H); MS (ESI+) m/z 337 (M+H)+; Anal. Calculated for C17H21FN2O2S: C, 60.69; H, 6.29; N, 8.33. Found: C, 60.67; H, 6.41; N, 8.25.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:24])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]2[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:21])[CH3:20])[NH:3][N:2]=1)=[O:24])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCC1C(C)CCCC1(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCC2C(C)CCCC2(C)C)[nH]n1
Yield: 31.7 %

Procedure:
Hydrazine hydrate (0.867 mL, 17.9 mmol) was added to a stirring room temperature solution of 52 (5.2981 g, 17.9 mmol) in EtOH (17.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 97:3 Hexanes:2N NH3 in EtOH) to obtain 1.6604 g (31.8%) of 53. Partial 1H (CDCl3, 400 MHz): δ 12.45 (1H, broad s), 6.58 (1H, s), 4.32 (2H, q, J=7.1 Hz), 2.63 (2H, t, J=8.3 Hz), 1.31 (3H, t, J=7.1 Hz), 0.90 (3H, s), 0.83 (3H, s), 0.78 (3H, d, J=6.8 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 106.04, 60.66, 48.99, 34.03, 30.10, 24.89, 14.17 ppm. HPLC: 12.000 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([Cl:17])=[C:8]2[C:3]=1[C:4](=[O:18])[CH2:5][CH2:6][S:7]2.[BH4-].[Na+].O>C(O)C>[OH:18][CH:4]1[C:3]2[C:8](=[C:9]([Cl:17])[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reaction time: 1 h
Yield: 106.8 %

Procedure:
13.0 Grams (45.7 mmol) of 5-methyl-6-ethoxycarbonyl-8-chlorothiochroman-4-one was dissolved in 50 ml of ethanol, and 1.73 g (45.7 mmol, 1 eq.) of sodium borohydride was added with an ice bath cooling. The reaction mixture was stirred for 1 hour. After the completion of the reaction, 20 ml of water was added, and the solvent was distilled off. Then, the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 14.0 g (yield 100%) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([N:9]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Yield: 18.5 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (3.60 g, 20.2 mmol) was added to a suspension of 5-aminoindole (2.53 g, 19.1 mmol) in ethanol (30 ml) and the mixture heated at reflux for 16 h. The mixture was allowed to cool, sodium carbonate (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 h. The mixture was allowed to cool, filtered and the filtrate evaporated. The residue was dissolved in 1M hydrochloric acid (100 ml) and extracted with dichloromethane (2×50 ml). The aqueous phase was made basic with 4M sodium hydroxide (30 ml) and extracted with ethyl acetate (2×100ml). The extracts were washed with brine (100 ml), combined and dried (MgSO4). The residue from evaporation of the extracts was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia, to give 1-(5-indolyl)piperazine (0.71 g, 18%), as a cream solid; δH (DMSO-d6) 2.94 (4H, m, 2×piperzinyl CH2), 3.00 (4H, m, 2×piperazinyl CH2), 6.29 (1H, m, 3-H), 6.84 (1H, dd, J 9.0,2.0 Hz, 6-H), 7.00 (1H, d, J 2.0 Hz, 2-H), 7.24 (2H, m, 4-H, 7-H), and 10.82 (1H, br s, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[S:38][C:37]([C:39](O)=[O:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:37]4[S:38][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(S(C)(=O)=O)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (44.3 mg, 0.21 mmol)
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)c1ccccc1Oc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
At 0° C., a solution of N-methyl-2-phenoxybenzamide (22.2 g, 97.7 mmol) in THF (175 ml) was added dropwise to a suspension of sodium borohydride (9.20 g, 244 mmol) in THF (100 ml). The reaction mixture was stirred at 0° C. for 20 min. A solution of iodine (24.8 g 97 mmol) in THF (125 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol 500 ml was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia as eluent, to give 3.04 g of N-methyl-N-(2-phenoxybenzyl)amine.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-].[Na+].[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(Sc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The starting material is prepared as follows: The mixture of 19.6 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 280 ml of N aqueous sodium hydroxide and 11.8 g of 4-acetamidothiophenol is stirred for 24 hours at room temperature under nitrogen. It is filtered, the filtrate made strongly acidic with concentrated hydrochloric acid, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-nitro-5-sulfamoylbenzoic acid, melting at 168°. 8.2 g thereof are added portionwise to the mixture of 16 g of iron powder, 1.7 g of ammonium chloride, 70 ml of water and 0.8 ml of N hydrochloric acid while stirring. After heating it for 4 hours at the steam bath it is filtered hot, the precipitate taken up in 200 ml of N aqueous sodium hydroxide and the solution filtered. The filtrates are acidified with concentrated hydrochloric acid and the precipitate formed recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid melting at 207°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
Commerically available 2-chlorobenzoic acid (80.0 g), (0.5 mol), was added portionwise to chlorosulphonic acid (320 g) with vigorous stirring. The reaction was heated to 95° C. for 6 hrs then cooled overnight to room temperature. The solution was quenched onto ice/water (1.5 kg/324 ml) and stirred for 15 min. The precipitated product was filtered, water washed and dried at 50° C. in vacuo, to give the title compound (111.1 g, 85.2%) as a white solid with m.p. 140° C. δ (CDCl3): 7.42 (1H,m), 8.27 (1H,m), 8.75 (1H,m).
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(O)C>[OH:9][C:8]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH3:12])[CH:14]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Cn1ccc2ccccc21
Solvent: O
Solvent: CCO
Product: Cn1cc(C2(O)C(=O)NC(=O)NC2=O)c2ccccc21

Procedure:
Alloxan hydrate (1.6 g., 0.01 mole) 1-methylindole (1.3 g., 0.01 mole) and ethanol (50 ml.) was combined and the mixture refluxed for 0.5 hour, then concentrated to half-volume, diluted with water and the resulting product recovered by filtration [2.7 g., Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].N([O-])=[O:18].[Na+]>Cl>[C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Agent: Cl
Agent: [Na+]
Product: CC(=O)N1CC2CC2(c2ccc(O)cc2)C1

Procedure:
A solution of 3-acetyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane in 8N hydrochloric acid is diazotized at 0° C, with aqueous sodium nitrite. The solution is then allowed to stand at ambient temperature until the evolution of nitrogen ceases. This mixture is then extracted with ether, and the extract is dried over sodium sulfate, filtered and then evaporated under reduced pressure to give 3-acetyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH2:18][O:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:19][CH2:18][CH2:17][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:22][CH:23]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: OCCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a refluxing mixture of 1.05 g (0.0081 mol) N-(2-hydroxy-ethyl)piperazine, 0.75 g (0.0054 mol) dry potassium carbonate and 5 ml toluene, a solution of 0.76 g (0.0027 mol) 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene in 3 ml toluene was added dropwise. The reaction mixture was refluxed for 11 h and then cooled to room temperature. It was diluted with toluene (100 ml) and extracted with 2N hydrochloric acid (100 ml). The acidic extract was washed with one portion of toluene, then rendered basic by addition of 4N sodium hydroxide solution (75 ml) and extracted with toluene (100 ml). The toluene solution was washed successively with two portions of water and once with brine. Evaporation in vacuo gave a yellowish oil, which was redissolved in acetonitrile (20 ml). The title compound was precipitated as the dimaleate salt with an excess of a maleic acid solution in acetonitrile. By recrystallization from hot acetonitrile/methanol 1.29 g (78% of the theoretical yield) of the title compound was obtained as white crystals, m.p. 163° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:12]([O:14]C(=O)OCC)C.CC(C)([O-])C.[K+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12](=[O:14])[CH:9]=[C:8]2[OH:10]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.7 %

Procedure:
1-(5-Fluoro-2-hydroxy-phenyl)-ethanone (1.54 g, 10 mmol) and diethylcarbonate (2.42 mL, 20 mmol) were placed in a dry flask and dissolved in anhydrous tetrahydrofuran (30 mL.) The solution was then added drop-wise via cannula to a rapidly stirring solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 30 mL) The reaction was permitted to stir overnight (10 h) at room temperature under positive pressure of nitrogen. The crude reaction was concentrated under reduced pressure and partitioned between methyl tert-butyl ether and water. The layers were separated and the organic phase discarded. The aqueous phase was acidified to pH 5 and extracted three times with equal volumes of methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated to give the title compound (1.4 g, 78% yield.) MS ESI(−) m/e: 179.16 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][C:22]4[C:21]5[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=5)[N:25]=[CH:24][CH:23]=4)=[CH:33][CH:34]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 22.5 °C
Reaction time: 10 h

Procedure:
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-m-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.18 g (95%) of the 9-[(3-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ7.65 (dd, 1H, J=1 and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J=8 Hz), 7.0 (s, 1H), 6.85 (d, 1H, J=8 Hz), 5.5 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.3 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288, 1174, and 1119. MS (ES) m/e 348.5.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.[I:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[I:13][C:12]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COCc1cn2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
[step 3] To 2-(methoxymethyl)imidazo[1,2-a]pyridine (1.8 g, 11 mmol) obtained in step 2 were added DMF (22 mL) and N-iodosuccinimide (2.75 g, 12 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate. Filtration, concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=10/1 v/v) gave 3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (3.1 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[N:21](CC5C=CC(OC)=CC=5)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]>C(#N)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: COc1ccc(CN2CC(C)(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)OC2=O)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CNC(=O)O4)cc3)oc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.1 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[3-(4-methoxybenzyl)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl}benzamide (598 mg, EXAMPLE 65) in 18.0 ml of acetonitrile and 6.0 ml of water was added 1.52 g of ceric ammonium nitrate. The mixture was stirred at room temperature for 15 h, and then concentrated in vacuo. The residue was dissolved in 10 ml of dichloromethane and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 2 column volumes to remove all the impurities. The column was then flushed with methanol (5 column volumes) to provide the title compound (242 mg, 52%) as a white solid. Mass spectrum (ESI) 419.1 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:44]([C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]([C:55]#[N:56])=[CH:47][CH:46]=2)[C:43]([S:57][CH2:58][C:59](O)=[O:60])=[N:42][CH:41]=1>ClCCl>[Br:39][C:40]1[N:44]([C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]([C:55]#[N:56])=[CH:47][CH:46]=2)[C:43]([S:57][CH2:58][C:59]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:60])=[N:42][CH:41]=1
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Glycine ethyl ester hydrochloride (76 mg, 0.541 mmol, 1.2 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.676 mmol, 1.5 equiv.), 1-hydroxy-7-azabenzotriazole (92 mg, 0.676 mmol, 1.5 equiv.) and 2,6-lutidine (0.16 mL, 1.35 mmol, 3.0 equiv) were added to a solution of 2-(5-bromo-1-(4-cyanonaphthalen-l-yl)-1H-imidazol-2-ylthio)acetic acid (175 mg, 0.451 mmol) in dichloromethane (2.25 mL) and stirred at room temperature for 18 hours. The crude product was purified by SGC (0-100% ethyl acetate/hexanes) to afford the title compound containing some 1-hydroxy-7-azabenzotriazole. The impure product was dissolved in ethyl acetate (50 mL), washed with aqueous HCl solution (0.1M, 2×30 mL), saturated aqueous NaHCO3 solution (30 mL), and saturated sodium chloride solution (30 mL). The organics were dried over sodium sulfate, filtered, and concentrated to afford ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetate as a yellow oil (199 mg, 93%).