Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:35]([C:27]3[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:40])[CH:26]=3)(=[O:37])=[O:36])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of (5-amino-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (125.0 mg, 0.38 mmol) and 3,5-di-(trifluoromethyl)benzene-1-sulfonyl chloride (0.117 g, 0.38 mmol) in dry tetrahydrofuran (5 mL) was added diisopropylethylamine (0.2 mL, 0.94 mmol) at 0° C. under nitrogen. After 2 hours of stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The collected organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in hexane) gave [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (163.2 mg, 71%). MS cald. for C24H23ClF7NO5S 605, obsd. 604 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:18][C:19]#[N:20]
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of 14.99 g of 2-chloro-4-(3-chlorophenoxy)phenol, 4.44 g of chloro acetonitrile and 8.94 g of potassium carbonate in 150 ml dimethylformamide was stirred at a temperature of 70° to 80° C. in an oil bath for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with 100 ml of ethyl acetate. The extracts were conbined together, washed twice with 200 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 14.0 g of [2-Chloro-4-(3-chlorophenoxy)phenoxy] acetonitrile as a crude product.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=2)=[O:9].[OH-].[Na+].C1(CBr)CC1>O.CN(C)C=O>[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH2:2][CH:3]1[CH2:5][CH2:4]1)[CH:13]=2)=[O:9]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Agent: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a tetrahydrofuran (8 mL) solution of 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (395 mg, 2.07 mmol) described in Production Example 73-1-1 was added 5 N aqueous sodium hydroxide solution (414 μL, 2.07 mmol), which was concentrated under a reduced pressure. To an N,N-dimethylformamide (8 mL) solution of the residue was added cyclopropylmethyl bromide (241 μL, 2.48 mmol) at room temperature followed by stirring at room temperature for 12 hours. Moreover, after stirring at 50° C. for 4 hours, water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (297 mg, 59%) as a white solid.
Reaction SMILES: C(O[CH2:5][C:6]1[C:7]2[N:8]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=O)C.[SH:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>Br.C(O)(=O)C>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]([CH2:5][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC(=O)OCc1cccn2c(C)c(C)nc12
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2c(CSc3nc4ccccc4[nH]3)cccn2c1C
Temperature: 25 °C
Yield: 106.4 %

Procedure:
A mixture of 2.0 g (12 mmole) of 3-(acetoxymethyl)-2-pyridinamine, 1.7 g (17 mmole) of 3-chloro-2-butanone, and one crystal of potassium iodide was heated at 100° for 4.5 hours. The mixture was allowed to cool and was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid was triturated with diethyl ether and collected by filtration to yield 738 mg of 8-(acetoxymethyl)-2,3-dimethylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C12H14N2O2 : C, 66.04; H, 6.47; N, 12.84. Found: C, 66.01; H, 6.38; N, 13.05.] A mixture of 700 mg (3.2 mmole) of 8-(acetoxymethyl)-2,3-dimethylimidazo[1,2-a]pyridine and 482 mg (3.2 mmole) of 2-mercaptobenzimidazole in 10 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Spinning disk chromatography on silica gel (using 1% by volume ethanol-dichloromethane as eluent) yielded 1.05 g of the title compound Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Cl[CH2:16][CH2:17][C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C1COCC1>[F:2][C:3]([F:13])([F:14])[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:17][C:18](=[O:19])[NH:12]2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)CCCl
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
The compound was prepared according to Rees and Tsoi Chem. Commun. 2000, 415. A suspension of (4-trifluoromethoxyphenyl)-hydrazine hydrochloride (300 mg, 1.32 mmol, 1.00 eq), 3-chloropropionyl chloride (167 mg, 1.32 mmol, 1.00 eq), and PS-DIEA (1.30 grams (g), 5.28 mmol, 4.00 eq) in THF (20 mL) was stirred at ambient temperature for 12 h. The solution was then filtered, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (120 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-hexyloxyethoxy)phenyl borate (190 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give 7-[4-(2-hexyloxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 107) (200 mg).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: Nc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(N)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 53.9 %

Procedure:
157 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 242 mg of 4-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 119 mg of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15](=[O:27])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][C:8]=1[N+:37]([O-:39])=[O:38])C.[OH-].[Na+]>CCO.O.CCOC(C)=O.Cl>[C:29]([NH:28][C@H:14]([C:15](=[O:27])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([N+:37]([O-:39])=[O:38])[CH:9]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)COc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
A mixture of {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-nitro-phenoxy}-acetic acid ethyl ester of Step E (0.124 g, 0.226 mmol) in EtOH (2 mL) is treated with 0.5 mL of 2 N NaOH. After 1.5 h, the reaction is diluted with water, EtOAc, and 10% HCl. The layers are separated and the organic layer washed with water, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to provide {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-nitro-phenoxy}-acetic acid which is used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)([CH3:38])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (45 mg, 0.092 mmol) in tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (0.154 mL, 0.462 mmol). The mixture was stirred at room temperature for 30 min. Additional methylmagnesium bromide (0.100 mL, 0.300 mmol) was added at 0° C., and the mixture was stirred at room temperature for another 30 min. The reaction was quenched with water (10 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (20.9 mg, 0.041 mmol, 44.1% yield) as a pale yellow solid. LCMS (M+H)+=504.0. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.74 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 7.98 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.24 (m, 1H), 5.12 (s, 1H), 1.83 (s, 3H), 1.50 (s, 6H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:13]([O-])=O.[Na+].[S:17](=[O:19])=[O:18]>Cl.C(O)(=O)C>[NH2:13][S:17]([C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:19])=[O:18]
Reactant: O=S=O
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1Cl
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
To methyl 5-amino-2-chlorobenzoate (16.2 g) in concentrated hydrochloric acid (40 ml)/acetic acid (120 ml) suspension, a sodium nitrite (7.6 g) aqueous solution (20 ml) was added under ice cooling and the mixture was stirred at that temperature for 45 minutes. Next, the inside temperature of the reaction vessel was cooled to −5° C., copper (II) chloride 2-hydrate (3.7 g) and a 21% sulfur dioxide in acetic acid solution (60 ml) were added, and the mixture was raised to room temperature and stirred at 12 hours. Under ice cooling, distilled water was added to the reaction solution, the mixture was stirred at that temperature for 30 minutes, and the precipitate was collected by filtration. The filtrate was dissolved in tetrahydrofuran (50 ml), 28% ammonia water (10 ml) was added under ice cooling, and the mixture was stirred at that temperature for 15 minutes. The tetrahydrofuran was distilled off in vacuo, then ethyl acetate/hexane was added. The precipitate was collected by filtration to obtain the title compound (10.9 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:40].[OH-]>O1CCOCC1>[NH2:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)C[C@H](C)O1
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(N)n3)s2)C[C@H](C)O1
Temperature: 100 °C
Yield: 75 %

Procedure:
In a pressure vessel was placed N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.30 g, 0.503 mmol) and NH4OH (3 mL, 77 mmol) and 1,4-dioxane (3 mL) were added. The vessel was sealed and heated at 100° C. for 18 h. The reaction was cooled, concentrated onto silica and the residue was column chromatographed to give the title compound was obtained (0.22 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (br. s., 1H), 7.82 (d, J=5.3 Hz, 1H), 7.46-7.65 (m, 3H), 7.37-7.46 (m, 1H), 7.27 (t, J=6.7 Hz, 2H), 6.54 (br. s., 2H), 5.62 (d, J=5.3 Hz, 1H), 3.77 (d, J=12.2 Hz, 2H), 3.60-3.73 (m, 2H), 2.73 (t, J=11.6 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 577 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13](N1CCOCC1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:28].[K+]>C(O)(C)C>[CH2:1]([O:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13]([OH:14])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC(OCc1ccccc1)c1ccc(F)cc1)N1CCOCC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)CCCC(OCc1ccccc1)c1ccc(F)cc1
Yield: 79.9 %

Procedure:
10 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-1-morpholin-4-yl-pentan-1-one was added to 100 ml of isopropyl alcohol and 7.5 gms of potassium hydroxide. Heated the reaction mass at reflux temperature and maintain for about 36 hours and distilled off solvent completely. To the obtained oily mass 60 ml of water was added and washed with dichloromethane. Layers were separated and acidify the aqueous layer with hydrochloric acid and adjusted the pH to 2.0. The obtained aqueous layer was extracted with dichloromethane and dried the organic layer over sodium sulphate followed by concentration. 6.5 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-pentanoic acid was isolated in heptane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]#[N:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=O)cc3c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C#N)cc3c2)cc1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (840 mg), pyridine (0.23 mL) and N,N-dimethylformamide (20 mL) was added dropwise oxalyl chloride (0.25 mL) under ice-cooling, and the mixture was stirred for 2 hr. Pyridine (0.23 mL) and oxalyl chloride (0.25 mL) were successively added, and the mixture was further stirred for 30 min. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of diethyl ether-hexane to give the title compound (660 mg, yield 92%) as yellow crystals. The obtained yellow crystals were recrystallized from ethanol-hexane to give yellow crystals. melting point 209-210° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:58]1[CH:62]=[C:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=2)[N:60]=[CH:59]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:72]CCl>>[ClH:72].[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:60]3[C:61]([CH2:63][C:64]4[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=4)=[CH:62][N:58]=[CH:59]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: ClCCl
Reactant: OCc1ccc(-c2ccccc2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccc3)nc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-phenyl-5-hydroxymethylpyridine (264 mg, 1.43 mmol) and diisopropylethylamine (0.522 mL, 3.00 mmol) in dichloromethane (10 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.252 mL, 1.50 mmol) and the mixture stirred at -78° C. for 15 minutes. To this mixture was added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (608 mg, 1.43 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-5% NH4OH in CH2Cl2). The amine was converted to the HCl salt by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid. FAB MS 351 (MH+)
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC[C@H](NCc1ccccc1)C(=O)O
Solvent: O
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Yield: 98.9 %

Procedure:
N-Benzyl-glutamic acid (35 g) was dissolved in 300 ml of water and refluxed for 15 hours. The solution was extracted with methylene chloride, washed with brine, dried over sodium sulfate and concentrated to yield 32 g of N-benzyl-5-oxo-proline. The acid (55.25 mmoles, 12.1 g) was dissolved in 15 ml of DMF and 30 ml acetonitrile. The solution was cooled to -25° C. Oxalyl chloride (5.0 ml) in 10 ml acetonitrile was added. The solution was stirred vigorously for 30 minutes. A solution of t-butanol (135 mmoles, 10.0 g) and pyridine (13.2g) in 10 ml acetonitrile was added over 30 minutes and then warmed to 0° C. Brine and ethyl acetate were added. The organic phase was diluted and washed with water, dried and concentrated to yield 10.7 g of N-benzyl-5-oxo-L-proline t-butyl ester. (MS)