Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 22 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a freshly prepared sat. solution of hydrogen chloride in methanol (100 ml) was added trans-4-hydroxy-L-proline (10.0 g, 76.26 mmol). The resulting mixture was stirred at 22° C. for 24 h, concentrated in vacuo and triturated with acetone at 0° C. Filtration afforded the title compound (12.8 g, 92%) as a white solid.
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:26])[CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH2:3][CH3:4])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.ClCCl>[CH:1]([NH:5][C:6]([CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)[C:8]([CH3:11])([CH3:12])[CH2:9][O:10][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])([CH2:3][CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Reaction time: 3.5 h

Procedure:
To a stirring solution comprised of two (2) N-sec-butyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-4-hydroxy-3,3-dimethyl-butyramide diastereomers (1.63 g; 4.38 mmol) in pyridine (10 mL) at 0° C. under a nitrogen atmosphere is added methanesulfonyl chloride (0.75 g; 6.5 mmol). The reaction mixture is stirred cold for 3.5 hours. The reaction mixture is diluted with dichloromethane and is washed with 1N aqueous hydrochloric acid and with brine. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo (the water bath temperature is not raised above 23° C.) to afford 1.892 g of a foam; HPLC UV purity: 99.3% (two diastereomers.)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].CCN(CC)CC.Br[CH2:27][CH2:28][Cl:29]>CN(C=O)C>[Cl:29][CH2:28][CH2:27][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:9])=[O:8])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: ClCCBr
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2CCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.3 %

Procedure:
To a stirring solution of 2,3-dihydro-1H-indole-5-sulfonic acid thiazol-2-ylamide (10.0 g, 35.6 mmol), Et3N (5.0 mL, 3.6 g, 35.6 mmol), and DMF (10.0 mL), under N2, was added 1-bromo-2-chloroethane (2.9 mL, 5.1 grams, 35.6 mmol). The solution was stirred at room temperature for 3 days. The mixture was partitioned between water and ethyl acetate. The organic portion was evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 3% MeOH in CH2Cl2 to obtain the desired amine (3.1 g, 9.0 mmol, 25% yield) as a clear oil. 1H-NMR (DMSO-d6) δ 7.39-7.37 (m, 2H), 6.83 (d, J=4.7 Hz, 1H), 6.43 (d, J=7.3 Hz, 2H), 6.28 (s, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.88 (t, J=5.8 Hz, 2H), 3.47 (t, J=8.7 Hz, 2H), 3.33 (s, 1H), 2.94 (t, J=3.7 Hz, 2H). LC/MS (10-99%) M/Z: M+1 obs=344.0; tR=2.88 min.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH3:44]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:36](=[O:45])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43][CH3:44])=[N:3][C:4]([CH3:27])=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)c(C)nc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1SC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccccc1SC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (255 mg, 0.5 mmol) in anhydrous THF (3 mL) was added 2 M isopropylmagnesiumchloride in THF (600 μL, 1.2 mmol) at −40° C. It was then warmed to 0° C. and stirred at the same temperature for 1 h and then N-Methoxy-N-methyl-2-methylsulfanyl-benzamide (422 mg, 1.00 mmol) was added in and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO) to provide 4-chloro-N-[5-chloro-6-methyl-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. Mass spectrum m/z: 601.4 (M+Na).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:18][C:17]1=[O:19]
Reactant: CCOC(N)=O
Reactant: CNc1sccc1C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2F)c2ccsc21
Temperature: 200 °C

Procedure:
A mixture of 500 mg of 2-methylamino-3-(o-fluorobenzoyl)thiophene, 716 mg of ethyl carbamate and 44 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure and, the residue is recrystallized from ethanol to give 1-methyl-4-(o-fluorophenyl)-1,2-dihyrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 221.5° - 222°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:18][OH:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:23][S:20]([O:1][CH2:2][CH2:3][C:4]1([CH2:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(CCO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred solution of tert-butyl 4,4-bis(2-hydroxyethyl)piperidine-1-carboxylate (500 mg, 1.83 mmol) in DCM (10 ml) were added mesyl chloride (0.33 ml, 4.2 mmol) and TEA (1 ml, 7.32 mmol) at −20° C. and the mixture was stirred for 30 min maintaining the same temperature. TLC revealed completion of the reaction and it was quenched with water and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica (100-200), EtOAc-hexane (30%)) to yield the desired compound. Yield: 70%
Reaction SMILES: [C:1]1([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:17]([O:10][C:9]([CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)=[O:11])[CH2:18][CH3:19]
Reactant: O=C(O)CCc1ccc(CCC(=O)O)cc1
Reactant: CCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CCCOC(=O)CCc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,3′-(1,4-phenylene)dipropanoic acid (250 mg, 1.125 mmol) DCM (15 ml) is added 4-dimethylaminopyridine (137 mg, 1.125 mmol) and propanol (3 ml, 40.1 mmol). The solution is cooled to 0° C. and dicyclohexylcarbodiimide (232 mg, 1.125 mmol) is added and the resulting solution is stirred at 0° C. for 30 minutes and 2 hours, at room temperature. Concentration in vacuo affords a white solid which is suspended in Et2O (50 ml) and filtered to remove any insoluble material. The filtrate is concentrated in vacuo and purification by chromatography (SiO2, EtOAc/iso-hexane) affords the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].[ClH:16].[CH2:17]([OH:19])[CH3:18]>>[ClH:16].[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:19][CH2:17][CH3:18])[CH3:2]
Reactant: CCO
Reactant: CCOc1cc(C(F)(F)F)ccc1C#N
Agent: Cl
Product: CCOC(=N)c1ccc(C(F)(F)F)cc1OCC
Temperature: 25 °C
Reaction time: 264 h
Yield: 67 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzonitrile (64 g) was dissolved in 750 mL of anhydrous ethanol. The solution was cooled to 0° C. and saturated with hydrogen chloride gas. The reaction flask was then sealed with a Teflon stopper and stirred at room temperature for 11 d. The progress of the reaction was checked every few days, and the solution was saturated again with hydrogen chloride gas. Nitrogen gas was bubbled through the solution to remove excess hydrogen chloride gas. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2-ethoxy-4-trifluoromethyl-benzimidate hydrochloride (59.5 g, 67% yield) as white solids.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O
Solvent: COCCOC
Product: Cc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-2-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (388 mg, 72%) as a brown solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>C(Cl)Cl>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)=[O:37]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)Cc1cccs1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 88.7 %

Procedure:
Compound (II) (3.1 g, 7.8 mmole), 2-thiopheneacetic acid (1.14 g, 8.0 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmole) were stirred in 50 mL of methylene chloride for 12 hrs. at ambient temperature. The reaction was diluted with methylene chloride, washed with 1N hydrochloric acid, 1N NaOH, water and brine. Purification of the residue obtained on evaporation was accomplished with silica gel chromatography using 50% ethyl acetate in hexanes as the eluent to yield 3.6 g of the title compound as a solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14]C1C=CC(C#N)=C(C(F)(F)F)C=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:14])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(N)=O

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([C@H]1COC(=O)N1[C:23](=[O:43])[C@H:24]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:25][C:26](=[O:33])[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@H:24]([CH2:25][C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:33])[C:23]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)N2C(=O)OC[C@@H]2C(C)C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
7.84 ml (12.5 mmoles) of butyllithium (as a 1.6M hexane solution) were added, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.73 ml (16.7 mmoles) of benzyl alcohol in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for 10 minutes, and then a solution of 3.50 g (8.36 mmoles) of 4(S)-isopropyl-3-[4-oxo-2(R)-(4-methoxybenzyl)-4-morpholinobutyryl]-2-oxazolidinone (prepared as described in Preparation 13) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was then stirred for 30 minutes, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column .chromatography (using a 4:1 by volume mixture of benzene and ethyl acetate as eluent), followed by recrystallization from diisopropyl ether, to give 3.09 g (yield 93%) of the title compound as white crystals, melting at 77°-79° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5](F)[CH:4]=1)#[N:2].Cl.[CH2:18]([NH2:20])[CH3:19].CN(C=O)C>O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([NH:20][CH2:18][CH3:19])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1F
Reactant: CCN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1cc(C#N)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
The product from Example 140 Part A (0.30 g, 1.36 mmol) and ethylamine hydrochloride (0.22 g, 2.72 mmol) were added together with 5 mL of DMF. The mixture was heated at 50° C. under N2 for 2 h. Water was added, and the mixture was extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (silica, EtOAc/hexane) to give 50 mg of the desired product. MS: 247.3 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[C:6](O)=[O:7].B.C1COCC1.Cl>C1COCC1>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][C:11]=1[O:12][C@@H:13]([CH3:18])[C:14]([F:15])([F:16])[F:17]
Reactant: C[C@H](Oc1ccc(C(=O)O)cc1C(F)(F)F)C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(CO)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
To a solution of 3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzoic acid (1.085 g) in THF (43 mL) was added dropwise a solution of BH3.THF in THF (1 M, 14 mL) at 0° C. The reaction mixture was warmed to room temperature and then stirred for 15 hours. To the reaction liquid was added 1 M hydrochloric acid at 0° C. to stop the reaction, followed by stirring for 30 minutes and extracting with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain {3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (570 mg) as a white oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[C:6]=2[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:2][C:3]2[C:11]3[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[C:6]=3[S:5][C:4]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)CCn1c(=O)c2c(CBr)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 40.4 %

Procedure:
To a solution of methyl 3-(5-(bromomethyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (30 mg, 0.064 mmol) in toluene (2 mL) was added (4-chlorophenyl)boronic acid (9.94 mg, 0.064 mmol) and aq. Cs2CO3 solution (1 M, 0.5 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (3 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give methyl 3-(5-(4-chlorobenzyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (13 mg, 40.6% yield) as a white solid. LCMS: MH+ 503 and TR=2.145 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:21]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:22][S:23]([O:20][CH2:19][CH:17]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:21]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:18]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (1.00 g, 3.29 mmol) in dry pyridine (10 mL) at room temperature was added dropwise MsCl (1.23 g, 10.74 mmol) at 0° C. Then the reaction mixture was stirred at room temperature for 2 hours under N2 protection. The reaction was poured into water and filtered. The filter cake was washed with water and dried to provide (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl methanesulfonate (1.20 g, yield: 90.1%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.37˜7.51 (m, 2H), 7.28˜7.33 (m, 2H), 7.18˜7.24 (d, J=8.4 Hz, 1H), 6.9-6.98 (m, 1H), 6.65˜6.72 (m, 1H), 4.46˜4.53 (m, 1H), 4.31˜4.38 (m, 1H), 2.90 (s, 3H). MS (M+H)+: 383.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:41])[CH3:42])=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(NC(=O)c4cccs4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(NC(=O)c4cccs4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 256d (276 mg, 0.462 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (33 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.27-1.35 (m, 6 H), 6.80-6.91 (m, 5 H), 6.99 (d, J=9.19 Hz, 1 H), 7.21-7.25 (m, 1 H), 7.63 (dd, J=8.82, 2.57 Hz, 1 H), 7.81 (d, J=8.46 Hz, 1 H), 7.87 (d, J=4.04 Hz, 1 H), 8.01-8.03 (m, 2 H), 8.82 (s, 1 H), 8.91 (d, J=8.46 Hz, 1 H), 10.39 (s, 1 H) MS (ESI+) m/z 497 (M+TFA+H)+; (ESI−) m/z 495 (M+TFA−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9]S(C)=O)[CH:7]=1.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=O)=[CH:19][CH:18]=1)#[N:16].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:23]([CH:22]=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][CH:25]=3)=[CH:9][C:8](=[O:13])[C:6]=2[CH:7]=1
Reactant: N#Cc1ccc(C=CC=O)cc1
Reactant: CS(=O)CC(=O)c1cc(Br)ccc1O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=Cc2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
A mixture of 3.9 g of 5'-bromo-2'-hydroxy-2-(methylsulfinyl)acetophenone, 2.2 g of p-cyanocinnamaldehyde, 50 ml of toluene and 0.1 ml of piperidine was refluxed for 4 hrs. The mixture was chilled, and the precipitate was filtered and recystallized from DMF, mp 275°-76° ; yield 1 g (20%); λ max mμ (ε) 223 (22,700), 273 (12,900), 330 (41,000); ν max 840 (m), 980 (m), 1280 (m), 1640 (m), 1660 (ms), 2240 (m) cm-1.