Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Br)cc2)n(COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of compound 10b (1.00 g, 3.94 mmol) in DMF (5 mL) was added sodium hydride (200 mg, 5.00 mmol) in portions at 0° C., and the mixture was stirred for 20 min before 2-(trimethylsilyl)ethoxymethyl chloride (730 mg, 4.37 mmol) was added. The reaction mixture was stirred at rt overnight, and was quenched with H2O (50 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:5 v/v) to obtain compound 10c as a yellow solid (600 mg, 40% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22BrN3O2Si: 383.1 (M+H). Found 383.1.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[O:44]=[C:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:58]=1)[C:53](O)=[O:54].[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:92])[C@H:74]([CH2:87][CH2:88][CH:89]([CH3:91])[CH3:90])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:53](=[O:54])[C:52]1[CH:51]=[C:50]([N:46]2[CH2:47][CH2:48][CH2:49][C:45]2=[O:44])[CH:58]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:56]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:92])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH2:87][CH2:88][CH:89]([CH3:91])[CH3:90])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Reactant: CC(C)CC[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC(C)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-2-(3-methyl-butyl)-6-phenyl-hexanoic acid bicyclo[2.2.1]hept-2-ylamide (D33).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:14][S:23]([C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[F:15])(=[O:25])=[O:24])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Cc1nc(N)ccc1COCC1CC1
Product: Cc1nc(NS(=O)(=O)c2cc(F)ccc2F)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.053 g) and 2,5-difluoro-benzenesulfonyl chloride (0.059 g) as a light yellow solid (0.063 g). MS (ESI−): 367.0 ([M−H]−)
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[O:13]1[CH2:17][CH2:16][CH:15](CO)[CH2:14]1.N1C=CC=CC=1.C(N(CC)CC)C.[CH2:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[O:13]1[CH2:17][CH2:16][CH:15]([CH2:7][O:6][C:5]([N:43]2[CH2:44][CH2:45][N:40]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:41][CH2:42]2)=[O:11])[CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: OCC1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(OCC1CCOC1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 251.2 %

Procedure:
To a cooled (0° C.) solution of triphosgene (5.0 g, 17 mmol) in 50 ml dichloromethane under a nitrogen atmosphere was added dropwise a solution of tetrahydro-3-furanmethanol (5.4 g, 53 mmol) in 10 ml dichloromethane. Pyridine (4.3 ml, 53 mmol) was added dropwise, and the solution was warmed to room temperature. After 2 hours at room temperature a mixture of triethylamine (7.5 ml, 52 mmol) and N-benzylpiperazine (9.5 ml, 54 mmol) was added dropwise with cooling. The resulting mixture was refluxed for 1 hour. The solution was stirred at room temperature overnight under an nitrogen atmosphere. The mixture was washed with aqueous sodium bicarbonate solution (5%, 2×50 ml), and with a solution of saturated aqueous NaCl (50 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The residue was co-evaporated three times with toluene (50 ml) to yield 4-benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (13.0 g, 81%) as a brownish oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N+:10]([O-])=[O:11])[C:5]([NH:13][C:14]([C:16]([O:18]CC)=O)=[O:15])=[CH:4][CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]2[C:5]([NH:13][C:14](=[O:15])[C:16](=[O:18])[N:10]2[OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(C#N)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: N#Cc1c(Cl)ccc2[nH]c(=O)c(=O)n(O)c12
Yield: 142.8 %

Procedure:
To a solution of 1.0 g (3.36 mmol) 6-chloro-3-ethoxalylamino-2-nitrobenzonitrile in 75 ml tetrahydrofuran was added 25 ml dimethylformamide and 1.0 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 100 mg 5% Pd-C as a catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid gave 0.57 g (72%) of 7-chloro-8-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. 280° C. decomp H-NMR (DMSO-d6) 12.3 (2H, broad s), 7.5 (2H, s). MS (m/e): 237 (M+, 10%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH2:29])=[CH:26][CH:25]=[CH:24][CH:23]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C.C(=O)(O)[O-].[Na+]>[NH2:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH:18][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc2ccccc2c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1c(NC(=O)c2cccc(C(F)(F)F)c2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 500 mg of 3-trifluoromethylbenzoic acid in 6 ml of anhydrous hexamethylphosphoramide (HMPA) and 0.6 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 380 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water, and dried to give 780 mg of 4-amino-3-(3-trifluoromethylbenzoylamino)quinoline B1 as a crude product. It is suspended in 15 g of polyphosphoric acid and heated at 120° C. for 4 hours with stirring. The mixture is poured into ice-water and neutralized with 1N sodium hydroxide. The resulting solid is filtered, washed with water and dried. It is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent, yielding 350 mg (47%) of C1 as colorless crystals.
Reaction SMILES: [CH:1]1([C:6](=[O:17])[CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21]>>[CH:1]1([C:6]2([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[O:17][C:18](=[O:23])[CH2:19][C:20](=[O:21])[CH2:22]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SCC(=O)C2CCCC2)cc1
Reactant: COC(=O)CC(C)=O
Product: COc1ccc(SCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1

Procedure:
1-Cyclopentyl-2-(4-methoxy-phenylsulfanyl)-ethanone (from Step 2 below) was subjected to the methyl acetoacetate dianion addition reaction described in the synthesis of Example A(82), to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc2c(cc1OC)C(=O)C(=CC1CCN(Cc3ccccc3)CC1)C2

Procedure:
According to the process disclosed in U.S. Pat. No. 4,895,841, 5,6-dimethoxy-1-indanone was condensed with 1-benzyl-4-formylpiperidine in the presence of lithium diisopropylamide to give 5,6-dimethoxy-2-[[1-benzyl-4-piperidinyl]methylene]-1-indanone, which was then reduced with platinum oxide catalyst to give donepezil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](=[O:24])(=[O:23])[NH:20][CH2:21][CH3:22])=[C:14]2[N:13]=[CH:12][C:11]=1[C:25]([O:27]CC)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH2:21]([NH:20][S:19]([C:18]1[CH:17]=[N:16][N:15]2[C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[Cl:1])=[C:11]([C:25]([N:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39]3)=[O:27])[CH:12]=[N:13][C:14]=12)(=[O:24])=[O:23])[CH3:22]
Reactant: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OCC)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 18.2 %

Procedure:
Using ethyl 7-(2-chloro-5-methylphenylamino)-3-(N-ethylsulfamoyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.084 g, 0.205 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine (0.030 g, 0.183 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.019 g, 16%) was obtained.
Reaction SMILES: FC(F)(F)S(O[S:7]([C:10](F)(F)F)(=O)=O)(=O)=O.[NH2:16][C:17]1[N:18]=[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:20]([C:24]2[CH:25]=[CH:26][C:27](=[O:33])[N:28]([CH:30]([CH3:32])[CH3:31])[N:29]=2)=[N:21][C:22]=1[Br:23].[CH2:40](Cl)Cl>CS(C)=O.CC(C)=O>[Br:23][C:22]1[N:21]=[C:20]([C:24]2[CH:25]=[CH:26][C:27](=[O:33])[N:28]([CH:30]([CH3:32])[CH3:31])[N:29]=2)[C:19]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:18][C:17]=1[N:16]=[S:7]([CH3:10])[CH3:40]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: ClCCl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CC(C)n1nc(-c2nc(Br)c(N=S(C)C)nc2-c2ccccc2)ccc1=O
Temperature: -55 °C
Reaction time: 1 h

Procedure:
To a solution of DMSO (0.75 ml) in CH2Cl2 (5 ml) was added trifluoromethanesulfonic anhydride (1.5 ml) dropwise at <−75° C. under nitrogen. A suspension of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (3.00 g) in a mixture of DMSO (5 ml) and CH2Cl2 (6 ml) was added and stirred at −65° C. for 2 hours and at −55° C. for one hour. The reaction mixture was quenched with 1N aq. NaOH (20 ml) and stirred at 15° C. for 10 minutes. An organic layer was collected, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6-{6-bromo-5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone (3.16 g).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)=[C:2]=[S:3].[C:16]([C:18]1([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)[CH2:21][CH2:20][CH2:19]1)#N.CN(C)C=[O:37].Cl>O.C([O-])(O)=O.[Na+].CO>[C:10]([C:7]1[N:8]=[CH:9][C:4]([N:1]2[C:16](=[O:37])[C:18]3([CH2:21][CH2:20][CH2:19]3)[N:22]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=3)[C:2]2=[S:3])=[CH:5][C:6]=1[C:12]([F:15])([F:13])[F:14])#[N:11]
Reactant: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Reactant: CN(C)C=O
Reactant: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 80 °C

Procedure:
Crude 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile 9 (1.390 g, 6.07 mmol) is placed in a 50 mL round-bottomed flask and 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide 10 (0.5 g, 2.022 mmol) is added to the flask. The mixture is left under vacuum (using an oil pump) for 1 hour. N,N-dimethylformamide (DMF) (6 ml) is added, the flask sealed under argon with a stopper and heated to 80° C. in a CEM microwave reactor for 20 hours. Methanol (10 ml) and 2N HCl (6 ml) is added and the mixture is refluxed for 2 hours. The mixture is diluted with water (30 ml) and saturated aqueous NaHCO3 (30 ml) is added. The mixture is extracted with ethyl acetate (3×20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:42])([F:43])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34]([O:8][CH2:7][CH2:6][O:5][CH2:4][C:3]3[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:13])=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: OCCOCc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
22.1 g of 2-(2,6-dichlorobenzyloxy)ethanol and 10.1 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.5 g of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 50 ml of toluene at 0° to 10° C. After the dropwise addition, the reaction mixture was gradually heated and, at 40° C., it was stirred for one hour to complete the reaction. After cooling the reaction solution to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, then dehydrated. After distilling off toluene under reduced pressure, the resulting colorless, viscous, oily product was allowed to stand for about 1 month to obtain 49.2 g of crystalline 2-(2,6-dichlorobenzyloxy)ethyl 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionate. m.p. 51° to 53° C.
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2(O)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:31][C:32]([CH3:37])([CH3:38])[C:33]([CH3:35])([CH3:36])[O:34]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Pyridine (0.353 mL, 4.380 mmol) and trimethylsilyl triflate (0.396 mL, 2.189 mmol) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-pyran-4-ol (Example 130-(3); 0.55 g, 1.095 mmol) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (548 mg, 87%).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.ClCC[S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([S:37]([CH2:4][CH2:2][OH:1])(=[O:39])=[O:38])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)CCO)C3)ccc1-2

Procedure:
Following the procedure for 394, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235, 2-chloroethanesulfonyl chloride, and 1.0 equivalents of triethylamine were reacted to give 445. LCMS: RT=8.49 min, [M+H]+=476. 1H NMR δ (ppm) (DMSO-d6): 8.29 (1H, d, J=8.20 Hz), 8.06-8.03 (1H, m), 7.22 (1H, dd, J=8.27, 1.86 Hz), 7.13 (1 H, d, J=1.82 Hz), 5.82-5.72 (1 H, m), 4.36-4.26 (4 H, m), 4.10-3.94 (3H, m), 3.45-3.35 (4 H, m), 2.72-2.65 (2 H, m), 1.50 (6 H, d, J=6.59 Hz). 1 Exchangeable proton not seen
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][OH:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2sccc2Br)cc1
Reaction time: 8 h

Procedure:
A mixture of (3-bromothien-2-yl) (4-methoxyphenyl)methanone PG,47 (2.5 g) and hydroxylamine hydrochloride (1.5 g) and 15 ml of pyridine was stirred at room temperature overnight and then heated at 100°-115° C. for 4 hours. A thin layer chromatography analysis showed the reaction to be complete. The mixture was quenched with water and extracted with ether. The ether phase was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Upon evaporation of the ether, an oil was obtained which crystallized upon standing overnight. The solid was recrystallized from ether/pentane to give a pure crystalline product (2.39 g, m.p. 110°-115° C.).
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[F:13][C:14]([F:26])([F:25])[C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([CH3:24])[CH2:18]1)=[O:16].[BH4-].[Na+]>CC(O)C>[F:26][C:14]([F:13])([F:25])[C:15]([N:17]1[CH2:22][CH2:21][CH:20]2[N:5]3[CH2:4][CH2:3][O:2][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]([C:6]3=4)[C:19]2([CH3:24])[CH2:18]1)=[O:16]
Reactant: CC1CN(C(=O)C(F)(F)F)CCC1=O
Reactant: NN1CCOc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC12CN(C(=O)C(F)(F)F)CCC1N1CCOc3cccc2c31
Temperature: 25 °C
Yield: 89.7 %

Procedure:
2,3-Dihydro-4H-1,4-benzoxazin-4-amine hydrochloride (0.0830 g, 0.444 mmol) and 1-trifluoroacetyl-3-methylpiperidin-4-one (0.0929 g, 0.444 mmol) were combined in 2-propanol (3.75 mL) and stirred at reflux for 3.75 hours under N2. The reaction mixture was cooled to room temperature, NaBH4 (0.0523 g, 1.38 mmol) was added and the reaction mixture was refluxed for 1 hour under N2. The cooled reaction mixture was quenched with CH3OH (2 mL) and partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with H2O, dried over Na2SO4, filtered and concentrated to yield crude 8-trifluoroacetyl-6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.130 g). MS (ESI+) for C16H17F3N2O2 m/z 327.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:23].F[P-](F)(F)(F)(F)F.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[N:22]([CH3:23])[CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (100 mg, 0.3 mmol), HATU (188 mg, 0.5 mmol), dimethylamine (0.2 mL, 2M in THF) and DIPEA (0.23 mL, 1.3 mmol) in DMF (2 mL) was stirred for 16 h at ambient temperature. The crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 275.0 [M−55]+; tR (HPLC conditions c): 4.68 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([OH:18])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:28](OS(C(F)(F)F)(=O)=O)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)Cl.CCOC(C)=O>[CH2:11]([O:10][CH2:9][CH:8]([O:18][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)CC(O)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(COCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl-4-(benzyloxy)-3-hydroxybutanoate XXXV [Tetrahedron (1993), 49(10), 1997-2010] (2.3 g, 8.84 mmol) in DCM (100 mL) at 0° C. was added 2,6-lutidine (3.07 mL, 26.52 mmol) and TBSOTf (4 mL, 4. 17.68 mmol). After stirring for 16 h at 0° C., the reaction was diluted with EtOAc (400 mL). The mixture was washed with 1N HCl, saturated aq NaHCO3, water and dried. The extract was dried (MgSO4) and concentrated under reduced pressure. Purification of the crude product by column chromatography (100% hexane→25% EtOAc/hexane) afforded tert-butyl 4-(benzyloxy)-3-(tert-butyldimethylsilyloxy)butanoate XXXVI (3.1 g, 8.15 mmol, 92.1% yield) as a colorless oil.