Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:18].[CH3:19][Mg]Br>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][C:7](=[O:18])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[CH:12]=1)[CH3:19]
Reactant: C[Mg]Br
Reactant: COCCCN1C(=O)COc2ccc(C=O)cc21
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(C(C)O)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The solution of 1.0 g of 4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde and 30 ml of tetrahydrofuran is cooled to 0° C. and admixed dropwise with 1.4 ml of methylmagnesium bromide (35% in THF). The reaction mixture is stirred at 0° C. for a further 15 minutes, subsequently quenched with saturated ammonium chloride solution (50 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed successively with ice-water (50 ml) and brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (3:1 EtOAc-heptane); Rt=2.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][C:9]2=O)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccc(C2CNc3c(ccc4ccccc34)S2)cc1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-naphtho[2,1-b ][1,4]thiazin-2(3H)-one (38.45 g) and sodium borohydride (22.32 g) in tetrahydrofuran (1.0 liter) is added dropwise with stirring boron trifluoride etherate complex (100 ml) at room temperature, and the mixture is refluxed for 2 hours. After cooling, to the mixture are added methanol (200 ml), 10 hydrochloric acid (300 ml) and conc. hydrochloric acid (150 ml) in this order and the mixture is further refluxed for 4 hours. To the reaction mixture is added ice water and the mixture is made alkaline with potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent. The residue is recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (32.3 g, yield 88%) as crystals.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(OP(OC2C=CC=CC=2)([N:70]=[N+:71]=[N-:72])=O)=CC=1>C1COCC1>[N:70]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:71]=[N-:72]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a mixture of tert-butyl (4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.2 g, 3.0 mmol), DIAD (1.2 mL, 5.9 mmol) and PPh3 (1.6 g, 5.9 mmol) in THF (20 mL), diphenylphosphonic azide (1.3 mL, 5.9 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-15% EtOAc in hexanes) to provide the sub-title compound (1.09 g, 86%). LCMS calc. for C15H33N4O2Si (M+H-Boc)+: m/z=329.2. found 329.2.
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]([CH:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH2:38]>>[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH:38][C:19](=[O:20])[CH:18]([CH3:22])[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2
Reactant: Nc1nncs1
Reactant: COC(=O)c1ccc(C(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)C(=O)O)cc1
Product: COC(=O)c1ccc(C(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)C(=O)Nc2nncs2)cc1
Yield: 25 %

Procedure:
Example 153 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-(4-(methoxycarbonyl)phenyl)-2-methylpropanoic acid and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 35 mg (25% yield, 3 steps). MS found: (M+H)+=516.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][O:51]C1CCCCO1)[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33]C1CCCCO1.C[Si](OS(O[Si](C)(C)C)(=O)=O)(C)C>CO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]
Reactant: C(CCCCCOC1CCCCO1)CCCCOCC(COCCCCCCCCCCOC1CCCCO1)OCCCCCCCCCCOC1CCCCO1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: CO
Product: OCCCCCCCCCCOCC(COCCCCCCCCCCO)OCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of 13 g 1,2,3-tris(10-[tetrahydropyranyloxy]decyloxy)propane, 1 g bis(trimethylsilyl)sulphate and 250 ml methanol is stirred at room temperature for 2 hours. The reaction mixture is evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent and recrystallisation from acetonitrile to yield 7.1 g of 1,2,3-tris(10-hydroxydecyloxy)propane.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 30 g (0.121 mole) of the amide in 254 ml of trifluoroacetic acid at 0° under an argon atmosphere was added dropwise with stirring a solution of 7.5 ml (0.12 mole) of conc. nitric acid in 56 ml of trifluoroacetic acid. The reaction mixture was stirred at 0° for 1/2 hour and at room temperature for 2 hours. The solvents were evaporated. The residue was dissolved in ethyl acetate which was extracted with 5% hydrochloric acid, dilute sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and activated charcoal. After filtering, the solvents were removed to give 34.8 g (98%) of crude (2-trifluoroacetamidoethyl)-3-nitro-4-methoxybenzene which was an amber-colored solid. This material was recrystallized from 400 ml of 1:3 ethyl acetate-hexane to give 25.3 g (71.5%) of the product, m.p. 92.5°-93.0°. The mother liquors were concentrated and recrystallized to give a second crop, 4.59 g (13%), m.p. 90°-92° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30](Br)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CC#N.C(Cl)Cl.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCC(Br)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCC(c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-bromopropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (67.1 mg, 0.106 mmol) in MeCN (200 μL) was added pyrrolidine (1 mL, 12.0 mmol). The reaction was stirred at room temperature for 16 hours and then purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA). The resulting solution was diluted with EtOAc (25 mL), washed with 1 M NaHCO3 (20 mL), extracted with EtOAc (25 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. To the residue was added 200 μL CDCl3, which resulted in a mixture that was diluted with CH2Cl2 (20 mL) and water (5 mL), and washed with 1 M NaOH solution (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-pyrrolidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. Rf=0.14 (25% EtOAc/hexanes). LCMS=583.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, diastereomers present) δ 7.94 (s, 1H), 7.84 (s, 2H), 7.67-7.48 (m, 3H), 5.70-5.68 (m, 1H), 5.08-4.96 (m, 1H), 4.64-3.34 (m, 1H), 4.02-3.94 (m, 1H), 3.48-3.39 (m, 1H), 2.54-2.35 (m, 5H), 2.01-1.91 (m, 1H), 1.76-1.72 (m, 4H), 0.79-0.77 (m, 3H), 0.72-0.66 (m, 3H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([NH:26]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(Oc2ccc(N)c3ccccc23)n1
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution of impure tert-butyl 4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)naphthalen-1-ylcarbamate described above (0.77 g, ˜50% purity, 0.8 mmol) in TFA (10 mL) was heated at reflux for 8 hr and then kept at RT for 16 hr. The reaction mixture was evaporated in vacuo and the residue was taken up into EtOAc and was washed with saturated aq NaHCO3 solution and with brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate in isohexane, 50-100%, gradient elution) to afford the title compound (111 mg, 54%) as a brown solid; m/z 253 (M+H)+, (ES+)+
Reaction SMILES: O[Li].O.[C:4]1([C:14]([NH:16][C@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([C:14]([NH:16][C@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
LiOH.H2O (0.272 g, 3.62 mmol, 5 eq) dissolved in water (0.6 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(1-naphthamido)-2,3-dihydro-1H-indene-5-carboxylate (B-36) (0.25 g, 0.724 mmol, 1 eq) in MeOH (3 ml), and the resulting mixture was stirred for 16 h at RT. After monitoring by TLC, further LiOH.H2O (0.272 g, 3.62 mmol, 5 eq) was metered in, and the reaction mixture was heated to 40° C. and stirred for 1 hour. Then the reaction solution was concentrated under reduced pressure, the residue was taken up in water and diethyl ether, and the phases were separated. The aqueous phase was acidified with 1 M HCl and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Yield: 96% (0.23 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.[ClH:19].[NH2:20][OH:21].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=[N:20]\[OH:21]
Reactant: NO
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(/C(=N/O)c1ccccc1F)C2

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanone (29.5 g), hydroxylamine hydrochloride (16.5 g) and ammonium acetate (27.5 g) were heated in 80 ml of refluxing ethanol-water (3:1 mixture) for 19 hours. The mixture was cooled and the precipitated product was collected (25.2 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].C(N(CC)CC)C.[Cl-].[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>C(OCC)C>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[C:28](=[O:29])[CH2:27][C:26]([O:25][CH3:24])=[O:31]
Reactant: COC(CNc1c(C)cccc1C)OC
Reactant: COC(=O)CC(=O)O
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N(CC(OC)OC)c1c(C)cccc1C
Yield: 33.9 %

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-2,6-dimethyl aniline (4.45 g, 0.02 mol), triethylamine (2.76 ml, 0.02 mol) in ethyl-ether (25 ml.), malonic acid methyl ester monochloride (2.1 ml, 0.02 mol) was added dropwise in 15' at 0°-5° C. under stirring. The reaction mixture was then stirred 1 hour at 0° C. and 10 minutes at room temperature, then it was filtered, washed twice with 10 ml of a hydrogen chloride solution (5%), then with water till a neutral pH (3×10 ml). The organic phase was anhydrified on anhydrous Na2SO4 and the solvent was evaporated. The residue (yellow oil) was purified by chromatography on a silica gel column using hexane-ethyl acetate (7:3) as eluent. Thereby 2.1 g of the desired product (oil) were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(OC(O)C)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(Nc2ccccc2)n1

Procedure:
A solution of 2,6-dichloropyrazine (1 g, 62 mmol) and aniline (1.25 g, 13.4 mmol) in ethoxyethanol (20 mL) containing DIPEA (2.5 mL, 13.4 mmol) was heated at reflux for 3 days under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed successively with H2O (50 mL), 1M HCl (2×50 mL), H2O (50 mL) and brine (50 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with EtOAc-hexane (20:80-50:50) to separate pure product from the lower fractions (230 mg, 17%).
Reaction SMILES: [CH3:1][C@H:2]([N:5]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].[N:24]([Si](C)(C)C)=[N+:25]=[N-:26]>CN(C=O)C.CO.[Cu]I>[N:24]1[NH:25][N:26]=[C:3]([C@@H:2]([N:5]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH3:1])[CH:4]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H](C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](c1cn[nH]n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 79 %

Procedure:
A mixture of (S)-tert-butyl but-3-yn-2-yl(3-((tert-butoxycarbonyl)amino)propyl)carbamate (710 mg, 2.18 mmol), azidotrimethylsilane (452 μl, 3.26 mmol) and copper (I) iodide (21 mg, 0.11 mmol) in DMF/MeOH (1:1, 3.4 mL) was heated to 100° C. for 8 h. Upon cooling, the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo and purified via silica gel chromatography (EtOAc-Heptane, 30-80%) to afford the title compound (636 mg, 79%) as an oil. LCMS: Rt=0.78 min, m/z=370.1 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][OH:15])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])([OH:3])=[O:2].N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[Si:32]([O:15][CH2:14][C:13]1[C:12]2[C:7](=[C:8]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1c(C(=O)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.3 %

Procedure:
To a solution of 3-carboxy-8-(2,6-dichlorobenzoylamino)-4-hydroxymethylquinoline (1.11 g) in dimethylformamide were added imidazole (637 mg) and tert-butyldiphenylsilyl chloride (2.57 g) under ice-cooling, and the mixture was stirred for 5 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the solution of the obtained residue in dioxane (10 ml) was added 1N sodium hydroxide solution (2.9 ml), and the mixture was stirred for 30 minutes at ambient temperature. The mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in isopropyl alcohol-diisopropyl ether, and insoluble material was filtered off. The filtrate was concentrated in vacuo to give 4-(tert-butyldiphenylsilyloxymethyl)-3-carboxy-8-(2,6-dichlorobenzoylamino)quinoline (1.22 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si](CC)(CC)CC)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOCC.[NH4+].[Cl-]>C1COCC1>[F:15][C:12]([F:13])([F:14])[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30])[CH:2]([CH3:1])[CH2:10]2)([OH:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2C(CO)c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1C(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
To a solution of 19 mg (0.036 mmol) of 2-[2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-yl]-2-phenyl-ethanol in 0.5 mL THF were added 0.043 mL (0.043 mmol) of a 1M TBAF solution in THF. After stirring at RT for 24 hrs the mixture was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 2:1 yielded 9.3 mg (62%) of 1,1,1,3,3,3-hexafluoro-2-[1-(2-hydroxy-1-phenyl-ethyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-propan-2-ol, yellow viscous oil, MS: 420 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[O:29]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1
Yield: 24.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(p-tolyloxy)piperidin-1-yl]methanone (548 mg) described in Preparation Example 193 and isothiazolidine 1,1-dioxide (177 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (146 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:6]2[CH2:5][CH2:4][N:3]([CH:8]3[CH2:17][CH2:16][C:15]4[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=4[CH2:9]3)[C:2](=[O:1])[CH2:7]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (20 mg, 0.078 mmol) in DMF (1 mL) was added 1-(2-Iodoethyl)-4-nitrobenzene (26 mg, 0.094 mmol) and K2CO3 (43 mg, 0.31 mmol). The mixture was allowed to stir at RT for 16 hours. LC showed product formation. The desired product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 405 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1[O:28][N:27]=[C:26]([OH:29])[CH:25]=1.C(=O)([O-])O.[Na+].Cl>O.CO.CS(C)=O>[CH3:23][C:24]1[O:28][N:27]([C:12]2[CH:13]=[CH:14][C:9]([S:6](=[O:8])(=[O:7])[N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])[C:26](=[O:29])[CH:25]=1
Reactant: Cc1cc(O)no1
Reactant: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(-n2oc(C)cc2=O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 600 g of N,N-dibutyl-4-chloro-3-nitrobenzenesulfonamide, 220 g of 5-methyl-3-hydroxyisoxazole, 300 g of sodium hydrogen carbonate and 1.5 liter of dimethylsulfoxide was reacted at 80° C. for 6 hours. The reaction mixture was cooled to 40° C., 1.2 liter of methanol was added thereto, and then 400 ml of concentrated hydrochloric acid was added thereto at 25° C. After stirring for 30 minutes, 800 ml of water was added thereto. The crystals thus deposited were collected by filtration, washed with water, recrystallized from methanol and dried. Yield: 613 g (86.6%). Melting point: 84° to 86° C.