Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)F.[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:47]=[CH2:48])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:45][CH3:46])=[CH:27][C:26]=1[CH2:25][CH2:24]3)(C(C)(C)C)([CH3:11])[CH3:10]>>[C:18]([C@H:19]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:47]=[CH2:48])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([C:40]([F:43])([F:42])[F:41])([O:44][Si:5]([CH3:6])([CH3:7])[CH3:8])[C:40]([F:41])([F:42])[F:43])[CH2:34][C@:18]12[CH2:17][O:16][SiH:9]([CH3:11])[CH3:10])[C:31]1[CH:30]=[CH:29][C:28]([O:45][CH3:46])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(=O)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Reactant: C[Si](C)(C)C(F)(F)F
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)C[C@]1(CO[SiH](C)C)[C@@H](C(C)(C)C)CC[C@@H]21

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 200 mg of alcohol 16a yields 200 mg of the column-chromatographically stable trimethylsilyl ether 17a as a light yellow, viscous mass (GC-MS: m/z theor.: 720, pract.: 720). The latter is, without the reaction with tetrabutylammonium fluoride-trihydrate being performed, used in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:15])=[C:8]([C:12]=1[CH2:13][CH3:14])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl[C:17]([O:19][CH2:20][CH3:21])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:15]=[C:17]([O:19][CH2:20][CH3:21])[O:10][C:9](=[O:11])[C:8]=2[C:12]=1[CH2:13][CH3:14])([O-:3])=[O:2]
Reactant: CCc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1nc2ccc([N+](=O)[O-])c(CC)c2c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 1.3 g (6.2 mmoles) of 5-nitro-6-ethyl-2-aminobenzoic acid in 40 mL of dry pyridine was cooled in an ice-water bath under inert atmosphere. Ethyl chloroformate, 2 mL (21 mmoles), was added dropwise over a five-minute period. A mild exotherm was observed and a solid separated from solution immediately upon addition. The suspension was stirred in the ice-water bath for 60 minutes, then warmed to room temperature and stirred under inert atmosphere overnight. Approximately half the pyridine was removed in vacuo, and the residual mixture was poured over ice. The precipitated solid, an orange brown color, was collected and air-dried. 0.76 g (47% yield) 6-nitro-5-ethyl-2-ethoxy-3,1-benzoxazin-4-one was obtained. NMR(CDCl3): 1.36(t,3H,J=7.5 Hz), 1.47(t,3H,J=7.2 Hz), 3.27(q,2H,J=7.2 Hz), 4.56(q,2H, J=7.5 Hz), 7.36(d,1H,J=9.0 Hz), 7.98(d,1H,J=9.0 Hz). MS(m/z): 282(M+ +H2O).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[N:9]=[CH:8][N:7]=1)=[O:5].[C:33]1([Mg]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:11]=1)(=[O:5])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(C)OC)ncn3)CC1)C(=O)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4ccccc4)ncn3)CC1)C(=O)N2
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 100 mg (0.227 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acidmethoxy-methyl-amide were cooled to −10° C. in 5.00 mL THF and combined with 0.400 mL (0.400 mmol) phenylmagnesium bromide solution (1M in THF). The mixture was stirred for 1 h at −10° C. and then heated to 0° C. Then 0.200 mL (0.200 mmol) phenylmagnesium bromide solution (1M in THF) were added, the mixture was stirred for 1 h and then heated to RT. The reaction mixture was combined with a saturated ammonium chloride solution and extracted with EtOAc. The combined organic phases were dried and evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and evaporated down by half. The precipitate formed was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22](OCC)=[O:23])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.[NH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([NH:27][C:22]([C:10]2[N:11]([CH3:21])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (50 mg, 0.125 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (2×1 mm, silica) (40% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.[CH2:13]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[CH2:13]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc([N+](=O)[O-])c1

Procedure:
Treatment of 3-nitroacetophenone (10 g) with methyltriphenyl phosphonium bromide (28 g) and n-butyllithium in hexane (78.4 mmol), as described in Example 1a, gave 3-(1-methylethenyl)nitrobenzene (9.5 g), δ (60 MHz, CDCl3) 2.1 (3H, s, CH3), 5.2 and 5.5 (2H, 2s, CH2), 7.2 to 8.2 (4H, m, ArH). Treatment of the above 3-(1-methylethenyl)nitrobenzene (9.5 g) with hydrogen and palladium on carbon (10%, 1.9 g) as described in Example 1a, gave 3-(1-methylethyl)aniline (6.15 g), δ (60 MHz, CDCl3) 1.1 (6H, d, (CH3)2), 2.6 (1H, m, CH) 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:19][CH:20]([CH3:22])[CH3:21])[C@@H:10]1[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([O:19][CH:20]([CH3:21])[CH3:22])[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)O[C@@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)OC1C(=O)C(NC(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Under argon to a solution of (±)-(1R,2R,3R)-3-tert- butoxycarbonylamino-1,2,3,4-tetrahydro-1-isopropyloxy-2-naphthalenol (50 mg) in anhydrous methylene chloride (4 ml) was added Dess-Martin periodinane (100 mg). Agitation was maintained at room temperature for 2 hours. The reaction mixture was filtered on a silica gel column (10 g, elution with ethyl acetate:cyclohexane. 1:9) to afford the title compound as an oil (38 mg).
Reaction SMILES: C1COCC1.[OH-].[Na+].[C:8]12([C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.Cl>O>[C:8]12([C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2
Reactant: CCOC(=O)COc1cccc(C23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(C23CC4CC(CC(C4)C2)C3)c1
Reaction time: 6 h
Yield: 89.8 %

Procedure:
5 mL of THF and 0.65 mL of 1N aqueous sodium hydroxide solution were added to 110 mg (0.35 mmol) of ethyl [3-(adamantan-1-yl)phenoxy]acetate at room temperature, and the mixture was stirred for 6 hours. 1N hydrochloric acid was added to acidify the reaction mixture, and water was added. The precipitated solids were collected by filtration, washed with water, and air-dried, thereby giving 90 mg of [3-(adamantan-1-yl)phenoxy]acetic acid (yield: 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17](O)=[O:18])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:20][N:21]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[CH2:23][O:22]1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[C:17](=[O:18])[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:9]2=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:20][N:21]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[CH2:23][O:22]1
Reactant: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Br)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CON(Cc2ccc(N3C(=O)c4ccccc4C3=O)cc2Br)C1=O

Procedure:
This compound was prepared in a manner analogous to that of Example 10, using 2.0 grams (0.004 mole) of 2-[[2-bromo-4-[(2-carboxyphenyl)carbonylamino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone and 5.0 grams (0.061 mole) of sodium acetate in 50 mL of acetic anhydride. The solid was recrystallized from ethyl acetatehexane to yield 2-[(2-bromo-4-phthalimidophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 158°-159° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:16])[CH2:13]3)[C:10]=2[C:17]([O:19]CC2C=CC([N+]([O-])=O)=CC=2)=[O:18])=[CH:6][CH:5]=1)=[O:3].C(=O)(O)[O-].[Na+:36]>O1CCOCC1.O.[Pd]>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:16])[CH2:13]3)[C:10]=2[C:17]([O-:19])=[O:18])=[CH:30][CH:31]=1)=[O:3].[Na+:36]
Reactant: CS(=O)c1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)c1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1
Yield: 109.8 %

Procedure:
A mixture of a solution of 70 mg of 4-nitrobenzyl 3-(4-methylsulphinylphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 13 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. Then, the mixture was filtered through Gelite, and lyophilized to yield 58 mg of the title compound as a pale yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10](O)=[O:11])[CH:7]=1.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10]([Cl:16])=[O:11])[CH:7]=1
Reactant: O=C(O)C=Cc1cc(Br)ccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(5-Bromo-2-fluoro-phenyl)-acrylic acid (1.3 g, 5.0 mmol) prepared in Step 1 was added to thionyl chloride (10.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 1.4 g of the titled compound as an unpurified dark brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26]>CC#N>[C:25]([CH2:24][CH2:23][CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)#[N:26]
Reactant: N#CCCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCC#N)CC1
Yield: 75 %

Procedure:
A mixture of 2-methoxy-phenylpiperazine (8 g), K2CO3 (2.5 eq) and 4-bromobutyronitrile (1.05 eq) in CH3CN (150 mL) was refluxed for 10 h. After filtration and concentration in vacuo, the residue is taken up in AcOEt (1000 ml), washed with H2O, the organic layer is washed with aqueous HCl (50 mL, 1 M). Then the acid layer is washed with AcOEt (2×20 ml) and neutralized with aqueous NH3 (28% in H2O) until pH 11. Extraction is carried out with AcOEt, the organic layer is dried with Na2SO4 and concentrated in vacuo. The residual solid is crystallized in hexane to give the title compound (6.8 g, 75%, mp 74° C.). 1H NMR (200 MHz, CDCl3) δ 1.80-1.94 (m, 2H), 2.43-2.57 (m, 4H), 2.62-2.67 (m, 4H), 3.09 (m, 4H), 3.87 (s, 3H), 6.85-7.04. 13C NMR (50 MHz, CDCl3) δ 14.9, 22.7, 50.5, 53.2, 55.3, 56.3, 111.1, 118.1, 119.8, 120.9, 122.9, 141.1, 152.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.FC(F)(F)C(O)=O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([C:25]5[NH:26][CH:27]=[CH:28][N:24]=5)[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1cccc(-c2ncc[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
Into a sealed tube were added 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (368 mg, 1.0 mmol), 3-(1H-imidazol-2-yl)-phenylamine (210 mg, 1.32 mmol), trifluoroacetic acid (847 μL, 11.0 mmol) and 1-butanol (10 mL). The above mixture was heated at 80° C. for 24 h. After that time, the mixture was concentrated in vacuo, and the residue was dissolved in DMSO for submission for MS-directed purification to obtain brown oil, which was purified again to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.52 (s, 9H), 2.58 (brs, 2H), 3.68 (brs, 2H), 4.14 (brs, 2H), 6.30 (brs, 1H), 6.68 (s, 1H), 7.16 (s, 2H), 7,45 (t, 1H, J=8.0 Hz), 7.57-7.60 (m, 1H), 7.76-7.79 (m, 1H), 8.21 (t, 1H, J=1.6 Hz), 9.26 (s, 1H). MS (ES+): m/z 458.06 (100) [MH+]. HPLC: tR=2.17 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:34][S@@](C(C)(C)C)=O)([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:23]=[C:22]([F:33])[CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@:12]([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:23]=[C:22]([F:33])[CH:21]=2)([NH2:34])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc([C@@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)Oc1ccc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (398 mg, 0.678 mmol) in MeOH (1.5 mL) was added HCl (1.5 mL, 4 M solution in dioxane) and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with ether (50 mL) and the organic layer was washed with sat. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated to give (R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine as a colorless oil (334 mg, 100% yield). LCMS: RT=1.76 min [M−NH2] 467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.04 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 6.99 ppm, 4H, m; 6.89 ppm, 1H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm, 2H, d, J=6.15 Hz; 5.87 ppm, 1H, m; 4.42 ppm, 1H, m; 3.47 ppm, 2H, s; 1.27 ppm, 6H, dd, J=7.91, 6.15 Hz.
Reaction SMILES: [N:1]1([CH2:9][C:10]([O:12]C(=O)C2C=CC=CC=2)=[O:11])[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:21]([NH:6][C:5]1[CH:7]=[CH:8][N:1]([CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:3])[N:4]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccn(CC(=O)OC(=O)c2ccccc2)c(=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1) (10 g, 38 mmol) in 10 mL pyridine was added 6.6 g (47 mmol) of benzoyl chloride and stirred overnight at room temperature. The solution was evaporated under reduced pressure. The residue was dissolved in 1 M KOH and stirred for 3 h after which the Ph was adjusted to 2 with conc. HCl. The target compound (2) precipitated out. Yield: 9.3 g (90%). 1H NMR (d6-DMSO): δ 4.59 (s, 2 H, CH2O), 7.31 (d, 1 H, H5), 7.5-8.2 (7 H, aromatic, NH, H6). MS (FAB) m/z 273 (M+H)+ (calcd 273).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:20]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a suspension of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine (7.0 g, 13.84 mmol) and powdered sodium bicarbonate (5.88 g, 70 mmol) in DMF (100 mL) was added excess of iodoethane (10.91 g, 70 mmol) at room temperature. The resulting suspension was stirred for 20 h at which time TLC analysis of the mixture indicated the absence of staring material and the excess iodoethane and some DMF was removed on a rotary evaporator under vacuum. The remaining residue was diluted with 150 mL of ethyl acetate and washed successively with water (2×100 mL), brine solution (100 mL) and dried over MgSO4. Filtration of the drying agent and removal of the solvent afforded a white solid which was crystallized from acetonitrile. The resulting crystalline solid was collected by filtration and dried under high vacuum to afford 5.58 g (77%) of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine ethyl ester as a white solid. mp 230-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].ClCCl.[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: CC(C)C(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture (ice bath, 0° C.) of 30 parts of 1-(4-amino-3-nitrophenyl)-2-methyl-1-propanone and 390 parts of dichloromethane were added dropwise 33 parts of acetyl chloride. Upon complete addition, the reaction mixture was stirred for 12 hours at room temperature. The whole was poured into water and after the addition of sodium carbonate, stirring was continued for 15 minutes. The separated organic layer was dried, filtered and evaporated, yielding 36 parts (100%) of N-[4-(2-methyl-1-oxopropyl)-2-nitrophenyl]acetamide (interm. 14).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]#[CH:20]>CN(C=O)C>[CH2:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of isatin (200 mg, 1.36 mmol) in DMF (5 mL) was added cesium carbonate (487 mg, 1.5 mmol). The reaction was stirred at room temperature for 90 minutes. Propargyl bromide (243 uL, 1.63 mmol) was then added. The reaction was stirred overnight at room temperature, concentrated in vacuo, dissolved in EtOAc and washed with saturated NaHCO3(aq) (1×). The layers were separated and the aqueous layer was extracted with additional EtOAc (2×). The combined organic phases was dried over Na2SO4, filtered and concentrated in vacuo. Further purification of the residue was not necessary. The title compound was obtained as an orange solid (255 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 2.31 (t, J=2.54 Hz, 1H), 4.55 (d, J=2.54 Hz, 2H), 7.12-7.15 (m, 1H), 7.19 (dt, J=7.52, 0.78 Hz, 1H), 7.63-7.68 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:19]=1[C:15]1=[N:16][O:17][CH2:18][CH:14]1[CH2:13]2.[Br:20]Br>O>[Br:20][C:11]1[CH:10]=[CH:9][C:8]([S:7][CH3:6])=[C:19]2[C:12]=1[CH2:13][CH:14]1[CH2:18][O:17][N:16]=[C:15]12
Reactant: CSc1cccc2c1C1=NOCC1C2
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1ccc(Br)c2c1C1=NOCC1C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
120 ml of sulfuric acid (98 percent strength) were cooled to 0° C., and 11.2 g (54.8 mmol) of 8-methylthio-3a,4-dihydro-3H-indeno[1,2-c]isoxazol were added a little at a time. 9.2 g (57.5 mmol) of bromine were then added dropwise, and the mixture was stirred at 0° C. for 2 hours. The resulting solution was poured into 2 l of a mixture of water and ice, the mixture was stirred for 1.5 hours and the precipitated solid was filtered off with suction and then washed and dried. This gave 11.4 g (73%) of 5-bromo-8-methylthio-3a,4-dihydro-3H-indeno[1,2-c]isoxazol of a brown solid of m.p. 127-135° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([C@@H:23]([CH2:35][NH:36]C(OC(C)(C)C)=O)[CH2:24][O:25][Si:26]([CH3:34])([CH3:33])C(C)(C)C(C)C)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.N1C=CN=C1.C[Si](Cl)(C)[C:51]([CH:54]([CH3:56])[CH3:55])([CH3:53])[CH3:52]>CN(C)C=O>[CH2:16]([O:15][C:11]1[CH:12]=[CH:13][C:8]2[N:7]3[C@H:23]([CH:24]([C:51]([CH3:53])([CH3:52])[CH:54]([CH3:56])[CH3:55])[O:25][SiH:26]([CH3:33])[CH3:34])[CH2:35][NH:36][C:4](=[O:5])[C:6]3=[CH:14][C:9]=2[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3cc(OCc4ccccc4)ccc3n21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 8, intermediate a), from 5-benzyloxy-1-{(S)-1-(tert-butoxycarbonylamino-methyl)-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-ethyl}-1H-indole-2-carboxylic acid ethyl ester to give a mixture of the desired compound and the unprotected hydroxymethyl compound. The mixture was dissolved in N,N-dimethylformamide and 1 equivalent of imidazole was added. At 0° C., 1 equivalent of dimethylthexylsilyl chloride was added and the cooling bath was removed. The reaction mixture was poured on water and was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel using n-hexane:ethyl acetate (1:2 v/v) as eluant to give the desired product as a light yellow foam (35%).