Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH3:34]OC(=O)C1C=CC=NC=1N>>[CH3:34][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[N:17][CH:18]=1
Reactant: COC(=O)c1cccnc1N
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: COC(=O)c1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product from Example 11, Part D (331 mg, 1 mmol) and 2-aminonicotinic acid methyl ester (316 mg, 2.1 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (269 mg, 58%). 1H NMR (300 MHz, CDCl3) δ 8.83 (d, J=2 Hz, 1H), 8.27 (dd, J=8 Hz, 2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 7.87 (br s, 1H), 7.69 (d, J=7 Hz, 1H), 7.46 (m, 1H), 7.31 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (t, J=9 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.70 (m, 1H), 4.25 (d, J=15 Hz, 1H), 3.92 (s, 3H), 2.52 (m, 2H), 1.98 (m, 2H). MS: m/z (MH+) 466.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Nc1noc2ccc(C=O)cc12
Product: Nc1noc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Amino-benzo[d]isoxazole-5-carbaldehyde (intermediate 68) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>ClCCl>[I:1][CH2:2][CH2:3][O:4][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCCI
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 17 h

Procedure:
To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that the reaction temperature did not rise above 30° C. Upon complete addition the solution was left stirring for 17 h, then washed with water (2×50 mL) and brine (50 mL) and dried over MgSO4. Evaporation of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98%) as a colourless liquid.
Reaction SMILES: [BH3-]C#N.[Na+].C(OC([NH:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[OH:35][C:36]1[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O.CO>C(O)(=O)C>[NH2:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:36]=2[OH:35])[CH2:27][CH2:28]1)=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: Cc1cccc(C=O)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH3CN (0.40 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL) and acetic acid (0.040 mL). The resulting mixture was stirred at 50 overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1 (1 mL), loaded onto a Varian™ SCX column, eluted with ethyl acetate/methanol=5:1 (5 mL) and concentrated. The residue was dissolved in methanol (2 mL), and a 4 M dioxane solution of HCl (0.50 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL), concentrated and purified by preparative TLC to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl) glycyl]aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compd. No. 2106). The purity was determined by RPLC/MS (97%). ESI/MS m/e 447.0 (M++H, C23H28F2N4O3).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=O>C1(C)C=CC=CC=1>[C:5]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH:17]=[CH:18]2)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#CCOc1cccc2c1CCC=C2
Temperature: 120 °C

Procedure:
Trimethylsilyl cyanide (28.2 g) and a catalytic amount of aluminum trichloride was added to a toluene solution of 5-methoxy-1-tetralone (25 g) and the reaction heated for 2 hours. The solution was evaporated to dryness. Pyridine (100 ml) was then added, followed by dropwise addition of phosphorous oxychloride (40 ml). Upon complete addition the reaction was heated to 120° C. for 2 hours. The reaction was cooled and poured onto ice containing aqueous hydrochloric acid. The mixture was extracted with ether (100 ml). The organic layer was separated, dried, filtered and evaporated affording the desired product as an oil which solidified upon standing.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:27])([F:26])[C-:11]([C:22]([F:25])([F:24])[F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:20][C:12]([F:21])([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[C:11]([C:22]([F:25])([F:24])[F:23])([C:10]([F:27])([F:26])[F:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 66 %

Procedure:
Benzyl bromide, 4.77 g (0.028 mol), was added dropwise to a solution of 15.0 g (0.031 mol) of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide in 50 mL of acetonitrile at 25° C. and the reaction mixture was stirred overnight and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were dried (MgSO4) and then distilled to give 7.5 g (66%) of 3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pentylbenzene as a colorless liquid: b.p. 62°-63° (5 mm); 19F NMR (CDCl3) δ -62.7 ppm (t,t, 6F), -80.7 ppm (t, 3F), -106.3 ppm (m, 2F) and -123.3 ppm (2F); 1H NMR (CDCl3) δ 3.52 ppm (s, 2H) and 7.27 ppm (s, 5H). Anal. Calcd. for C13H7F13 : C, 38.07; H, 1.72; F, 60.21. Found: C, 37.82; H, 1.73; F, 60.42.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 78.4 %

Procedure:
A stirred mixture of 10.0 g (0.063 mole) of 3-fluoro-4-nitrophenol, 17.0 g (0.090 mole) of 4-fluorophenylmethyl chloride, and 12.42 g (0.090 mole) of anhydrous potassium carbonate in 80 mL of methyl ethyl ketone was heated at 70° C. for approximately 17 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated under reduced pressure, leaving 13.10 g of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether as a solid; m.p. 90°-91° C.
Reaction SMILES: C[N:2]([CH3:11])[C:3]1C=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1C=N[NH:16][CH:17]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:17]=[N:16][N:2]([CH2:3][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:9][O:10]2)[CH:11]=1
Reactant: CN(C)c1cccc(CO)c1
Reactant: Brc1cn[nH]c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Brc1cnn(CC2CCCCO2)c1

Procedure:
The title compound was prepared by substituting (tetrahydro-2H-pyran-2-yl)methanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7]>C1COCC1.C(O)C.[OH-].[Na+]>[Si:28]([O:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C:12]3[C:11]4[C@:25]([CH3:26])([CH2:24][CH2:23][C:22]=32)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:37])=[O:2])[CH2:9][CH:10]=4)[C:16]1([CH3:35])[CH3:36])([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester (3.6 g) is dissolved in a mixture of 150 ml of THF, 120 ml of ethanol and 18 ml of 1M sodium hydroxide. The mixture is stirred for 20 hours at room temperature and 2hours at 50° C. After aqueous work-up and crystallisation from ethanol/water, 2.48 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid is isolated.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH3:13])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 3,5-dibromo-4-nitropyrazole 1 (0.934 g, 3.45 mmol) in 5 mL of absolute DMF were added dropwise 0.16 g of sodium hydride (6.67 mmol) in DMF (100 mL) over a period of 1 h. After cessation of gas generation, 0.26 mL of CH3I (3.89 mmole) was added dropwise and stirred at room temperature for overnight. The solvent was then evaporated under vacuum and the residue was poured into water, The separated solid was filtered, washed with water and dried under vacuum to afford 0.713 g of 2 (yield 72.6%). Preparation of N-benzyl-3-bromo-1-methyl-4-nitro-1H-pyrazol-5-amine (3): 3,5-dibromo-1-methyl-4-nitropyzole 2 (2.85 g 10 mmol) was heated in a solution of 10 mL of benzylamine for 6 h at 80° C. After cooling to room temperature, the reaction mixture was poured into water and the yellow solid formed. Then it was filtered, washed with water, dried and recrystallized from toluene to afford 3 g of 3 in yield of 96%. Preparation of 5-amino-1-methyl-4-nitro-1H-pyrazole-3-carbonitrile (4): A mixture of CuCN (0.135 g, 1.5 mmol) and 3 (0.312 g, 1 mmol) in solution of DMF (10 mL) were refluxed for 8 h before it was poured on water and filtered. The filtrate and the separated yellow solid, which was dissolved in concentrated ammonium hydroxide, were extracted by EtOAc. The organic layer was dried using Na2SO4 and purified by flash column chromatography (EtOAc: PE=2:1˜1:1) to afford 0.108 g of 4 in yield of 42%. Preparation of 4,5-diamino-3-cyano-1-methylpyrazole (5): A mixture 4 (0.257 g, 1 mmol) and 10% Pd/C (0.3 g) catalyst in 20 mL ethanol were stirred in hydrogen atmosphere at room temperature for 48 h. After filtration, the solvent was removed under reduced pressure to 2-3 mL before 98% H2SO4 was added dropwise until pH=1. The formed solid was filtered and washed with small amount of ethanol to afford 0.106 g of 5 in yield of 45%: 1HNMR (300 MHz, DMSO-d6) δ 3.00 (3H); 13CNMR (75 MHz, DMSO-d6) δ 35.9, 110.3, 114.2, 114.5, 138.4; MS (EI) 137.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.O[N:23]1[C:27]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:23][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
N-t-Butoxycarbonyl-L-phenylalanine (2.65 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (20 ml). To the solution were added a 40% aqueous solution (0.8 ml, 10.3 mmol) of methylamine, 1-hydroxybenzotriazole (1.48 g, 11.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12.0 mmol) under cooling with ice water. The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and each once with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was separated by filtration, the solvent was distilled off under reduced pressure. The resultant solids were washed with diisopropyl ether to obtain 2.41 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N:22](C=O)C.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32]N>CCN(CC)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[C:17](/[O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)\[C:18]([NH2:22])=[O:20])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: NOC1CCCCO1
Solvent: CCN(CC)CC
Product: NC(=O)/C(=C\c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a mixture of 3.16 g (E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid and 170 ml DMF are added 1.06 g HOBtxH2O and 7.02 g Et3N. This mixture is stirred for 70 min at ambient temperature. 3.99 g EDCxHCl are added and the reaction mixture is stirred for additional 45 min. 0.812 g O-(tetrahydro-2H-pyran-2-yl)-hydroxylamin are added and the reaction mixture is stirred overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried, evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: [CH:1]1([C:6]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[C:9]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.Cl[Si:52]([CH3:55])([CH3:54])[CH3:53]>C1COCC1.O>[CH3:53][Si:52]([CH3:55])([CH3:54])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[C:9]([C:24]([CH3:26])([CH3:27])[CH3:25])[CH:8]=2)[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC=C3)c1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC([Si](C)(C)C)=C3)c1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
To a solution of 0.45 g (0.88 mmol) of 1-(cyclopentadienyl)-1(3,6-di-tert-butylfluorenyl)diphenylmethane in 30 ml of THF, 0.54 ml (0.97 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 16 hours. After the resulting solution was cooled to −78° C., a solution of 0.22 ml (1.76 mmol) of chlorotrimethylsilane in 10 ml of THF was slowly added, followed by stirring at room temperature for 6 hours. To the reaction solution, 20 ml of water was added to terminate the reaction. The resulting solution was subjected to extraction with diethyl ether, then dried over anhydrous magnesium sulfate and vacuum evaporated to dryness to obtain a yellow solid. The solid was washed with a small amount of methanol and dried under reduced pressure to obtain 0.42 g of an opaque white solid (yield: 81.8%) The analyzed values are given below.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:24]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:25]([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 70 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a solution of 6-nitro-2,3,4,9-tetrahydro-1H-carbazole (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 mmol) in DMF (8 mL) was added 1-bromo-2-methylpropane (0.314 mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 9-isobutyl-6-nitro-2,3,4,9-tetrahydro-1H-carbazole (296 mg, 1.087 mmol, 94%) as a yellow powder.
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[CH2:9]([NH2:11])[CH3:10].CCO>O1CCCC1.CC(C)=O.CCO>[CH2:9]([NH:11][CH2:8][CH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[CH3:10]
Reactant: O=S1(=O)CCCCO1
Reactant: CCN
Solvent: CCO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCNCCCCS(=O)(=O)O
Temperature: 5 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 1,4-butanesultone (2.66 g, 18.6 mmol) in tetrahydrofuran (total volume: 4 mL) was added via syringe pump over a 4 hour period to ethylamine (70% w/w in water, 24 mL, 372 mmol) at 5° C. The solution was stirred at 5° C. for an additional 3 hours before it was warm up to room temperature. The reaction was stirred in these conditions overnight. The solvent was coevaporated with EtOH (1×25 mL). The solid was suspended in 50% acetone/EtOH (50 mL). The suspension was stirred for 5 minutes, the solid was filtered and dried in vacuo. Yield: 75%. 1H NMR (D2O, 500 MHz) δ ppm 2.95 (m, 4H), 2.82 (m, 2H), 1.68 (m, 4H), 1.13 (t, 3H, J=7.3 Hz), 1.14 (t, 3H, J=7.3 Hz). 13C (D2O, 125 MHz) δ ppm 50.27, 46.68, 42.99, 24.66, 21.48, 10.64. ES-MS182 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.[Br:21]Br.O>C(O)(=O)C>[Br:21][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)naphthalene (9.68 g, 36.6 mmol) and glacial acetic acid (150 mL) was slowly added a solution of bromine (5.85 g, 36.6 mmol) in glacial acetic acid (20 mL). The mixture was stirred for 1 hour and the resulting suspension was poured into water (200 mL) and the solid product was collected by filtration. The solid was triturated first with water and then with ethyl acetate to yield 11.25 g (90%) of the title compound as a white solid: mp 172-174° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.05 (3H, s), 7.04 (2H, d, J=8.56 Hz), 7.30 (1H, d, J=9.01 Hz), 7.67 (2H, d, J=8.65 Hz), 7.81 (1H, dd, J=1.61 Hz, J=8.84 Hz), 7.87 (1H, d, J=9.04 Hz), 7.94 (1H, d, J=1.47 Hz), 8.27 (1H, d, J=8.92 Hz); MS (EI) m/z 343 (M)+.
Reaction SMILES: [CH2:1]1[C:5]([Cl:6])=[N:4][O:3][C@@H:2]1[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].[C:12]1([CH2:25][O:26][C:27](Cl)=[O:28])[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+].Cl>O>[Cl:6][C:5]1[CH2:1][CH:2]([CH:7]([NH:11][C:27]([O:26][CH2:25][CH:12]2[C:24]3[CH:16]=[CH:17][CH:18]=[CH:19][C:23]=3[C:22]3[C:13]2=[CH:14][CH:15]=[CH:20][CH:21]=3)=[O:28])[C:8]([OH:10])=[O:9])[O:3][N:4]=1
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C(NC(C(=O)O)C1CC(Cl)=NO1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of AT-125 (178 mg; 1 mmole), 9 fluorenylmethylchloroformate (285 mg, 1.1 mmole), and potassium bicarbonate (370 mg; 3.7 mmole) in 5 ml of water was stirred for 20 hours at room temperature. The gelatinous mixture is acidified to pH 2 with hydrochloric acid, evaporated to dryness under reduced pressure, and extracted with acetone. The acetone extracts are adsorbed onto silica gel and chromatographed on 40 g of silica gel with methylene chloride:isopropanol:acetic acid (100:3:1). Fractions of 20 ml are collected and monitored by TLC (U.S. visualization). The first 8 fractions contain components derived from the chloroformate reagent only including 9 fluorenylmethyl alcohol. Fractions 11-17 contain 206 mg of chromatographically homogeneous 3-chloro-α-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid, and fractions 21-50 contain 132 mg of chromatographically homogeneous 3-chloro-α-[[(3-chloro-4,5-dihydro-5-isoxazolyl)- [[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino]-4,5-dihydro-5-isoxazoleacetic acid. Crystallization of fractions 11-17 from aqueous methanol and recrystallization from acetone-cyclohexane yields 3-chloro-α -[[(9H-fluoren-9ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid m.p. 175°-176°.