Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred solution of 58 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate in 240 parts of benzene is added dropwise a solution of 46.2 parts of benzeneacetyl chloride in 80 parts of benzene at a temperature between 40°-70° C. Upon completion, the whole is stirred and refluxed for 6 h. 15. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, then dried and evaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane, yielding 47 parts of ethyl 4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxyate; mp. 108° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[S:16][C:17]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:18][CH:19]=1)=[O:14])(C)(C)C>C(Cl)Cl>[CH2:36]([S:35][CH2:34][CH2:33][N:23]([S:24]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH2:22][CH2:21][CH2:20][C:17]1[S:16][C:15]([C:13]([OH:14])=[O:12])=[CH:19][CH:18]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN(CCSCc2ccccc2)S(=O)(=O)c2cccnc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(CCCN(CCSCc2ccccc2)S(=O)(=O)c2cccnc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
TFA. A solution of 5-(3-((2-benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl)-amino)-propyl)-thiophene-2-carboxylic acid tert-butyl ester prepared of Example 3, Step B (0.038 g) in 1 mL CH2Cl2 was cooled to 0° C. and 1 mL TFA was added. The mixture was warmed to room temperature and was stirred for 1 h. The CH2Cl2 and TFA were removed by evaporation, azeotroping with added CH2Cl2 to yield the title compound (46.3 mg). MS 475 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Br:23]N1C(=O)CCC1=O>C(#N)C>[Br:23][C:14]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([F:8])[CH:4]=2)=[N:10][C:11]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][CH:13]=1
Reactant: Fc1cc(-c2cccc(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Br)c(Cl)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (516 mg, 1.60 mmol) and N-bromosuccinimide (286 mg, 1.60 mmol) in acetonitrile (12 mL) was stirred at 90° C. for 3 hr in a sealed vessel. Volatiles were removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude material was purified by column chromatography over silica gel (heptanes/ethyl acetate gradient) to yield 608 mg of the desired product. LCMS (m/z): 402.0 [M+H]+; Retention time=1.03 min.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:23]=[C:24]([NH2:27])[NH:25][N:26]=2)=[CH:14]1.C([O-])=O>ClCCCl>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:23]=[C:24]([NH:27][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[NH:25][N:26]=2)=[CH:14]1
Reactant: Nc1cc(-c2c[nH]c3ccccc23)n[nH]1
Reactant: O=C(O)CCCN1CCCCC1
Agent: O=C[O-]
Solvent: ClCCCl
Product: O=C(CCCN1CCCCC1)Nc1cc(-c2c[nH]c3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a suspension of 4-piperidin-1-yl-butyric acid (621.0 mg, 3.0 mmol, 1.5 eq) in 1,2-dichloroethane (6 mL), N,N′-carbonyldiimidazole (453.0 mg, 2.8 mmol, 1.4 eq) was added and the mixture was stirred at room temperature for 1 hour. 5-(1H-indol-3-yl)-2H-pyrazol-3-ylamine (400.0 mg, 2.0 mmol, 1.0 eq) in 1,2-dichloroethane (6 mL) was added; the reaction was stirred at room temperature for 2 days, then 1 day at 70° C., to allow complete migration of the acyl group from the ring nitrogen to the exocyclic nitrogen. The reaction then was allowed to cool down to room temperature and the mixture was washed with saturated Na2CO3 and evaporated under reduced pressure; the crude was purified by preparative HPLC to give 320.0 mg (yield: 41%) of the title compound as formate salt.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.OC1C2N=NNC=2C=CC=1.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](O)=[O:31].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]([NH:2][CH:3]([C:9](=[O:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31]
Reactant: CCOC(=O)C(N)C(=O)c1cccs1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1c(F)cccc1F)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a stirred mixture of crude ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (0.44 g), hydroxybenzotriazole monohydrate (0.417 g, 2.7 mmol) and 2,6-difluorobenzoic acid (0.431 g, 2.7 mmol) in DMF (5.5 mL) was added triethylamine (0.38 mL, 5.2 mmol) followed by 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.575 g, 3.0 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between water and DCM. The organic phase was separated, washed with water, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 20% EtOAc in hexane as eluant to afford ethyl 2-(2,6-difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate (0.123 g, 0.35 mmol, 20%). 1H NMR (CDCl3) 1.27 (3H, t), 4.28 (2H, m), 6.21 (1H, d), 7.00 (2H, t), 7.26 (1H, dd), 7.44 (2H, m), 7.83 (1H, dd), 8.20 (1H, dd). LCMS (1) Rt: 2.10 min; m/z (ES+) 354.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
Solid K2CO3 (16.3 g, 0.12 mol, 1.2 equiv) was added to a solution of crude 14 (20.6 g, ˜0.10 mol, 1.0 equiv) in DMF (200 mL) followed by benzyl bromide (17.1 g, 11.9 mL, 0.10 mol, 1.0 equiv). The yellow suspension was heated at to 80° C.-90° C. for 4.5 hr. The mixture was cooled to room temperature and stirred for 48 hr. The mixture was poured into H2O (750 mL) and the aqueous mixture extracted with EtOAc (500 mL). The organic phase was diluted with heptanes (500 mL) and the solution washed with H2O (3×250 mL), brine (300 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving brown oil that crystallized. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded on a column of silica gel (250 g) packed in heptanes. The column was eluted with heptanes (1 L), 2.5% EtOAc/heptanes (2 L) and 5% EtOAc/heptanes (2 L). Product-containing fractions were concentrated under reduced pressure. The slightly oily solid was pumped on high vacuum for 0.5 hr, then triturated with cold heptanes (100 mL), filtered, washed with a small volume of heptanes and dried to give 17.8 g (62%) of 15 as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O>O1CCCC1>[O:29]1[CH2:30][CH2:31][N:26]([CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-bromo-5α-pregnane-3,11,20-trione (500 mg) in dry tetrahydrofuran was treated at reflux with morpholine (0.5 ml) for 1/2 hour, and poured into water. The oily precipitate was extracted into ether and the extracts were washed with water, dried (Na2SO4) and evaporated to the crude product which was purified by preparative t.l.c. in ethyl acetate and crystallisation from ether to give the title compound (220 mg). m.p. 159°-164°C [α]D +98° (c=1.1%)
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.S(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CN1C=CN=C1.CN(C)C(=O)C>C(O)C.O.C(N(CC)CC)C>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cn1ccnc1
Agent: O=S(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A flask containing a stirred mixture of thymidine (5.0 g, 20.6 mmol), diphenyl sulphite (19.34 g, 82.6 mmol), N-methylimidazole (0.34 ml. 4.27 mmol) and N,N-dimethylacetamide (50 ml) was immersed in an oil bath, maintained at 156°±1° C. After 45 minutes, the products were cooled to 0° C. and were then poured, with stirring, into a cooled (0°C.) mixture of triethylamine (50 ml) and water (90 ml). After 40 minutes, by which time it had warmed up almost to room temperature, the resulting solution was extracted with chloroform (4×50 ml). The remaining aqueous layer was concentrated under reduced pressure and the viscous oil obtained was dissolved in absolute ethanol (30 ml), and the solution was re-evaporated. After one further evaporation from absolute ethanol (30 ml) solution, the residue was triturated with ether (3×30 ml). Dichloromethane (50 ml) was then added and the resulting colourless solid precipitate was collected by filtration and washed with dichloromethane (2×10 ml). After the combined filtrate and washings had been concentrated to ca. 30 ml, petroleum ether (b.p. 30°-40° C. 15 ml) was added, and the resulting mixture was refrigerated (4° C.) for 24 hr. A second crop of colourless solid was obtained; it was collected by filtration and was washed with dichloromethane (2×5 ml). The two crops of colourless solid were combined and dried in vacuo at 75° C. to give virtually pure 2,3'-anhydrothymidine [found, in material recrystallized from 90% ethanol and dried in vacuo over P2O5 at 100° C.: C,49.6; H,5.7; N,11.6. C10H12N2O4. H2O requires: C,49.6; H,5.8; N,11.6%]; yield, 3.0 g (64.8%); RF 0.38 [butan-1-ol - acetic acid - water (5:2:3 v/v]; λmax (95% ethanol): 247.5 (ε7 760), λmin 219 nm (ε4 750); δH [d6 -DMSO, 250 MHz]: 1.76(3H,d, J 0.9 Hz), 2.4-2.6 (2H,m), 3.49 (2H,m), 4.19(1H, dt, J 2.4, 6.5 Hz), 5.04 (1H,t, 5.4 Hz), 5.25(1H,m), 5.82 (1H,d, 3.7 Hz , 7.56 (1H,m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[OH-].[NH4+:16]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH2:16])=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (25 g) in ethanol (200 mL) was added 30% ammonium hydroxide (38 mL). After stirring 5 hours at room temperature, the reaction was concentrated in vacuo. The residue was suspended in water and filtered. The filter pad, washed with water then diethyl ether, gave 17.68 g of the title compound, CIMS (1% NH3 in CH4): 242=M+ +C2H5, 214=M+ +H (Base), 213=M+, 168=M+ -OEt.
Reaction SMILES: [N:1]1([CH2:14][C:15]([OH:17])=[O:16])[C:12](=[O:13])[C:11]2[N:9](C)C=N[C:6]=2N(C)[C:2]1=O.O1C=CC[CH2:20][CH2:19]1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>[NH2:9][C@H:11]([C:12]([N:1]1[CH2:2][CH2:20][CH2:19][C@H:14]1[C:15]([OH:17])=[O:16])=[O:13])[CH3:6]
Reactant: C1=COCCC1
Reactant: Cn1cnc2c1c(=O)n(CC(=O)O)c(=O)n2C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The compound 1 and 3,4-dihydro-2H-pyran in CH2Cl2 and pyridinium p-toluenesulfonate are stirred at room temperature for 12 h as indicated in the schematic below. Then the solution is diluted with EtOAc and washed with half-saturated brine to remove the catalyst. The solvent is evaporated and the residue is treated with NaOH(1N) and EtOH for 30 min. The solution is acidified with AcOH, and the product is extracted with EtOAc. The EtOAc solution is dried, evaporated to give the THP ether 2. The compound 2, DCC and HOBT in CH2Cl2 are stirred at room temperature for 60 min. Then MEEA-EDA HCI (N-(2-aminoethyl)[2-(2-maleiimidoethoxy)ethoxy]acetamide) and N-methylmorpholine are added. The reaction is stirred for 2 h., and then quenched by addition of AcOH. The precipitate is removed by filtration. The filtrate is washed with diluted HCl, NaHCO3, and dried. The crude product is used for the next step. The crude product is treated with 2N HCI H2O/EtOH 1:1) for 30 min. EtOH is evaporated. The product is extracted with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, and dried. Evaporation of the solvent gives a residue, which is purified by flash column chromatography to afford 3. This compound can be purified further by HPLC on a reverse phase column and lyophilized to produce the modified MMPI.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:19])[S-:18])[CH:13]=[CH:12][CH:11]=1.C([NH+](CC)CC)C.C(OC(C)C)(C)C>C(#N)C>[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:18])[S:19][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: Cc1cccc(NC(=S)SCC(=O)C(C)(C)C)n1
Temperature: 2 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (40.0 g) is added to a suspension of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (64.0 g) in anhydrous acetonitrile (600 cc) at a maximum temperature of 20° C. The reaction is continued for 2 hours at 20° C. The insoluble hydrobromide of triethylamine is removed by filtration and washed with acetonitrile (50 cc). The organic phases are combined and evaporated under reduced pressure (20 mm.Hg) at 45° C. The residual oil is treated with diethyl ether (1200 cc). After 1 hour at 20° C., the ethereal solution is filtered, washed twice with distilled water (total 400 cc), dried over sodium sulphate and evaporated. The product obtained (60.0 g) is dissolved in boiling diisopropyl ether (870 cc) and the boiling solution is filtered. After 1 hour's cooling at 2° C., the resulting crystals are filtered off, washed twice with ice-cold diisopropyl ether (total 100 cc) and dried under reduced pressure (0.1 mm.Hg) at 40° C. to give 3,3-dimethyl-2-oxobutyl (6-methylpyrid-2-yl)dithiocarbamate (44.1 g) melting at 80° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].Cl[S:13]([OH:16])(=[O:15])=[O:14]>ClC(Cl)=C(Cl)Cl>[NH2:4][C:3]1[C:2]([F:1])=[C:8]([F:9])[C:7]([F:10])=[C:6]([F:11])[C:5]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1cc(F)c(F)c(F)c1F
Solvent: ClC(Cl)=C(Cl)Cl
Product: Nc1c(F)c(F)c(F)c(F)c1S(=O)(=O)O
Yield: 102 %

Procedure:
2,3,4,5-Tetrafluoroaniline (16.5 g, 0.1 mol) was added dropwise over 20 minutes with stirring to a mixture of chlorosulfonic acid (14 g, 0.12 mol) in tetrachloroethylene (100 mL) with ice bath cooling. A yellow precipitate formed immediately.. When the addition was complete, the mixture was heated at reflux for three hours, during which a light tan granular solid formed. The solid was collected by filtration, washed with ether, and dried in vacuo to give the title compound (25 g); m.p. 272°-276° .
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:13])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][C:24](Cl)=[O:25].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][C:24]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:8]=2[CH:9]=1)=[O:25]
Reactant: CCN1C(=O)COc2ccccc21
Reactant: COc1ccc(CC(=O)Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 1, 4-ethyl-4H-benzo[1,4]oxazin-3-one (10.2 g) was reacted with (2-chloro-4-methoxy-phenyl)-acetyl chloride and AlCl3 in 1,2-dichloroethane 3 h at 0° C. The crude product was purified by column chromatography (silica gel, heptane/AcOEt 2:1) to give the title compound (12.3 g) as a white solid. MS (m/e)=360.1 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:21][C:17]1[CH:16]=[C:15]([CH2:14][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(N)c1
Yield: 101.1 %

Procedure:
A suspension of platinum oxide (0.35 g) in ethyl acetate (100 ml) containing methyl 4-chloro-2-(3-nitrophenyl)acetamidobenzoate (9.96 g, 28.6 mmol) was shaken under an atmosphere of hydrogen at 40 psi until hydrogen uptake had ceased. The suspension was filtered and the filtrate evaporated to leave methyl 2-(3-aminophenyl)acetamido-4-chlorobenzoate as a pale green solid (9.22 g); δ (CDCl3) 3.65 (2H, s, CH2), 3.66 (3H, s, OCH3), 6.61 (1H, dd, J 7.9 and 2.1 Hz, ArH), 6.70 (1H, s, ArH), 6.74 (1H, d, J 7.6 Hz, ArH), 7.01(1H, dd, J 8.6 and 2.0 Hz, 5-H), 7.14(1H, d, J 7.7 Hz, ArH), 7.89(1H, d, J 8.6 Hz, 6-H), 8.81 (1H, d, J 2.0 Hz, 3-H) and 11.03 (1H, br s, CONH).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[C:1]([N:21]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[O:13])[C:15]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c1C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C(=O)OC(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cccc(C)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (423 mg, 1.62 mmol) followed by titanium isopropoxide (645 mg, 2.27 mmol) to 6-Methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (423 mg, 1.62 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (6.7 mL) and sodium borohydride (92 mg, 2.43 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-6-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (27 mg, 3%). Add acetic anhydride (0.037 mL, 0.39 mmol) dropwise to a solution of the amine (27 mg, 0.055 mmol) and pyridine (0.038 mL, 0.43 mmol) in dichloromethane (0.5 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (28 mg, 96%); MS (ES+): 531 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:16])C.C(O)(=O)C.Br>[Ti]>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Agent: [Ti]
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 148.88888888888889 °C
Reaction time: 0.42 h

Procedure:
One hundred and sixty-six (166) g (0.933 mole) of p-acetoxyacetophenone, 100 g (0.98 mole) of acetic anhydride, 250 g (4.17 moles) of acetic acid, 3.5 g (0.0014 mole) of Co(OAc)2.4H2O, 3.5 g (0.0014 mole) of Mn(OAc)2.4H2O, and 4.7 g (0.0028 mole) of 48% HBr were combined in a two-liter titanium-clad autoclave. The reaction mixture was heated to 300° F. and pressurized to 300 psi. Air was introduced at a rate of 0.75 scf/min. During the run, a solution of 54 g (0.53 mole) of acetic anhydride and 13 g (0.217 mole) of acetic acid was added through a pump. The run time was 25 minutes. Analyses of the total reactor effluent and wash showed: p-acetoxybenzoic acid, 87 mole % yield, p-hydroxybenzoic acid, 1.2 mole % yield, and p-acetoxyacetophenone, 3.5 mole % yield.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[C:8]([CH3:14])[CH:7]=1)([OH:3])=[O:2].C(OCC)(OCC)OCC.O>FC(F)(F)C(O)=O>[CH:11]([C:9]1[NH:10][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][C:8]=1[CH3:14])=[O:12]
Reactant: Cc1cc(CCC(=O)O)[nH]c1C(=O)O
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A solution of 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid (1.3 g, 6.59 mmol) in trifluoroacetic acid (6 mL) was stirred at room temperature for 10 minutes. It was then cooled to 0° C. and to it was added triethyl orthoformate (6 mL). The mixture was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes. The reaction was poured into water (50 mL) and extracted with ethyl acetate. The extract was dried and concentrated to give 1.2 g of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (br s, 1H), 11.50 (br s, 1H), 9.44 (s, 1H, CHO), 5.85 (s, 1H), 2.74 (t, J=7.4 Hz, 2H, CH2), 2.54 (t, J=7.4 Hz, 2H, CH2), 2.23 (s, 3H, CH3). MS 182 [M++1].