Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.Cl[C:44]1[N:53]=[CH:52][C:51]2[C:46](=[CH:47][C:48]([Cl:54])=[CH:49][CH:50]=2)[N:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[Cl:54][C:48]1[CH:47]=[C:46]2[C:51]([CH:52]=[N:53][C:44]([N:22]3[CH2:23][CH:24]([C:26]4[C:27]([C:32]5[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=5)=[N:28][CH:29]=[CH:30][N:31]=4)[CH2:25]3)=[N:45]2)=[CH:50][CH:49]=1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ncc4ccc(Cl)cc4n3)C2)cc1F
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
4-(3-(Azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.150 g, 0.239 mmol), 2,7-dichloroquinazoline (0.062 g, 0.310 mmol), and potassium carbonate (0.165 g, 1.19 mmol, Aldrich) were mixed in butan-1-ol (2 mL) in a sealed tube. The reaction mixture was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mixture was purified via silica gel flash column chromatography eluting with 50% to 100% EtOAc in hexanes to yield give 99 mg (92%) of a light yellow solid. 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3 H) 4.29-4.38 (m, 1 H) 4.46-4.58 (m, 4 H) 6.75-6.85 (br. m., 1 H) 7.18 (dd, J=8.61, 1.56 Hz, 1 H) 7.36 (d, J=12.32 Hz, 1 H) 7.40 (dd, J=8.12, 1.27 Hz, 1 H) 7.60 (d, J=8.41 Hz, 1 H) 7.63 (br. s., 1 H) 8.27 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.15 Hz, 1 H) 8.65 (d, J=2.15 Hz, 1 H) 8.97 (s, 1 H). m/z=449 (M+1).
Reaction SMILES: O[Li].O.[CH3:4][C:5]1[CH:10]=[C:9]([NH:11][CH3:12])[CH:8]=[C:7]([CH3:13])[C:6]=1/[CH:14]=[CH:15]/[S:16]([N:19]1[CH2:24][CH2:23][C:22]([NH:28][C:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]2([CH3:42])[CH2:41][O:40][CH2:39]2)([C:25]([NH2:27])=[O:26])[CH2:21][CH2:20]1)(=[O:18])=[O:17].[Cl-].[NH4+]>C(O)C>[CH3:13][C:7]1[CH:8]=[C:9]([NH:11][CH3:12])[CH:10]=[C:5]([CH3:4])[C:6]=1/[CH:14]=[CH:15]/[S:16]([N:19]1[CH2:24][CH2:23][C:22]2([N:28]=[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3([CH3:42])[CH2:39][O:40][CH2:41]3)[NH:27][C:25]2=[O:26])[CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC(NC(=O)CCCCCCCCC3(C)COC3)(C(N)=O)CC2)c(C)c1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(CCCCCCCCC2(C)COC2)NC3=O)c(C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
LiOH.H2O (16.6 mg, 0.396 mmol) was added to a solution of 1-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-4-[9-(3-methyl-oxetan-3-yl)-nonanoylamino]-piperidine-4-carboxylic amide (96 mg, 0.098 mmol) in ethanol (1.0 mL), and the mixture was stirred at 50° C. for two hours. A 50% saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 8-[(E)-2-(2,6-Dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-2-[8-(3-methyl-oxetan-3-yl)-octyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (54.8 mg, 100%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)=[N+]=[N-].S([O-])([O-])(=O)=O.[Mg+2].[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[CH:28]=O>[Pd].C(O)C.C(Cl)Cl>[CH2:32]([O:31][C:27](=[O:30])[CH:28]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CN=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.499 g (1.81 mmole) of cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40° for 1 hour. The solution was filtered through celite and the solvent was removed in vacuo to afford a colorless gum which was dissolved in 15 ml of methylene dichloride. Anhydrous magnesium sulfate was added followed by addition of a solution of 0.314 g (1.91 mmole) of benzyl glyoxalate in 10 ml of methylene dichloride. The reaction mixture was stirred at room temperature under argon for 2.5 hours then was allowed to stand at 0° overnight. After filtering the reaction mixture, the solvents were removed in vacuo to give a semi-crystalline residue which was recrystallized from ethyl acetate-hexane to give N-(cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl)iminoacetic acid benzyl ester as a colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]([OH:25])=[O:24])=[O:34])(=[O:11])=[O:12]
Reactant: O=C(O)CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (44 mg, 0.11 mmol) in CH2Cl2 (2 ml) and acetonitrile (2 ml) was added mCPBA (27 mg, ˜0.11 mmol). The reaction was stirred at room temperature for 4 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20-30% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (34 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.[CH2:26](Br)[C:27]#[CH:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:27]#[CH:26])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(2-propynyloxy) -phenyl]-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.35 ppm (d,1H), 6.98 ppm (d,1H), 6.67 ppm (s,1H), 4.77 ppm (m,2H), 3.99 ppm (s,3H), 2.58 ppm (t,1H);
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(OCC)(OCC)(OCC)C>[CH3:13][C:14]1[O:11][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc(C(=O)O)c1O
Agent: CCOC(C)(OCC)OCC
Solvent: O
Product: Cc1nc2cccc(C(=O)O)c2o1

Procedure:
A solution of 3-amino-2-hydroxy-benzoic acid (9.40 mmol) and p-toluenesulfonic acid monohydrate (0.34 mmol) in triethyl orthoacetate (5.77 mL) is heated to reflux for 5 h and concentrated in vacuo. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]1([NH:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:28]([CH2:29][CH2:30][OH:31])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OCCNC1CCCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N(CCO)C1CCCC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2-(cyclopentylamino)ethanol to give 289. MS: (ESI+)=425.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=O)[CH3:13]>OS(O)(=O)=O>[CH3:13][C:12]1[C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[CH3:8])[N:9]=[C:10]([OH:15])[CH:11]=1
Reactant: CC(=O)CC(=O)Nc1cc(C)ccc1C
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c(C)cc(O)nc12
Temperature: 25 °C
Yield: 28 %

Procedure:
A 5.50 g (26.8 mmol) sample of N-(2,5-dimethylphenyl)-3-oxobutanamide in 10.0 mL of H2SO4 was microwaved at 140° C. for 5 minutes. After the reaction was cooled to room temperature it was quenched into ice-H2O. The resulting mixture was basified with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were washed with H2O (1×15 mL), brine (1×20 mL), dried over MgSO4 and concentrated to give the desired title compound (1.4 g, 28%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.41 (s, 3 H) 2.69 (d, J=1.17 Hz, 3 H) 2.73 (s, 3 H) 6.48 (s, 1 H) 6.90 (d, J=7.33 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 8.87 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:4][CH:3]=1.CC(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[OH:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccccc1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred and refluxing mixture of 23.4 parts of (4-chlorophenyl) (2-fluorophenyl)methanone in 280 parts of 2-propanol are added portionwise 3.7 parts of sodium borohydride. Upon completion, stirring is continued for 2 hours at reflux temperature (±80° C.). The reaction mixture is cooled and decomposed by the addition of water. The 2-propanol is evaporated and the residual product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 4-chloro-α-(2-fluorophenyl)benzenemethanol as a residue.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([NH:15][CH:16]([CH3:19])[CH2:17][OH:18])=[O:14])=[O:4].CN(C)C(CCCCCC1C=C(C=CC=1)C(NC(C)CO)=O)=O>>[CH3:23][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([NH:15][CH:16]([CH3:19])[CH2:17][OH:18])=[O:14])=[O:4]
Reactant: CC(CO)NC(=O)c1cccc(C=CCCCC(=O)N(C)C)c1
Agent: CC(CO)NC(=O)c1cccc(CCCCCC(=O)N(C)C)c1
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)N(C)C)c1

Procedure:
The alkyne 8 (0.100 g, 0.3 mmol) was synthesized by Lindlar catalyzed reduction using method E to obtain a mixture of 16 and 3-(5-dimethylcarbamoyl-pentyl)-N-(2-hydroxy-1-methyl-ethyl)-benzamide (13) which were separated by reverse-phase HPLC chromatography (20% acetonitrile/80% water 20 min isocratic program) (16, 34 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:9]=[C:10](Br)[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[F:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)c(F)c(N)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccc2)c(F)c(N)c1OC
Temperature: 90 °C
Reaction time: 36 h
Yield: 92.1 %

Procedure:
Methyl 3-amino-5-bromo-4-fluoro-2-methoxybenzoate (I-230) (504 mg, 1.81 mmol) was dissolved in 1,4-dioxane (10 ml), then under nitrogen atmosphere at room temperature, phenylboronic acid (456 mg, 3.62 mmol), tripotassium phosphate (770 mg, 3.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.18 mmol) were added. After stirred at 90° C. for 36 hours, this was cooled to room temperature. The insoluble matter was separated by filtration with washing with ethyl acetate, the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:1) to obtain the entitled compound (459 mg, 92%) as a colorless gel substance.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:36])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:37].[H][H]>[Pd].CC(O)C>[ClH:37].[NH2:11][CH2:12][C:13](=[O:36])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17]
Reactant: [H][H]
Reactant: O=C(CCC(=O)OCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCC(=O)O
Yield: 69.2 %

Procedure:
This compound was prepared from the product of 10b (0.70 g; 1.4 mmol), 12 M HCl (0.12 mL; 1.4 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.30 g (70%) product was obtained (white solid).
Reaction SMILES: C[Li].[CH2:3]([O:5]CC)[CH3:4].[CH3:8][C:9]1([CH3:36])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3([CH3:35])[C:25]4[CH:26]=[C:27](C=CC(O)=O)[CH:28]=[CH:29][C:24]=4[O:23][CH2:22]3)[CH:12]=[CH:11][C:10]1=2.Cl>C1COCC1>[CH3:35][C:21]1([C:13]2[CH:12]=[CH:11][C:10]3[C:9]([CH3:8])([CH3:36])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]=3[CH:14]=2)[C:25]2[CH:26]=[C:27]([C:3](=[O:5])[CH3:4])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CCOCC
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C=CC(=O)O)cc43)ccc21
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
A 1.6M methyllithium solution in ethyl ether (3.4 ml, 5.4 mmol) is added to a solution of 3-Methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-carboxylic acid (Example 2) (900 mg, 4.47 mmol) in THF (50 ml) at -20° C. The mixture is stirred for 4 h at -20° C. and is then poured onto ethyl acetate and a 1N hydrochloric acid solution. The organic phase is washed 2 times with water, dried over anhydrous magnesium sulphate and concentrated in vacuo at 40° C. in a rotary evaporator.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH3:4][CH2:5][CH3:6].[C:7]([OH:10])(=[O:9])[CH3:8]>>[CH2:1]=[CH:2][CH3:3].[C:7]([O:10][CH:5]([CH3:6])[CH3:4])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CCC
Solvent: C=CC
Product: CC(=O)OC(C)C

Procedure:
In a continuous autoclave with a reaction volume of 200 ml, at 110° C. and 40 bar, 16.9 g of propylene, 34.4 g of propane and 116.7 g of acetic acid per hour are reacted in the presence of 15.7 g of “Amberlyst 35 wet” as a catalyst. The effluent stream is decompressed, and the liquid and gaseous phase are analyzed separately by GC. At a propylene conversion of 90%, isopropyl acetate is obtained with a selectivity of over 96%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[NH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[C:1]([CH3:2])=[O:3]
Reactant: CC(=O)Nc1ccccc1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C

Procedure:
81.3 g of acetanilide are suspended in 600 ml of carbon disulphide and 76.7 g of butyryl chloride and, in portions, 198 g of aluminium trichloride are added while stirring. The mixture is stirred for some time at 30°-35° and heated at the boil for 18 hours. It is then allowed to cool, stirred into 200 ml of ice-water and extracted twice with 500 ml of ethyl acetate each time. The organic phases are combined, washed with 500 ml of additional acid and twice with 500 ml of 15% strength sodium carbonate solution each time, dried over magnesium sulphate and concentrated to 150 ml under reduced pressure. The residue obtained by concentration is allowed to cool, filtered with suction, washed twice with diethyl ether and dried under reduced pressure. p-Acetaminobutyrophenone having a melting point of 141°-143° is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.94 min; [M+H]+=395.16.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: COc1ccc(I)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-n2c3ccccc3c3ccccc32)cc1

Procedure:
A mixture of 9H-carbazole (5.51 g, 33 mmol, available from Aldrich, Milwaukee, Wis.), 4-iodoanisole (10 g, 43 mmol, available from Aldrich), powdered potassium carbonate (36.43 g, 264 mmol), copper powder (8.38 g, 132 mmol) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane, 0.56 g, 2.1 mmol, obtained from Aldrich) was refluxed in o-dichlorobenzene (30 ml, obtained from Aldrich) under nitrogen for 24 hours. The copper and inorganic salts were filtered. The solvent was removed by distillation. The product, 9-(4-methoxyphenyl)carbazole, was recrystallized, washed with methanol, filtered, and dried. The yield was 8.432 g (93.7%). The 1H-NMR spectrum (300 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 4.04 (s, 3H, OCH3), 7.24-7.63 (m, 8H, Ar.), 8.35-8.40 (m, 4H, Ar.). The 13C-NMR spectrum (75.4 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 55.95 (OCH3), 110.07, 115.44, 120.03, 120.68, 123.53, 126.25, 128.90, 130.65, 141.78, 159.26 (all Ar). The infrared absorption spectrum of the product was characterized by the following the following absorption frequencies (KBr windows, in cm−1): 3040 (C—H Ar), 2900 (C—H Alk), 1250 (C—O—C). The mass spectrum of the product was characterized by the following ions (in m/z): 274 (M+).
Reaction SMILES: [NH3:1].[C:2]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13]C)=O)[CH2:7]1)(=[O:4])[CH3:3]>CO>[C:2]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([NH2:1])=[O:13])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@H](NC(C)=O)C1
Solvent: CO
Product: CC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ammonia gas was passed into a solution of (1R,3S)-methyl 3-acetamidocyclopentanecarboxylate (180 mg, 0.96 mmol) in MeOH (5 ml) at −78° C. in a pressure bomb. The reaction mixture was slowly warmed up to room temperature and stirred for 18 h at 100° C. The reaction mixture was concentrated under reduced pressure to afford 150 mg of (1R,3S)-3-acetamidocyclopentanecarboxamide as brown oil.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.S(Cl)([Cl:21])=O.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:21][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1
Reactant: CCOC(=O)C1CCC(O)C=C1c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-hydroxy-2-phenylcyclohex-2-enecarboxylate (100 mg, 0.407 mmol) in toluene(2 ml) was added thionyl chloride(0.074 ml, 1.02 mmol) at 5° C. After stirring for 3 hr. at room temperature. AcOEt was added to the reaction mixture and it was washed with water, sat.NaHCO3 aq. and brine, dried over MgSO4. Concentration of the organic layer afford 110 mg of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate(y=100%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.25-7.37(5H, m), 6.27 and 6.18(1H, d and t, J=4.6 and 1.7 Hz), 4.87-4.91 and 4.74-4.79(1H, m), 4.03 and 3.96(2H, q, J=6.9 and 7.1 Hz), 3.68-3.76(1H, m), 2.05-2.37(4H, m), 1.09 and 0.97(3H, t, J=6.9 and 7.1 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].[CH2:46]([O:48][C:49]1[C:50](=O)[C:51](=[O:56])[C:52]=1[O:53]CC)[CH3:47]>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:50]2[C:51](=[O:56])[C:52](=[O:53])[C:49]=2[O:48][CH2:46][CH3:47])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNc2c(OCC)c(=O)c2=O)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reaction time: 6 h

Procedure:
To a solution of 100 mg of 4-((S)-3-Amino-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml DCM and 0.1 ml triethylamine, 32 mg 3,4-Diethoxy-cyclobut-3-ene-1,2-dione was added at RT. After stirring for 6 h, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.