Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:17]1([C:15]([NH:14][C:12]2[NH:11][C:10]3[CH:20]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)[CH:7]=[CH:8][C:9]=3[N:13]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (159 mg, 516 μmol) and 3-(trifluoromethyl)benzoic acid (191 mg, 1.01 mmol) in pyridine (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (375 mg, 1.96 mmol) and N,N-dimethylpyridine-4-amine (18.5 mg, 151 μmol), and the mixture was stirred at room temperature for 12 hr. Methanol (5 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was diluted with methanol (1 mL) and ethyl acetate (30 mL), washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and the obtained crude crystals were recrystallized from acetone and diisopropyl ether to give the title compound (135 mg, 54%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13]C(=O)C(C)(C)C)=O)C.[OH-].[K+].[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[CH3:24]>C(O)C.[OH-].[Na+]>[C:26]1([C:23]2[CH:24]=[C:5]([C:4]([OH:20])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[N:9][CH:8]=3)[N:13]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(=O)c1cnccc1NC(=O)C(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)nc2ccncc12
Temperature: 100 °C

Procedure:
[4-(2,2-Dimethyl-propionylamino)-pyridin-3-yl]-oxo-acetic acid ethyl ester (532 mg, 1.91 mmol) was taken up in ethanol (1.9 mL) and 4N KOH (1.9 mL, 4 equiv) was added. The solution was refluxed for 2-3 h at 100° C., acetophenone (0.446 mL, 2.0 equiv) was added neat, and the reaction was allowed to reflux overnight. Upon cooling to room temperature, the solution was diluted with 1N NaOH and extracted twice with ether. The product was precipitated from the aqueous layer by the addition of glacial AcOH (5-10 mL). The solids were collected by vacuum filtration, rinsed with cold water, and dried under high vacuum (white solid, 371 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.80 (d, J=5.6 Hz, 1 H), 8.56 (s, 1 H), 8.35-8.31 (m, 2 H), 8.03 (d, J=6.0 Hz, 1 H), 7.61-7.58 (m, 3 H). MS (LR-APCI) calcd. for C15H11N2O2 (M+H) 251.1; found 251.5.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13]>>[C:1]1([CH2:7][C:8]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Using General Procedure II-C, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([C:20]#[N:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile (5.1 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL water, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.6 g (15.5 mmol, 90%) of 6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile as an oil. MS: 298 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[CH2:3][CH3:4].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10]>C(Cl)(Cl)(Cl)Cl>[C:8]([O:7][C:2]([CH3:1])([CH2:5][CH3:6])[CH2:3][CH3:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC(C)(O)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)OC(C)(CC)CC
Temperature: 25 °C

Procedure:
Into a 100 ml long neck round bottom flask with a vacuum adapter is placed about 2 g of 3 A molecular sieves. The flask is connected to a vacuum line and placed under reduced pressure of about 0.02 mm of Hg. It is then heated, causing gas (air) to evolve from the sieves. Heating is continued until gas evolution ceases. Then the flask is allowed to cool to room temperature and the vacuum adapter is removed. Solvent in the form of 50 ml of carbon tetrachloride is then added to the flask along with 25 mmol of 3-methyl-3-pentanol and 25 mmol of methacryloyl chloride. A magnetic stirring bar is added to the contents of the flask and a condenser with a drying tube is attached to the neck of the flask. Then the flask and its contents are placed in a hot water bath and heated for 185 hours while being subjected to magnetic stirring. The contents of the flask are then cooled and filtered through a celite pad, filtered through a 20 cm Al2O3 column, the column washed with 100 ml of CH2Cl2 and the solvents are then evaporated under reduced pressure. The resulting product is pure monomeric 3-methyl-3-pentyl methacrylate ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH2:10]1COCC1.C[Mg]Br>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:9])[CH3:10])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc(Br)ccn1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccn1
Temperature: -78 °C

Procedure:
An oven-dried flask was cooled under argon, and to it was added 4-bromopicolinaldehyde (2.98 g, 16 mmol) and anhydrous THF (50 mL). The mixture was cooled to −78° C., and 3M methylmagnesium bromide in Et2O (6.4 mL) was added dropwise. The mixture was then allowed to warm slowly to room temperature, whereupon it was quenched with saturated NH4Cl solution. The aqueous layer was extracted with EtOAc, dried over Na2SO4, concentrated, and purified by column chromatography (gradient 0 to 60% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=5.3 Hz, 1H), 7.57-7.48 (m, 1H), 7.38 (dd, J=5.3, 1.4 Hz, 1H), 4.88 (q, J=6.6 Hz, 1H), 3.84 (br s, 1H), 1.51 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([O:46][C:47]([O:49]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:42][CH2:41]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([O:46][C:47]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:49])[CH2:44][CH2:45]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)N2CCCCC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of piperidine (382 μl, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.85 g of an oil. Purification of the oil on silica gel (230-400 mesh) using 5%-20% ethyl acetate-methylene chloride as the eluent gave 1.23 g (68%) of the title compound as a white crystalline solid, mp 56°-61° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:30]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COc1ccc(CN)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(OC)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.10 g, 0.28 mmol) was treated with p-methoxybenzylamine (0.05 mL, 0.4 mmol). Purification using silica gel, eluting with 5:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from EtOAc to give 105 as a white solid (m.p. 255-256° C.).
Reaction SMILES: [Br-].[Mg+2].[Br-].[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[NH4+].[Cl-:19]>C1COCC1>[Cl:19][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][O:4][CH2:9][CH2:8]3)=[CH:17][CH:16]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: [Cl-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: [Br-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluorophenyl)magnesium bromide (1M in THF, 10.6 ml. 10.6 mmol) at 0° C. was added a solution of 4-morpholinobenzaldehyde (1 g, 5.233 mmol) in THF (10 ml) dropwise. After being stirred at 0° C. for 10 minutes and room temperature for 4 hours, the reaction mixture was poured onto an iced aqueous NH4Cl. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give (4-chlorophenyl)(4-morpholinophenyl)methanol as a pinkish white solid (1.49 g, 99 yield). HPLC (Column: Shimadzu VP-0DS, C-18 Ballistic; 10-90% aq CH3OH/0.1% H3PO4, same for compounds hereafter unless noted) Rt: 2.117 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cnn(C)c2)on1
Reaction time: 24 h
Yield: 13.8 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 12 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H), 4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d, 1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.O>O1CCCC1>[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33][N:2]([CH3:1])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: CNC(=O)c1ccncc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cnccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 226 mg (1 mmol) N-methyl-3-o-tolyl-isonicotinamide in 10 ml tetrahydrofuran were added dropwise 1.3 ml (1.3 mmol) 1M potassium hexamethyldisilazide solution in tetrahydrofuran at room temperature. The white suspension was stirred for 30 min at room temperature and 0.18 ml (1 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added at the same temperature. The light brown suspension was stirred for 1 h and water was added. The aqueous layer was separated and washed with ethyl acetate. The combined organic layers were washed twice with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 440 mg (97%) of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][C:15]=2[Cl:20])[CH:13]=1)[C:8]([OH:10])=O)=[O:4].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:20][C:15]1[S:16][C:17]([Cl:19])=[CH:18][C:14]=1[C:12]1[CH:11]=[C:7]([C:8](=[O:10])[NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:6]=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: CN(C)CCN
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2cc(Cl)sc2Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.3 %

Procedure:
To a mixture of 3-methoxycarbonyl-5-(2,5-dichlorothiophen-3-yl)benzoic acid (0.7 g), N,N-dimethylethylenediamine (0.186 g) and 1-hydroxybenzotriazole (0.314 g) in dichloromethane (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.446 g) under ice cooling, and the solution was stirred for 7 hours at room temperature. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate solution with stirring. The organic layer was successively washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 5-(2,5-dichlorothiophen-3-yl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate (0.57 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(O)(=O)C>CO>[I:15][C:12]1[S:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1-c1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1ccc(I)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-nitro-phenyl)-thiophene (23 g, 0.11 mol) and N-iodosuccinimide (37 g, 0.165 mol) were dissolved in 110 ml of methanol. To this solution, acetic acid (10 g, 0.165 mol) was added. After stirring the reaction mixture for 4 hours at room temperature, the solvent was evaporated. The remainder was taken up in a mixture of ice and water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated, delivering 2-iodo-5-(2-nitro-phenyl)-thiophene (28 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]2[O:13][CH2:14][CH2:15][O:16][C:6]=2[CH:5]=1>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([NH2:10])=[CH:8][C:7]2[O:13][CH2:14][CH2:15][O:16][C:6]=2[CH:5]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1N)OCCO2

Procedure:
A mixture of 6.0 g. of 6-nitro-3,4-ethylenedioxybenzoic acid methyl ester, 150 mg. of 5% palladium on charcoal and 20 mls. of glacial acetic acid is hydrogenated under an initial hydrogen pressure of 30-40 p.s.i. and without external heating. After four hours the reaction mixture is filtered diluted with 80 ml. of ice water, stirred up one half hour and the resulting precipitate filtered off, water washed and dried to obtain 6-amino-3,4-ethylenedioxybenzoic acid methyl ester, m.p. 73°-77° C.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])(O)=[O:2].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:14][C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])=[O:2]
Reactant: Cc1cc(Cl)c(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a suspension of 2-carboxy-3-chloro-5-methylthiophene (1.2 g, 6.6 mmol) in methylene chloride (16 mL) at 0° C. were added oxalyl chloride (0.6 mL, 7.3 mmol) and a drop of DMF. The mixture was stirred at ambient temperature for 5 hours, then concentrated of all volatiles and dried in vacuo to afford 1.3 g (quantitative yield) of 2-chlorocarbonyl-3-chloro-5-methylthiophene as a pale yellow solid; NMR (DMSO-d6/TFA) 7.4 (s, 1), 2.5 (s, 3) ppm.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24](/[N:28]=[CH:29]\[NH:30]O)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]2[N:30]=[CH:29][N:28]=[C:24]2[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ON/C=N\c1cc(OCc2ccccc2)ccn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(COc2ccn3ncnc3c2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Trifluoroacetic anhydride (2.62 mL, 18.9 mmol) was added dropwise to a solution of (Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N-hydroxyformamidine (4.37 g, 17.9 mmol) in THF (180 mL), and the mixture was cooled to 0° C. The ice bath was then removed and the reaction was stirred for 12 hours. The reaction was concentrated to about 15-25 mL, then poured into 400 mL of iced 1 M NaOH. The mixture was stirred for 1 hour. The resulting white solids were collected by filtration, washed with hexanes, and dried under high vacuum for 1 hour to provide the desired product.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][O:4][N:3]1[C:13](Cl)=[O:14].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18]>ClCCl>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:13]([N:3]1[O:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]1[CH3:1])=[O:14])[CH:17]=[CH2:18]
Reactant: CC1c2ccccc2CCON1C(=O)Cl
Reactant: C=CCNCC=C
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)N1OCCc2ccccc2C1C

Procedure:
A solution of 2.6 g. of 88 percent 1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine-2-carbonyl chloride in 20 ml. of dichloromethane was added at room temperature to a solution of 2.23 g. of diallylamine in 30 ml. of dichloromethane. The mixture was then refluxed for two hours and after cooling was washed sequentially with aqueous 5 percent HCl, with aqueous sodium bicarbonate and with water. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was distilled at 140° C./0.02 mm Hg. Yield 2.3 g.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[BH4-].[Na+]>O>[OH:17][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]=2[CH:11]=[CH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1C=Cc1ccccc1C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
26 g. of 1-Methyl-5H-dibenzo[a,d]cyclohepten-5-one are dissolved in 200 ml. of dioxane, a solution of 9 g. of sodium borohydride in 35 ml. of water is added thereto and the mixture is stirred at room temperature for 4 hours. The mixture is subsequently evaporated under reduced pressure. The residue is shaken with ether and water. The ethereal phase is washed with water, dried over sodium sulfate, filtered and evaporated. The 5-hydroxy-1-methyl-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from petroleum ether and melts at 114°-116°C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][C:15]=2[N:16]=1.[CH2:25](O)[CH2:26][OH:27]>C1C=CC=CC=1>[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: O=CCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Reactant: OCCO
Solvent: c1ccccc1
Product: c1ccc2cc(Cc3nc4cc(CCC5OCCO5)ccc4o3)ccc2c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (2.9 g), ethylene glycol (0.685 g), P-toluenesulfonic acid monohydrate (0.175 g) and benzene (50 ml) was stirred for 3 hours under reflux. The reaction mixture was successively washed with aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate (MgSO4). The solvent was distilled off, whereby 5-[2-(1,3-dioxolan-2-yl)ethyl]-2-(2-naphthylmethyl)benzoxazole (2.95 g, 89%) was obtained. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms. Melting point: 85-86° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2cc(C(F)(F)F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a solution of 5-(trifluoromethyl)indan-1-one (0.7 g, 3 mmol) in THF (5 mL) cooled in an ice bath was added sodium borohydride (0.1 g, 3 mmol) followed by MeOH (1 mL). After being stirred for 30 min, the reaction was quenched with aqueous NaHCO3. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and, concentrated. The crude material was purified by flash chromatography on silica eluting with 20% EtOAc/hexane to afford the desired product (0.65 g, 92%) as an oil. LC/MS calculated for C10H9F3O: (M+H)+ 203; found 185.1 (M+H—H2O)+.