Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[CH:44]=[CH:43][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[C:20]([F:45])[CH:19]=1>ClCCCl.CN(C)C=O.C(OCC)(=O)C>[F:45][C:20]1[CH:19]=[C:18]([NH:17][C:12]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:44]=[CH:43][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])[CH:24]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)c(F)c1
Reactant: NC(=O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCCC4)CC3)c2)c(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
2-Phenylacetamide (203 mg) was dissolved in 1,2-dichloroethane (20 ml) under a nitrogen atmosphere, and then oxalyl chloride (0.174 ml) was added thereto, followed by stirring at 120° C. overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere. 4-(4-Amino-2-fluorophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (295 mg) was then added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under a reduced pressure to give a brown powder residue, which was then dissolved in ethyl acetate (10 ml) to extract with 1 N hydrochloric acid (5 ml). To the aqueous layer was added a 1 N aqueous solution of sodium hydroxide dropwise to make it neutral, followed by stirring overnight. The precipitated solid was filtered off, washed with water, and dried under aeration at 60° C. to provide the titled compound (116 mg, 28%) as pale pink powder.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([OH:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([OH:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)C=CCOc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
To a solution of N-[2-(4-(3-carbomethoxyprop-2-eneoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.5 g) in absolute ethanol (50 ml) was added 10% Pd/C (200 mg) and the mixture hydrogenated at ambient temperature and atmospheric pressure until hydrogen uptake had ceased,(approximately 30 minutes). The mixture was filtered and the ethanol evaporated to leave N-[2-(4-(3-carbomethoxypropoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine as a light yellow oil which crystallised from hexane (1,0 g) m.p. 50°-60°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl-].C[Al+]C.[OH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24](OCC)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:18]=2[CH:19]=1>ClCCCl>[OH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=3)[C:18]=2[CH:19]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CO)oc2c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(CO)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a solution of 2-amino-5-methyl pyridine (305 mg, 2.82 mmol) in DCE (10 mL) at 0° C. was added dimethylaluminum chloride (1M in hexanes, 2.82 mL) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(hydroxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (110 mg, 0.282 mmol) was then added, and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (90 mg, 71%) as a white solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 3.20 (s, 3 H) 4.58 (d, J=5.84 Hz, 2 H) 5.60 (t, J=5.84 Hz, 1 H) 6.61 (s, 1 H) 7.24 (d, J=8.67 Hz, 2 H) 7.66 (dd, J=8.48 , 2.26 Hz, 1 H) 7.70 (s, 1 H) 7.93 (d, J=8.67 Hz, 2 H) 8.06 (d, J=8.48 Hz, 1 H) 8.22 (d, J=2.26 Hz, 1 H) 8.24 (s, 1 H) 10.83 (s, 1 H). LCMS m/z 453.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]=1[CH3:30])=[O:15].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:10])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[CH3:30])=[O:15]
Reactant: Cc1c(COC(=O)C2C(C(O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1c(COC(=O)C2C(C(OC(=O)c3ccccc3)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.8 %

Procedure:
To a solution of 390 mg (0.821 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 3, in 2 ml of diethyl ether, 0.114 ml (0.98 mmol) of benzoyl chloride and 0.137 ml of triethylamine, were added, and the mixture was stirred at room temperature for 12 hours. Then, 0.23 ml of benzoyl chloride and 0.28 ml of triethylamine were further added, and the mixture was stirred overnight at room temperature. After an addition of 5 ml of hexane, the inorganic salts are filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 175 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-benzoyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Cl)(=[O:7])=[O:6])[CH:2]=[CH2:3].[I-].[Li+].[NH3:20]>>[CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:20])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1Cl
Agent: [I-]
Agent: [Li+]
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Temperature: 120 °C
Yield: 59 %

Procedure:
A mixture of N,N-diallyl-4-chloropyridine-3-sulfonamide (1.5 g, 5.5 mmol), lithium iodide (0.74 g, 5.5 mmol) and ammonia (7 M in methanol, 14 mL, 5.5 mmol) under an atmosphere of argon was heated at 120° C. for 2 h in a microwave reactor. Silica was added and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (95:5) as the eluent, gave the title compound in 59% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[C:8](=[O:15])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH2:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O-])(=[O:24])=[O:23])=[CH:18][CH:17]=1.[Na+].C(O)=O>CO.O>[C:11]([O:10][C:8](=[O:15])[NH:9][CH:6]([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ncco1
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
300 mg of oxazole 2-carboaldehyde was dissolved in a mixed solvent of 3 mL of methanol and 6 mL of water, added successively with 363 mg of tert-butyl carbamate, 552 mg of sodium p-toluenesulfonate and 0.76 mL of formic acid and stirred at room temperature for 16 hours and 30 minutes. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure, to afford 247 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)([C:13]([F:16])([F:15])[F:14])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([C:13]([F:16])([F:15])[F:14])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1N
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nc2c(Cl)c(Br)ccc2[nH]1

Procedure:
Synthesized as described in Example 195C from 4-bromo-3-chloro-1,2-benzenediamine and TFA: MS (ESI) m/z 301 (M+1).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)#[N:6]>CCO>[ClH:4].[CH2:1]([O:3][C:5](=[NH:6])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(C(=O)O)cc1
Product: Cl
Temperature: 5 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
A 500 mL, three-necked flask, equipped with a magnetic stir bar, nitrogen inlet, addition funnel, and a temperature probe was charged with anhydrous EtOH (125 mL). The vessel was cooled to 5° C. and acetyl chloride (97 mL, 1332 mmol) was added at a rate that maintained the temperature range of 5 to 10° C. When the addition was complete, 4-cyanobenzoic acid (25 g, 167 mmol) was added in portions over 15 min. No exotherm was noted during the addition of the solid. When the addition was complete, the white suspension was allowed to warm to 25° C. The reaction vessel was sealed with Parafilm® and stirred at 23° C. for 18 h. The Write suspension was vacuum filtered and the solid was rinsed with EtOH and dried to constant mass, furnishing 4-(ethoxy(imino)methyl)benzoic acid hydrochloride as a white solid (25 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br s, 1H), 8.26 (m, 2H), 8.14 (m, 2H), 4.70 (q, 2H), 1.51 (t, 3H). The filtrate was concentrated and treated with ether to give a white solid. The solid was collected by vacuum filtration and rinsed with ether to give ethyl 4-(ethoxy(imino)methyl)benzoate hydrochloride as a white solid (11 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 12.07 (br s, 1H), 8.24 (m, 2H), 8.15 (m, 2H), 4.66 (q, 3H), 4.37 (q, 3H), 1.49 (t, 3H), 1.35 (q, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][NH2:13]>>[F:11][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([NH:13][CH3:12])=[O:10]
Reactant: O=C=Nc1ccc(I)cc1F
Reactant: CN
Product: CNC(=O)Nc1ccc(I)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 4-Iodo-2-fluorophenyl isocyanate (6-1, 5.15 g, 19.6 mmol) in Hexanes (80 ml) was treated with a solution of Methylamine (2M in THF, 9.8 mL, 19.6 mmol, 1.0 eq). A white precipitate formed as the mixture stirred at 23 deg C. for 30 min. The precipitate was collected via filtration and air dried, affording the title compound, N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2), as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.89 (t, 2H, J=8.6 Hz), 7.47-7.38 (m, 2H), 6.31 (bs, 1H), 4.58 (bs, 1H), 2.88 (d, 3H, J-4.9 Hz). LRMS m/z: Calc'd for C8H8FIN2O (M+H) 295.1, found 294.9.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: Fc1ccc(CBr)c(F)c1
Product: Br
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccc(F)cc1F

Procedure:
According to the method of Example 172, 2-amino-5-chloronicotinamide was reacted with 1-(bromomethyl)-2,4-difluorobenzene to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)([CH3:4])[CH3:3].[CH3:19][NH:20][CH3:21]>O>[CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:20]([CH3:21])[CH3:19])[CH2:9]1)([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Solvent: O
Product: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
(1S-cis)-[3-[(Methylsulphonyl)oxy]cyclopentyl]carbamic acid 1,1-dimethylethyl ester (1.452 g, 5.20 mmol) in a solution of dimethylamine (33% in ethanol, 25 ml) was heated at reflux for 3.75 h, then allowed to cool. The solution was diluted with water (100 ml) and extracted with ethyl acetate(3×100 ml). The total organic solution was dried (Na2SO4) and evaporated to a yellow gum. This was purified on silica, eluting with dichloromethane:ethanol:0.88 ammonia (100:8:1) changing to (30:8:1) to give a brown film (0.988 g, 83%). A portion of this was evaporated from a solution in isopropyl ether to give the title compound (0.139 g) as a brown solid, m.p. 65°-67° C., [α]D -40.35°(CHCl3 c=0.57%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:26]([O:28]CC2C=CC=CC=2)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CCOC(C)=O>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:26]([OH:28])=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)OCc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To a stirred solution of 4-[2-benzyloxycarbonyl-2-(4-benzyloxy-phenyl)-ethyl]-benzoic acid methyl ester (Step C, 3.0 g, 6.66 mmol) in EtOH:EtOAc (50 mL, 1:1 ratio) at rt, was added 10% palladium on carbon (0.3 g), hydrogenated at 1 atm. H2 (gas) and the reaction mixture was stirred at rt for 14 h. The reaction mixture was filtered through celite plug and washed with ethyl acetate (50 mL) and concentrated under reduced pressure. The crude product was dried under vacuum for 3 h to afford 4-[2-carboxy-2-(4-hydroxy-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (1.6 g, 86%): 1H NMR (300 MHz, CDCl3): δ 7.83 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.08 (dd, J=4.62, 12.5 Hz, 2H), 6.66 (dd, J=6.6, 12.5 Hz, 2H), 3.79 (s, 3H), 3.75 (t, J=8.1 Hz, 1H), 3.22 (dd, J=8.4, 13.5 Hz, 1H), 2.93 (dd, J=7.2, 13.8 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(C)(C)C.[ClH:25]>C(O)C>[ClH:25].[C:18]1([C@@H:16]2[CH2:17][C@H:15]2[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[O:14])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Batch size: 7.5 g (21.6 mmol) N-[4-(trans-2-phenyl-cyclopro-pyl-carbonylamino)-butyl]-carbamic acid tert-butyl ester and 6.4 ml (77 mmol) concentrated hydrochloric acid in 150 ml ethanol.
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-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.Cl>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:29]2[C:14](=[O:15])[C:10]3[CH:11]=[C:12]4[CH2:13][CH:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:6][C:7]4=[CH:8][C:9]=3[C:17]2=[O:19])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(Cl)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-chlorobenzylamine (0.17 mL, 1.4 mmol). Purification using silica gel, eluting with 5:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 102 as a white solid (m.p. 260-261° C.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[CH:8]=[CH:7][CH2:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([OH:14])[C:4]=2[N:3]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>O1CCOCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:11]=[C:10]([NH:12][CH3:13])[C:9]4[CH:8]=[CH:7][CH2:6][C:5]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)([OH:14])[C:4]=4[N:3]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1C=CCC2(O)c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1C=CCC2(O)c1ccccc1
Yield: 43.6 %

Procedure:
A solution of 2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol (25 mg) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (29 mg) in dioxane (0.2 mL) and acetic acid (0.2 mL) was heated at 85° C. for 4 h. THF was removed in vacuo, and the residue was purified by reverse phase preparative to give the title compound (as its TFA salt) as an oil (18 mg). LC-MS (M+H)+=475.26. 1H NMR (TFA salt, 500 MHz, CD3OD) δ ppm 7.2-7.9 (m), 6.56 (1H, m), 6.18 (1H, m), 3.94 (3H, s), 3.20 (3H, s), 3.10 (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]1(C(O)=O)CNC1C=CC=CC=1.[NH3:31]>O>[CH3:8][C:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]=1[NH2:31]
Reactant: CC1=CC(C=CC#N)=CC(C)C1(CNc1ccccc1)C(=O)O
Reactant: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C=CC#N)cc(C)c1N
Temperature: 52.5 °C

Procedure:
Trifluoroacetic acid (600 ml) was slowly added to the residue of 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzyl phenylamine obtained from example 2 (161 gms) at 25 to 30° C. and the reaction mass was stirred at 45-60° C. till completion of reaction as monitored by TLC. After completion of the reaction, water (1800 ml) was added to the reaction mass, neutralized with aqueous ammonia and extracted with toluene. The organic layer was separated and concentrated to give 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine. The residue was admixed with 1:1 mixture of isopropanol and diisopropyl ether (1000 ml) and treated with HCl dissolved in isopropanol to yield 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine hydrochloride salt (II) which was cooled to 25-30° C., filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIa) was prepared by reacting 0.0284 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][C:4]1[N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#C[Si](C)(C)C)n1
Yield: 37.6 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (800 mg, 4.28 mmol) reacted with (PPh3)2PdCl2 (150 mg, 0.21 mmol), Cul (41 mg, 0.21 mmol) and ethynyltrimethylsilane (840 mg, 8.55 mmol) in triethylamine (30 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 8:2) to yield 330 mg (1.61 mmol, 38%) of (6-methyl-2-trimethylsilanylethynyl-pyridin-3-yl)amine as a beige solid.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>CC(C)=O>[CH3:3][S:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
In a water bath, methyl iodide (18.5 ml) and potassium carbonate (28.7 g) were added to an acetone (250 ml) solution of 4-hydroxythiophenol (25 g), and stirred at room temperature for 5 hours. The salt was removed by filtration, the solvent was evaporated away under reduced pressure, diethyl ether was added, and extracted with aqueous 2 N sodium hydroxide solution. The obtained aqueous layer was made acidic with aqueous 6 N hydrochloric acid solution, extracted with diethyl ether, and the organic layer was washed with aqueous saturated sodium chloride solution. After dried, the solvent was evaporated away under reduced pressure to obtain 4-(methylsulfanyl)phenol (27.3 g) as a pale yellow solid. In a water bath, 30% hydrogen peroxide water (67 ml) was gradually and added dropwise to an acetic acid (130 ml) solution of 4-(methylsulfanyl)phenol (27.3 g). After the addition, this was gradually heated up to 100° C., and stirred for 1 hour. The reaction solution was restored to room temperature, and neutralized with saturated sodium bicarbonate water. This was extracted with ethyl acetate, and washed with saturated sodium bicarbonate water and saturated saline water. After dried, the solvent was evaporated away to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:9]([C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(F)c([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fuming sulfuric acid (180 mL) is added dropwise to 4-fluoro-2-nitrotoluene (50.21 g) under an argon atmosphere. The internal temperature of the mixture is maintained at 0°-5° C. using an ice/sodium chloride bath. A preformed (ice bath) mixture of fuming nitric acid (30 mL) and fuming sulfuric acid (90 mL) is added dropwise to the previous solution over three hours. The reaction is then allowed to warm to room temperature. After stirring at room temperature for two hours, the mixture is poured slowly into ice and the products are extracted with methylene chloride (4×500 mL). The combined extracts are dried over magnesium sulfate, filtered and rotary evaporated. The crude product is purified by flash chromatography on silica gel, eluting with 5% ethyl acetate/hexane to afford 2,3-dinitro-4-fluorotoluene as a pale yellow solid.