Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Li+].[OH-].CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoate (504 mg, 1.32 mmol) was dissolved in a mixture of 1 M aq LiOH (2 mL), MeOH (2 mL), and THF (6 mL) and left to stir overnight. The mixture was concentrated in vacuo to remove MeOH and THF. The residue was diluted with dichloromethane (50 mL), washed with saturated aqueous citric acid (2×5 mL) and water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product as a yellow solid (417 mg, 1.13 mmol, 86%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>C1COCC1>[NH2:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(C(=O)O)cc34)n2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
To mixture of methyl 3-(6-(4-aminopiperidin-1-yl)pyrazin-2-yl)-1H-indole-5-carboxylate (236) (60 mg, 0.17 mmol) in THF (1 mL) was added 10% NaOH solution (1 mL). The reaction mixture was heated at 60° C. for 24 h and cooled to 0° C. 1N HCl solution was added to the mixture to attain pH7. The resulting mixture was stirred at RT for 2 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to obtain the title compound (30 mg, 57%). MS (ESI, pos. ion) m/z: 337.9 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:21][B:20](B2OC(C)(C)C(C)(C)O2)[O:19]1.C([O-])(=O)C.[K+]>[Pd].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:3][C:2]([B:20]([OH:21])[OH:19])=[CH:7]1
Reactant: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)nc(Nc2cccnc2)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a reflux condenser was charged with 186a (800 mg, 2.86 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.18 g, 8.57 mmol), Pd (dppf) Cl2 (204 mg, 0.28 mmol), potassium acetate (560 mg, 5.71 mmol), and dioxane (60 mL). After bubbling nitrogen through the mixture for 30 minutes, it was stirred at 100° C. for 3 h under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduce pressure. The residue solid was washed with petroleum ether (2×30 mL) to afford 186b (406 mg, 58%) as a brown solid. MS-ESI: [M+H]+ 247.3.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][N:16]2[CH:24]=1.C[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=CC=CC=2)[C:27]=1C1N=C2C=C(C(O)=O)C=CN2C=1>>[O:30]1[CH2:26][CH2:27][CH:28]([NH:29][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:22])[CH2:31][CH2:36]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)NC3CCOCC3)ccc2n1
Yield: 76 %

Procedure:
As described for Example 17, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid (64 mg, 0.2 mmol), instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid, was converted to the title compound (61 mg, 76%) which was obtained as an off white solid. MS: m/e=403.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([O:26]CC=C)=[O:25])=[CH:21][CH:22]=3)[C:17]([CH3:30])=[C:16]2[CH3:31])[CH3:14])=[CH:9][CH:8]=1)[CH3:5].N1CCOCC1>C1COCC1.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>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=3)[C:17]([CH3:30])=[C:16]2[CH3:31])[CH3:14])=[CH:11][CH:12]=1)[CH3:5]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O[C@@H](C)C(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.55 g, 1.26 mmol) and morpholine (1.0 mL, 12.6 mmol) in THF (5 mL) was degassed and then Pd(PPh3)4 (0.15 g, 0.13 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The solvent was removed and the residue was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 396 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH:12]=[CH:13][C:14](=S)[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2].O.[NH2:29][NH2:30]>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[N:16]=[N:15][C:14]([NH:29][NH2:30])=[CH:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(NN)nn2)c1

Procedure:
Reaction of 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione with hydrazine hydrate in boiling ethanol followed by evaporation of the reaction mixture under reduced pressure gave the title compound.
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([N:26](C)[C:27](=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH3:27])=[CH:24][CH:25]=3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)cc1
Yield: 86.8 %

Procedure:
Reaction of the above carbamate (235 mg, 0.414 mmol) with an excess of TFA (1.2 mL) in CH2Cl2 (6 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methylaniline (168 mg, 87%): 1H NMR (DMSO-d6) δ 8.23 (d, J=8.9 Hz, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.80 (t, JHF=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.67 (d, J=8.9 Hz, 2H), 6.63 (q, J=4.8 Hz, 1H), 4.01 (br s, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.76 (t, J=4.8 Hz, 4H), 2.79 (d, J=4.9 Hz, 3H).
Reaction SMILES: C([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH2:19][CH3:20])[C:12]([CH3:22])([CH3:21])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:19]([O:18][N:13]1[C:12]([CH3:22])([CH3:21])[CH2:11][CH:10]([OH:9])[CH2:15][C:14]1([CH3:16])[CH3:17])[CH3:20]
Reactant: CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The ester obtained in Example 3A is hydrolyzed using sodium hydroxide in aqueous methanol to give the title compound as a white solid melting at 86°-88° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>O>[C:2]1([C:1]2[NH:18][CH2:15][CH2:16][NH:17][C:10](=[O:12])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: O
Product: O=C1C=C(c2ccccc2)NCCN1

Procedure:
A solution of 192 g. (1 mol) of ethyl benzoylacetate in mixed xylenes (total volume 400 ml.) was added dropwise over a 1 hour period to a solution of 60 g. (67 ml.; 1 mol) of ethylenediamine in 1 l. of mixed xylenes refluxing under nitrogen. The reaction mixture was then refluxed for an additional hour after which the water was azeotroped off. The solvent was then distilled off over a 2 hour period and the resulting reaction product was allowed to stand at room temperature. The crystalline material formed was isolated by filtration, washed several times with chloroform and dried to obtain the crystalline product (59 g.). m.p. 207°-210° C. Lit. Ried et al., Chem. Ber. 87, 1811-1814 (1954), m.p. 209°-210° C.; Hofmann et al., J. Org. Chem. 27, 3565-3568 (1962), m.p. 206°-209° C.
Reaction SMILES: [C:1]([N:3]([CH2:14][C:15]#[CH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:24]>CO>[NH:2]=[C:1]1[N:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH2:14][C:15](=[CH2:16])[S:24]1
Reactant: C#CCN(C#N)c1cccc(C(F)(F)F)c1
Reactant: S
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=N)S1

Procedure:
To a solution of N-cyano-3-trifluoromethylaniline (5.0 g) in acetone (100 ml), potassium carbonate (7.4 g) and propargyl bromide (3.5 g) were added, and the resultant mixture was stirred at room temperature for 10 hours, followed by filtration of the reaction mixture. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was subjected to column chromatography to give N-cyano-N-propargyl-3-trifluoromethylaniline (3.8 g). The thus obtained N-cyano-N-propargyl-3-trifluoromethylaniline (1 g) and a catalytic amount of triethylamine were dissolved in methanol (30 ml), and the resultant mixture was cooled to 0° C. Hydrogen sulfide was gradually introduced into the mixture for 20 minutes while keeping the temperature at 0° C., followed by introduction of nitrogen gas to remove hydrogen sulfide. The solvent was removed by distillation, and the residue was subjected to column chromatography to give 0.2 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (ix)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1>CO.CCOC(C)=O.[Pd]>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(CN)cc(NC(=O)OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cc(CN)cc(C(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of about 92 mg of crude methyl 3-(aminomethyl)-5-(prop-1-en-2-yl)phenylcarbamate and 17.6 mg of 10% Pd/C in 7 mL of MeOH and 2 mL of EtOAc was stirred at r.t. under H2 balloon for 16 h. The mixture was filtered through Celite and concentrated to give the amine product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH:18]1([CH3:30])[CH2:23][CH2:22][CH:21]([CH:24]([CH3:26])[CH3:25])[CH:20]([C:27](Cl)=[O:28])[CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:27]([CH:20]1[CH2:19][CH:18]([CH3:30])[CH2:23][CH2:22][CH:21]1[CH:24]([CH3:26])[CH3:25])=[O:28]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: NCCc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar was charged with CH2Cl2 (30 mL), 2-bromo-phenethylamine (1.0 g, 5.00 mmol) and triethylamine (684 μl, 5.05 mmol). The reaction solution was treated with menthoyl chloride (1.02 g, 5.05 mmol) in one portion and stirred at ambient temperature for 30 minutes. The reaction was diluted with CH2Cl2 (50 mL) and washed with water (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a thick oil (1.8 g). Product was used for next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[CH:13].CON(C)[C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]#[C:13][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[O:18]
Reactant: C#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Product: COc1ccc2cc(C(=O)C#Cc3cc(C(F)(F)F)ccc3Cl)cnc2c1

Procedure:
The title compound was prepared with the alkyne from step B and N,7-dimethoxy-N-methylquinoline-3-carboxamide the intermediate from example 2 step E following the procedure described in example 2 step F. 1H NMR (CDCl3, 500 MHz): 9.62 (d, J=2.1 Hz, 1H), 8.97 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.69 (d, J=3.0 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.31 (dd, J=2.3, 8.9 Hz, 1H), 4.03 (s, 3H). LC-MS: 3.85 min. (M+H)=389.9.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])([OH:3])=O.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[O:14]1[CH2:15][CH2:16][C:11]2([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1]2=[O:3])[C:12]1=[O:13]
Reactant: O=C(O)c1ccccc1SC1CCOC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C1OCCC12Sc1ccccc1C2=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 15.5 g of α-[(2-carboxyphenyl)thio]-γ-butyrolactone, 100 ml of acetic anhydride and 20 ml of triethylamine is stirred at 140° C. for 3 hours, at the end of which time the solvent is distilled off. To the residue is added ice-water and the resultant precipitate is recovered by filtration and recrystallized from ethanol. By the above procedure there is obtained 9.4 g of 4',5'-dihydrospiro[benzo[b]thiophene-2(3H), 3'(2'H)-furan]3,2'-dione as pale-yellow platelets melting at 125°-127° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCC(F)(F)F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCC(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2,2,2-trifluoro-ethyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23](N)[CH3:24].C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:21]3[CH2:22][C@@H:23]([CH3:24])[N:20]=[C:18]23)=[CH:6][CH:7]=1
Reactant: CC(N)CN
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CN2C(=O)c3ccccc3[C@@](O)(c3ccc(F)cc3)C2=N1
Yield: 30.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (12.5 g) (Step 1 of Example 2), 1,2-diaminopropane (13.5 g), and toluene (150 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was evaporated to dryness. The residue was treated with hot ethanol (200 mL). The insoluble material was collected by filtration and dried to give the title compound (4.3 g) as a white solid m.p. 229-232° C. Mass spectrum (EI, M+) m/z 310. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, 1H), 7.62 (t, 1H), 7.51 (t, 1H), 7.33 (m, 3H), 7.10 (t, 2H), 7.04 (s, 1H), 4.13 (m, 1H), 4.02 (dd, 1H), 3.52 (dd, 1H), and 1.20 ppm (d, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)=[CH:8][C:9]=1[Cl:10])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:10][C:9]1[CH:8]=[C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc2[nH]ncc12)c1cc(Cl)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 3-Chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (73 mg, 0.21 mmol), lithium hydroxide monohydrate (88 mg, 2.09 mmol), THF (6 mL) and water (6 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 80 mg (100%). MS m/e 335.8 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:40]1[CH2:58][CH:41]1[CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH:55]([CH3:57])[CH3:56])=[CH:46][CH:45]=1>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH:30][CH2:58][CH:41]([OH:40])[CH2:42][O:43][C:44]3[CH:49]=[CH:48][C:47]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH:55]([CH3:57])[CH3:56])=[CH:46][CH:45]=3)([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)N)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)NCC(O)COc3ccc(COCCOC(C)C)cc3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 4.6 g (8.5 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-amino-2-methylpropoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 2.95 g (11 mmol) of 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene in 20 ml of isopropanol is heated under reflux for 6 hours while stirring. Working up and chromatographic purification analogously to Example 1 yield 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[[3-[4-(2-isopropoxyethoxymethyl)-phenoxy]-2-hydroxypropylamino]]-2-methylpropoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester in the form of a vitreous solid having the structure: ##STR38##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1.[CH3:32][NH:33][C:34](=[O:37])[CH2:35]Cl.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:35][C:34](=[O:37])[NH:33][CH3:32])[C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1
Reactant: OC[C@@H]1CN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)CCN1
Reactant: CNC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)C[C@H]1CO
Yield: 93.9 %

Procedure:
A mixture of (S)-7-chloro-3-[5-(3-hydroxymethylpiperazin-1-ylmethyl)-[1,2,4]-oxadiazol-3-yl]-1-[(tetrahydropyran-4-yl)methyl]-1H-indole (22 mg, 0.049 mmol), N-methyl-2-chloroacetamide (11 mg, 0.098 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and sodium iodide (7 mg, 0.049 mmol) in dimethylformamide (2.0 ml) was subjected to microwave irradiation at 160° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash column chromatography eluting with ethyl acetate to 33% (v/v) methanol in ethyl acetate to afford the title compound (23.9 mg, 0.046 mmol). EsIMS: m/z 539.8, 517.5 [M+H]+, 503.1, 200.6.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26]CC1C=CC=CC=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2>CO.C(OCC)(=O)C.[Pd]>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([OH:26])[C:12]1[CH:24]=[CH:23][C:15]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2
Reactant: CS(=O)(=O)NC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1ccc(C(O)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a mixture of 4-(adamantan-2-yl(benzyloxy)methyl)-3-chloro-N-(methylsulfonyl)benzamide (0.290 g, 0.59 mmol) in methanol (10 mL) and ethyl acetate (10 mL) was added palladium on carbon (10%, 50 mg) and the reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered over diatomaceous earth, and the filtrate was concentrated in vacuo. The obtained residue was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.065 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 12.20 (br s, 1H), 7.94 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 5.45 (br s, 1H), 5.23-5.14 (m, 1H), 3.31 (s, 3H), 2.37-2.27 (m, 1H), 2.11-1.35 (m, 13H), 1.11-1.01 (m, 1H); MS (ES−) m/z 396.2, 398.2 (M−1).