Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)[C:4]([CH3:19])=[N:3]1.[Cl:20]/[CH:21]=[CH:22]/[CH2:23][O:24][NH2:25]>C(O)C>[Cl:20][CH:21]=[CH:22][CH2:23][O:24]/[N:25]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:5]2[C:4]([CH3:19])=[N:3][N:2]([CH3:1])[CH:6]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: CCC(=O)C1C(=O)CC(c2cn(C)nc2C)CC1=O
Reactant: NOC/C=C/Cl
Solvent: CCO
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2cn(C)nc2C)CC1=O
Yield: 91.2 %

Procedure:
In 20 ml of ethanol was dissolved 2.62 g (10 mmols) of 5-(1,3-dimethyl-1H-pyrazol-4-yl)-2-propionylcyclohexane-1,3-dione and, 30 ml (12 mmols) of 0.4 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine was added to the solution. The mixture was reacted for 8 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 3.21 g of the product.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH:7]1[CH2:9][CH2:8]1)[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1>[CH:7]1([C@@H:4]2[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]2)[CH2:9][CH2:8]1
Reactant: N[C@H](CO)C1CC1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1COC[C@H](C2CC2)N1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
To a cold, stirred suspension of sodium hydride (600 mg, 14.99 mmol) in toluene (20 mL) was added dropwise a solution of (S)-2-amino-2-cyclopropylethanol (680 mg, 6.72 mmol)) in toluene (12 mL). The reaction mixture was then allowed to warm to room temperature and a solution of ethyl chloroacetate (824 mg, 6.72 mmol) in toluene (4 mL) was added dropwise. The resulting mixture was stirred for 3 h at room temperature. The mixture was then quenched with the addition of 10 mL of 1N aq. hydrochloric acid and concentrated under vacuum. The residue was diluted with THF, dried with magnesium sulfate, concentrated under vacuum and filtered through a pad of silica gel, flushing with additional THF. The resulting filtrate was concentrated under vacuum, and the residue was further purified by flash chromatography (ISCO, 12 g silica gel column, using a 0-100% ethyl acetate in n-heptane gradient as the eluent to afford 208 mg of (S)-5-cyclopropylmorpholin-3-one as a white solid (MS: (M+H)+=142.2).
Reaction SMILES: Cl.C(OCC)(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:36]([C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44]C)[CH:39]=1)=[O:37])[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH:29][C:30](=[NH:35])[C:31]([OH:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]>CCO.O1CCOCC1>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:36](=[O:37])[C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1)[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH:29][C:30](=[NH:35])[C:31]([OH:34])([CH3:32])[CH3:33])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: COc1cc(C(=O)C(C(=O)c2cccc(S(=O)(=O)NC(=N)C(C)(C)O)c2)=C2Nc3ccccc3N2)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc[nH]c(=O)c2)=C2Nc3ccccc3N2)c1
Reaction time: 1 h
Yield: 14.6 %

Procedure:
Under ice cooling, 4 N—HCl/ethyl acetate (0.09 mL) was added to an EtOH/dioxane (2/1) mixed solution (4 mL) of N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2-methoxypyridin-4-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (127 mg), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. An aqueous sodium hydrogencarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (18 mg).
Reaction SMILES: [H][H].C(OC(C)C)(C)C.[F:10][C:11]1[CH:34]=[C:33]([F:35])[C:14]2[NH:15][C:16]([C:18]3[C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23](=[N:31]O)[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[N:17][C:13]=2[CH:12]=1>C(O)C.O1CCCC1.[Ni]>[F:10][C:11]1[CH:34]=[C:33]([F:35])[C:14]2[NH:15][C:16]([C:18]3[C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]([NH2:31])[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[N:17][C:13]=2[CH:12]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)cc(F)c2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)cc(F)c4[nH]3)cccc21
Yield: 74.3 %

Procedure:
The procedure used in Example 6 is followed. In a 211 ml autoclave, dissolve 1.85 g of 4-(5,7-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 70 ml of ethanol and 70 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° for 6 hours. After cooling, the volume of hydrogen absorbed is 342 ml. After filtration of the catalyst, the filtrate is concentrated under reduced pressure and then taken up in a mixture of dichloromethane with a small amount of methanol and dried over magnesium sulphate, and the crude solid obtained is made into a paste with diisopropyl ether. In this way, we obtain 1.32 g of 4-(5,7-difluoro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a grey powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].O.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1
Reactant: COCOc1cc(Br)c(OCOC)c(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCOc1cc(Br)c(OCOC)c(CO)c1
Yield: 99.1 %

Procedure:
Treat a solution of 3-bromo-2,5-bis-methoxymethoxy benzaldehyde (9.40 g, 30.6 mmol) in EtOH (200 mL) with sodium borohydride (1.16 g, 30.6 mmol). Stir the reaction for 2 hours at ambient temperature and pour into H2O (200 mL) and saturated NaHCO3 (100 mL). Extract the H2O with EtOAc (3×100 mL) and wash the combined extracts with H2O (100 mL) and brine (50 mL) then dry (MgSO4) and filter. Concentrate the filtrate to afford the title product (9.31 g, 99%) as an oil. 1H NMR (CDCl3) δ 3.20 (t, J=6.9 Hz, 1H), 3.47 (s, 3H), 3.64 (s, 3H), 4.60 (d, J=6.9 Hz, 2H), 5.08 (s, 2H), 5.13 (s, 2H), 7.02 (d, J=2.9 Hz, 1H), 7.23 (d, J=2.9 Hz, 1H).
Reaction SMILES: COC[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.Cl>O1CCOCC1>[C:27]1([CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([C:6]3[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:8][C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]=3[OH:4])=[CH:20][CH:21]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCOc1c(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)cc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Oc1c(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)cc2ccccc12
Yield: 98.6 %

Procedure:
1-{[(Methyloxy)methyl]oxy}-2-{4-[(phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)naphthalene (185) (0.32 g, 0.72 mmol) was treated with 4.0M HCl in dioxane at room temperature to give 0.28 g (99%) of the title compound (186) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.14 (s, 2H), 5.48 (s, 1H), 7.14 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 7.34-7.40 (m, 1H), 7.40-7.50 (m, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.57-7.65 (m, 2H), 7.85 (s, 1H), 7.88-7.94 (m, 1H), 8.24-8.29 (m, 1H). LCMS (ESI): m/z 417 (M+Na)+, m/z 393 (M−H)−.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:40]([NH2:43])([CH3:42])[CH3:41]>ClCCl.CN(C=O)C>[CH:40]([NH:43][CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)([CH3:42])[CH3:41]
Reactant: CC(C)N
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)NCc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (236 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with isopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (100 mg, 39%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])N=N1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:26][C:24]1([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][B:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][S:1][C:5]3[O:12][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[CH:4]=3)=[CH:20][CH:19]=2)[O:25]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Oc1ccccc1-c1csnn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(CSc3cc4ccccc4o3)cc2)OC1(C)C
Temperature: 90 °C
Yield: 40 %

Procedure:
Starting material 2-[1,2,3]Thiadiazol-4-yl-phenol was prepared according to literature procedure (M. A. Abramov, W. Dehaen, B. D'hooge, M. L. Petrov, S. Smeets, S. Toppet and M. Voets Tetrahedron, 2000, 56, 3933–3940). 2-[1,2,3]Thiadiazol-4-yl-phenol (241 mg, 1.35 mmol), 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (406 mg, 1.37 mmol, 1 eq), and K2CO3 (396 mg, 2.87 mmol, 1.9 eq) was mixed in 8 mL of CH3CN and heat to 90° C. under nitrogen atmosphere. After reaction was complete as monitored by TLC, the mixture was cool to room temperature and solvent evaporated. The resulting crude material was subject to column chromatography (20% EtOAc in hexane) to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylsulfanyl]-benzofuran (198 mg) in 40% yield. NMR: G8475-125. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H)4.1 (s, 2 H) 6.6 (d, J=1.0 Hz, 1 H) 7.2 (m, 4 H) 7.4 (d, J=7.8 Hz, 2 H) 7.7 (d, J=8.1 Hz, 2 H).
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])([OH:4])=[O:3].[CH3:23]O>>[CH3:23][O:3][C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])=[O:4]
Reactant: CO
Reactant: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Agent: Cl
Product: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)OC
Yield: 90 %

Procedure:
10 ml of methanol and 3 ml of 10% methanolic hydrogen chloride were added to 2.86 g of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-ethyl-β-carboline, and the mixture was refluxed for 2 hours. After the reaction was completed, the mixture was concentrated to one third volume. The concentrated mixture was alkalified with an aqueous saturated sodium bicarbonate solution, and then extracted with benzene. The extract was washed with water, dried and evaporated to remove solvent. 2.70 g of 1,2,3,4-tetrahydro-1-(3-methoxycarbonylpropyl)-2-ethyl-β-carboline were obtained. Yield: 90%
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][CH3:5].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>CO.CCOCC.O>[CH3:6][C:2]([C:7]1[CH:11]=[CH:10][C:9](=[C:13]([CH3:15])[CH3:12])[CH:8]=1)([CH3:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)(C)C1=CC=CC1
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CO
Solvent: CCOCC
Product: CCCC(C)(C)C1=CC(=C(C)C)C=C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of 3.00 g (20.0 mmol) of (1,1-dimethylbutyl)cyclopentadiene in 30 ml of methanol, 14.6 ml (198.8 mmol) of acetone and 2.5 ml (29.9 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for 3 days. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.70 g (14.19 mmol) of a yellow liquid (yield: 71%). The analyzed values are given below.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][C@H:39]([OH:41])[CH3:40])[CH:37]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:34]=[N:35][N:36]([CH2:38][C@H:39]([OH:41])[CH3:40])[CH:37]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: C[C@@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnn(C[C@@H](C)O)c3)cc1-2
Yield: 9.6 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (418 mg, 1.02 mmol) and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol (307.4 mg, 1.22 mmol) were reacted to give 369 (44.8 mg, 10% yield, M+1 457.1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(NCCCn2ccnc2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(NCCCn2ccnc2)c1
Reaction time: 12 h
Yield: 74 %

Procedure:
28 g N-3-(imidazol-1-yl)propyl-3-nitroaniline was dissolved in 450 ml ethanol and 50 ml water, and 0.3 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced on a rotary evaporator. 18.2 g of black oil was obtained; this was distilled in a ball tube (265–387° C., 0.06–0.08 mbar). The product obtained was an amorphous orange solid.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[H-].[Na+].[C:17](=O)([O:20]C)[O:18][CH3:19]>C1C=CC=CC=1>[CH3:19][O:18][C:17]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:8])=[O:20]
Reactant: CC1(c2ccccc2)CCCCC1=O
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1CCCC(C)(c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-2-phenylcyclohexanone (4.7 g, 25 mmol) from Preparation 3 above, and sodium hydride (1.1 g of 60% dispersion in mineral oil, 28 mmol) in 15 mL of dimethyl carbonate and 75 mL of benzene, was heated under reflux for 4 h. The mixture was cooled to room temperature and poured into dilute ice-cold aqueous HCl. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to afford 6.36 g of 3-methyl-2-oxo-3-phenyl-cyclohexanecarboxylic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:32][CH2:33][CH2:34][CH2:35]I.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:32][CH2:33][CH2:34][CH2:35][O:30][C:19]1[CH:20]=[C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:10]([CH3:11])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:31])[CH:13]=1
Reactant: ClCCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCl)c1
Yield: 111.4 %

Procedure:
A solution of 300 mg (0.703 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f), 319 mg (2.11 mmol, 3 eq) of 1-chloro-3-iodopropane and 583 mg (4.22 mmol, 6 eq) of potassium carbonate in 10 ml of methyl ethyl ketone is refluxed for 7 hours. The insoluble matter is filtered off, the solvent is evaporated off and the oil obtained is chromatographed on silica gel (35 g FlashSmart column) eluted with 60/40 heptane/ethyl acetate. 394 mg of methyl 3-[2-(3-chloropropoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Quantitative yield.
Reaction SMILES: [C:1]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:28][O:29][NH2:30].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=[C:6]([C:1](=[N:30][O:29][CH3:28])[CH2:2][CH2:3][CH3:4])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CON
Reactant: CCCC(=O)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NOC)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12

Procedure:
1-(5-Butyryl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea, which may be produced as in Example 108 (46.0 mg, 0.13 mmol) and O-methylhydroxylamine HCl (18.0 mg, 0.22 mmol) in ethanol (1.0 mL) were charged with sodium acetate trihydrate (55.0 mg, 0.41 mmol). After 24 h the reaction was concentrated then taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organic was concentrated and the resulting oil chromatographed (0-10% isopropanol/CH2Cl2) to afford 1-ethyl-3-[5-(1-methoxyimino-butyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-urea. MS (APCI+): m/z 382.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13](O)([C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:12]3[C:7](=[C:8]([F:33])[C:9]([F:32])=[C:10]([F:31])[C:11]=3[F:30])[C:6]=2[C:5]([F:34])=[C:4]([F:35])[C:3]=1[F:36].P(Br)(Br)Br>>[F:1][C:2]1[C:14]2[CH:13]([C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=3)[C:12]3[C:7](=[C:8]([F:33])[C:9]([F:32])=[C:10]([F:31])[C:11]=3[F:30])[C:6]=2[C:5]([F:34])=[C:4]([F:35])[C:3]=1[F:36]
Reactant: OC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(F)c(F)c(F)c(F)c2-c2c(F)c(F)c(F)c(F)c21
Agent: BrP(Br)Br
Product: Fc1c(F)c(F)c2c(c1F)-c1c(F)c(F)c(F)c(F)c1C2c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
g (0.002 moles) of the product (X), obtained according to the preparation reported in the preceeding example 5, are heated with 10 ml (0.105 moles) of PBr3 to 110° C. for 40 minutes. The reaction mass is hydrolyzed in ice, extracted with ethyl ether, the ether extract is washed with an aqueous solution of NaHCO3 (10%), dried on Na2SO4, filtered and the ether solution is dried. The residue is dissolved in 20 ml of acetic acid and 1 g of Zn in powder form is added. The mixture is stirred for 1 h at room temperature, hydrolyzed in water and then extracted with ethyl ether. The ether extract is neutralized with an aqueous solution of NaHCO3 (10%), dried with Na2SO4, filtered and dried. The residue is purified on a silica gel column (eluant petroleum ether) obtaining, after evaporation of the pure fractions, 0.8 g of pure product (yield 76.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:17]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a stirring solution of 3-aminobenzoic acid (1.1 g, 7.9 mmol) in anhydrous THF (20 mL), 3-(trifluoromethyl)benzoyl chloride (2.0 g, 9.6 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from chloroform to afford the title compound as a white solid (1.2 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=3[C:13]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1c(N)ccc2c1CCC(=O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CCC(=O)CC2

Procedure:
The title compound was prepared from 2-amino-1-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179. Product was prepared as a white solid (18 mg, 30%). LCMS (m/e) 468 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 7.93 (d, 1H, J=7.1), 7.82 (s, 1H), 7.81 (d, 1H), 7.281 (s, 1H), 7.04 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 6.29 (m, 1H), 4.03 (m, 1H), 3.67 (s, 3H), 3.29 (s, 2H), 2.95 (m, 2H), 2.89 (m, 4H), 2.67 (m, 1H), 2.53 (m, 2H), 2.09 (d, 1H, J=9 Hz), 1.40 (d, 1H, J=9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[C:12]4[C:17]([CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.I[CH3:20].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:20])[C@@H:7]3[C:12]4[C:17]([CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2C

Procedure:
Using the same procedure as described in Example 2 for cis-4b,5,9b,10-tetrahydro-8-methoxyindeno[1,2-b]indole (239 mg, 1.0 mmol) was methylated with iodomethane, using sodium hydride (25 mg, 1.1 mmol) as the base, in THF (2 cm3). Extraction work-up (into diethylether), and purification by "suction" flash chromatography, yielded a clear gum. Yield: 158 mg, (63%) which solidified after bulb to bulb distillation (180° C. at 0.2 mm Hg), giving the title compound M.p. 72° C. 1H NMR (CDCl3) δ: 2.87 (3H, s,), 3.03 (1H, dd,), 3.36 (1H, dd,), 3.70 (3H, s,), 4.08 (1H, ddd,), 4.80 (1H, d,), 6.28 (1H, d,), 6.61 (1H, dd,), 6.77 (1H, dd,), 7.1-7.5 (4H, m,).