Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][BH:18][O:17]1.C(N(CC)CC)C.O>O1CCOCC1.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>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:18]2[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH3:15])[O:17]2)=[CH:3][CH:4]=1
Reactant: C[C@H]1COCCN1c1ccc(Br)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (3S)-4-(4-bromophenyl)-3-methylmorpholine (630 mg), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (630 mg) and triethylamine (1.03 mL) in 1,4-dioxane (10 mL) was added dichlorobis(triphenylphosphine)palladium(II) (86 mg), and the mixture was stirred overnight at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (470 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:14]1([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[SH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:11]([C:8]1[N:6]2[N:7]=[C:2]([S:21][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([O-:13])=[O:12]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
8.0 g (40.3 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine, 16.7 g (60.4 mmol) of triphenyl-methanethiol and 16.7 g (120 mmol) of potassium carbonate in 150 ml of dioxane are heated to 90° C. for 5 h under an argon atmosphere. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is dissolved in a little ethyl acetate and treated with 100 ml of diisopropyl ether. After 18 h, the crystalline precipitate is filtered off and dried. 12.69 g (72%) of the title compound are isolated. M.p.: 168-170° C.
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C=C2C(=C(C3=CCN(S(C)(=O)=O)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Example 48 (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added triethylamine (0.1 mL, 0.68 mmol) and methanesulfonyl chloride (30 mg, 0.25 mmol) and the mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in 2:1 ethyl acetate/hexane) provided the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.71 (s, 1H), 2.89 (s, 3H), 2.97 (s, 3H), 3.36-3.41 (m, 2H), 3.94-3.95 (m, 2H), 4.08 (s, 2H), 5.90 (s, 1H), 7.28-7.32 (m, 1H), 7.39 (dd, J=9.16, 5.49 Hz, 1H), 7.63-7.67 (m, 1H), 8.27 (d, J=4.88 Hz, 1H), 11.72 (s, 1H). MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][N:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.[OH-].[Na+]>>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=3)=[N:11][N:12]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A RBF was charged with 6-methoxypyridin-3-amine (155 mg, 1.25 mmol), 1-chloro-4-phenylphthalazine (300 mg, 1.25 mmol), and 2-butanol (4 mL). The vessel was sealed and the mixture was stirred overnight at 90° C. LC/MS shows completion of reaction. Reaction cooled to RT and purified by silica gel chromatography (1-5% MeOH/DCM) to afford N-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine as tan solid. MS [M+H]=329.1. Calc'd for C20H6N4O: 328.4. Step 2: In a 25 RBF was added N-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine (290 mg, 0.88 mmol), hydrobromic acid (2.4 mL, 44.2 mmol) and acetic acid (2.5 mL, 43.3 mmol), and a reflux condenser open to air was fitted and the RBF was heated to 130° C., while stirring, for 2 h. The reaction was cooled to RT, the mixture neutralized with 6N NaOH, upon which a yellow solid crashed out. The yellow solid was filtered, washed with water, placed in vacuum oven at 30° C. to dry, to afford 5-(4-phenylphthalazin-1-ylamino)pyridin-2-ol, as light yellow solid. MS [M+H]=315.2. Calc'd for C19H14N4O: 314.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2>>[N:18]12[CH2:19][CH2:20][CH2:21][C:14]1([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH2:17]2
Reactant: NCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(NCCC23CCCN2CCC3)cc1

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-4-nitrobenzene (2 04 g, 12.9 mmol) and 5-(2-aminoethyl)-1 -azabicyclo[3.3.0]octane (4.00 g, 25.9 mmol) were employed. In this case, the desired compound was obtained as a yellow liquid (2.93 g, 8 2.5%).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 26 %

Procedure:
The title compound was prepared by condensing 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76A) with 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 26% yield, mp>260° C. 1H-NMR (DMSO-d6) δ 8.73 (s, 1H), 8.31 (dd, J=1, 4 Hz, 1H), 8.26 (d, J=8 Hz, 2H), 8.05 (d, J=16 Hz, 1H), 7.89–7.97 (m, 3H), 7.82 (d, J=16 Hz, 1H), 7.17–7.21 (m, 1H), 6.89 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H). MS m/z=465([M+H]+, 65%), 256 (100%). HRMS (ES+) Calcd. for C23H20N4O5S: 465.1232. Found: 465.1240.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[CH2:11]([O:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][N:23]([CH2:30][C:31](O)=[O:32])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:17]=1)=[O:15])[CH3:12]>>[CH2:7]([N:6]([CH2:9][CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([CH2:30][N:23]([CH2:22][C:18]1[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH:21]=[CH:20][N:19]=1)[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:32])[CH3:8]
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)O)C(=O)C(F)(F)F)c1
Reactant: CCN(CC)CCCCN
Product: CCOC(=O)c1ccnc(CN(CC(=O)NCCCCN(CC)CC)C(=O)C(F)(F)F)c1

Procedure:
By General procedure Y from (4-aminobutyl)diethylamine and 2-(N-{[4-(ethoxycarbonyl)pyridin-2-yl]methyl}-2,2,2-trifluoroacetamido)acetic acid. Purification by column chromatography gave the title compound as oil. 1H NMR (300 MHz, chloroform-d): δ ppm 9.09 (t, 1H), 8.67 (m, 1H), 7.83 (m, 2H), 4.85 (m, 2H), 4.42 (q, 2H), 4.17 (m, 2H), 3.26 (m, 2H), 2.46 (m, 6H), 1.52 (m, 4H), 1.40 (t, 3H), 0.97 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl>[Br:18][C:10]1[C:3]2[C:4]([NH:5][CH:6]=[N:7][C:2]=2[Cl:1])=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: ClC(Cl)Cl
Product: Clc1nc[nH]c2ncc(Br)c1-2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in Chloroform (100 mL) was added NBS (6.08 g, 34.2 mmol), and the reaction mixture was stirred a 70° C. for 3 hours. The reaction was allowed to cool to room temperature, and the mixture was filtered, washing the solid with additional CHCl3 to afford 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].CS([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.[OH-].[Na+]>[C:16]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]=1[OH:15])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(S)cc2)CC1=O
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(=O)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O

Procedure:
To a solution of 8.0 g (0.029 mol) of 3-hydroxy-5-(4-mercaptophenyl)-2-propionyl-cyclohex-2-en-1-one in 150 mL of acetonitrile was added 6.80 g (0.0290 mol) of 2,5-bis(methylsulfonyl)pyridine and 8.0 g (0.0579 mol) of powdered potassium carbonate. The mixture was heated at reflux for 3 hours and cooled. The mixture was diluted with 500 mL of water and 50 mL of 1.0N NaOH and filtered through Celite®. The filtrate was acidified (pH 2) with concentrated HCl and extracted 4 times with 300 mL of methylene chloride. The organic layer was washed twice with 150 mL portions of water and dried over MgSO4. The solvent was removed in vacuo leaving 10.4 g (83 percent of theoretical) of the crude product which was purified by column chromatography using methylene chloride as the eluent. Recrystallization of the crude from ethanol gave the above named product in a yield of 5.10 g (41 percent of theoretical). The product melted at 167°-174° C.; 1H NMR (CF3CO2H): δ 1.25 (t, 3H, CH3CH2 --), 2.8-3.7 (m, 10H, ring protons and CH3SO2 --, CH3CH2 --), 7.3-8.9 (m, 7H, ArH).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][N:15](COCC[Si](C)(C)C)[C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(N2CCOCC2)cn3COCC[Si](C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2cnc3[nH]cc(N4CCOCC4)c3c2)cc1
Temperature: 80 °C
Yield: 38.4 %

Procedure:
A mixture of 61 (0.017 g, 0.038 mmol), 10% hydrochloric acid (1 mL), and ethanol (1 mL) was heated at 80° C. for 30 minutes. The mixture was cooled and poured into saturated NaHCO3 solution and extracted with AcOEt. The organic extract was dried (MgSO4), concentrated and purified by means of preparative TLC with CH2Cl2:methanol as eluent to afford 62 (0.0047 g, 39%) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 2.94 (s, 6H), 3.02-3.06 (m, 4H), 3.86-3.90 (m, 4H), 6.75-6.81 (m, 3H), 7.42-7.47 (m, 2H), 7.97 (d, J=0.21 Hz, 1H), 8.44 (d, J=0.21 Hz, 1H), 8.74 (bs, 1H).
Reaction SMILES: S(=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]=[S:12]=O)=O.O.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[F:10][C:6]1[C:5]2=[N:11][S:12][N:3]=[C:4]2[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:8][CH:7]=1
Reactant: O=S=Nc1cccc(F)c1N=S=O
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(F)c2nsnc12
Temperature: 25 °C

Procedure:
A solution of N,N′-disulfinyl-3-fluoro-1,2-diaminobenzene 39B (11.5 g, 52.75 mmol) in 80 mL of chlorosulfonic acid was heated at 110° C. for 8 hours. The mixture was cooled to r.t. and poured into water and extracted with EtOAc (50 mL) twice. The combined organic layer was washed with brine and dried over anhy. Na2SO4. The combined organic layer was concentrated in vacuo. Column chromatography (15% Petroleum/EtOAc) afforded 7.1 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.48 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H). LC-MS: m/z 253.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]>CO.[Pd]>[NH2:15][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(ethoxycarbonyl)-5-nitrobenzoic acid (5 g, 20.905 mmol) and 10% Pd/C (1.11 g, 1.045 mmol) in 100 mL of MeOH was stirred under H2 gas at room temperature. After 4 hours, the mixture was filtered through Celite and concentrated to give 3-amino-5-(ethoxycarbonyl)benzoic acid. To a solution of 3-amino-5-(ethoxycarbonyl)benzoic acid (2 g, 9.56 mmol) in 10 mL of DMF was added formaldehyde (about 37% wt % in H2O, 7.118 mL, 95.60 mmol) at room temperature. After 10 minutes, the solution was cooled to 0° C. and NaBH3CN (1.897 g, 28.68 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was diluted with EtOAc. The solution was washed with 5% citric acid and saturated brine and dried with Na2SO4. The solution was filtered and concentrated to give 3-(Dimethylamino)-5-(ethoxycarbonyl)benzoic acid Compound 1 (2.1 g, 92% in two steps). 1H-NMR (500 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.99 (s, 6H), 1.33 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, DMSO-d6) δ 166.99, 165.54, 150.14, 131.76, 130.79, 116.89, 116.25, 115.59, 60.79, 39.84, 14.05; ESI-MS: m/z (MH+): 238.1074 (calc'd), 238.1076 (found).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:18][CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
TFA (55.30 mL, 717.76 mmol, 15.0 eq) was added at 0° C. to a stirred solution of (tert-butoxy)-N-{4-[(fluoren-9-yl-methoxy)carbonylamino]phenyl}carboxamide (20.60 g, 47.85 mmol, 1.0 eq) in CH2Cl2 (900 mL). The resulting solution was allowed to come at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated to dryness and the residue was triturated in water. Then the mixture was filtered to afford 15.80 g of the expected crude product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([CH:12]=[C:13]3[C:18](=[O:19])[CH:17]4[CH2:20][CH2:21][N:14]3[CH2:15][CH2:16]4)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][CH:13]3[C:18](=[O:19])[CH:17]4[CH2:20][CH2:21][N:14]3[CH2:15][CH2:16]4)=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(-c3ccc(F)cc3)cc2)N2CCC1CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1C2CCN(CC2)C1Cc1ccc(-c2ccc(F)cc2)cc1
Yield: 38 %

Procedure:
A solution of 2-[4-(4-fluorophenyl)benzylidene]quinuclidin-3-one (1.3 g) in ethyl acetate (40 ml) was hydrogenated at atmospheric pressure for 4 hours over a catalyst of 10% palladium on carbon. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by medium pressure chromatography on silica gel using ethyl acetate as eluant to give 2-[4-(4-fluorophenyl)benzyl]quinuclidin-3-one as a colourless solid (38% yield), m.p. 122°-123° C., microanalysis, found: C, 77.5; H, 6.5; N, 4.4% C20H20FNO requires: C, 77.6; H, 6.5; N, 4.5%; NMR (CDCl3): 1.9-2.1 (4H, m), 2.5 (1H, m), 2.8-3.0 (3H, m), 3.1-3.3 (3H, m), 3.4 (1H, d of d), 7.1 (2H, m), 7.3-7.4 (2H, d) and 7.4-7.6 (4H, m); m/z 310 (M+H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1.O>C(Cl)(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]2[CH2:3][CH2:4][NH:5][C:24](=[O:25])[CH2:23][C:19]=2[CH:18]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)CC(=O)NCC2
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 28.8 %

Procedure:
The title compound was synthesized by referring to the synthetic method of EP285287. To a solution of(3-methoxyphenyl)acetic acid (16 g) in tetrahydrofuran (150 ml) were sequentially added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (10 ml) under a nitrogen atmosphere, the solution was stirred for 5 hours at room temperature, and then the reaction mixture was concentrated in vacuo to provide (3-methoxyphenyl)acetyl chloride (18.8 g). To a solution of aminoacetaldehyde dimethylacetal (11 g) and triethylamine (11 g) in chloroform (150 ml) was added (3-methoxyphenyl)acetyl chloride (18.8 g) on an ice bath, and the solution was stirred for 9.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), a solution of N-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)acetamide (24.9 g) in acetic acid (75 ml) was added dropwise to concentrated hydrochloric acid (50 ml), and the solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water, ethyl acetate and tetrahydrofuran were sequentially added thereto, insoluble material was removed by filtration, then the filtrate was concentrated in vacuo. To the residue was added water, the resulting solid was filtered and collected. To a solution of the resulting 8-methoxy-1,3-dihydrobenz[d]azepin-2-one (6.3 g) in acetic acid (100 ml) was added 10% palladium-activated charcoal (1.5 g), and the solution was stirred for 23 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, was neutralized by sequentially adding water and aqueous ammonia. The resulting solid was filtered to provide 8-methoxy-1,3,4,5-tetrahydrobenz[d]azepin-2-one (5.6 g). To a suspension of this compound (1.5 g) in tetrahydrofuran (15 ml) was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (15 ml), and the solution was refluxed for 2 hours. 5N hydrochloric acid (5 ml) was added thereto on an ice bath, the solution was refluxed for 45 minutes, and then neutralized with aqueous ammonia. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (752 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(O)=[O:34]>>[OH:34][C:2]1[C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=CO
Reactant: O=C(Nc1ccc(Cc2nc3ccnc(Cl)c3[nH]2)cc1)Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1ccc(Cc2nc3ccnc(O)c3[nH]2)cc1)Nc1cc(C(F)(F)F)ccc1F

Procedure:
2.4 A solution of 50 mg of “A2” in 1 ml of formic acid (98-100%) is refluxed for 8 hours and subsequently purified via an RP18 column, giving 3 mg of 1-[4-(4-hydroxy-3H-imidazo[4,5-c]pyridin-2-ylmethyl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (“A3”), Rf 2.88.
Reaction SMILES: [CH2:1]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:5]1[NH:6][C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1COCC[Si](C)(C)C)C(=O)C(F)CS2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc2c([nH]1)C(=O)C(F)CS2
Yield: 92.7 %

Procedure:
305 mg of the product of Stage B and 1.75 ml of trifluoroacetic acid were heated at 40° C. for 12 hours in 6.1 ml of dichloromethane. The mixture was poured into water, sodium bicarbonate was added until a pH of 6-7 was obtained. Extraction was carried out with methylene chloride and the solvent was eliminated under reduced pressure to obtain 180 mg of the expected product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: BrCCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
2.8 g of sodium hydride as a 60% dispersion in oil are added in small portions at RT to a solution of 13.35 g of 3,4-dichlorophenylacetonitrile in 100 ml of THF and the reaction mixture is stirred for 3 hours at RT. It is cooled to -20° C., a solution of 16 g of 2-(3-bromopropoxy)tetrahydropyran in 30 ml of THF is added dropwise and the reaction mixture is stirred for 3 hours while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over MgSo4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 11 g of the expected product.