Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]([CH2:15][CH2:16][CH2:17][P:18](=[O:29])([O:24]CCCC)[O:19]CCCC)C(OCC)=O)C1C=CC=CC=1.N1C=CC=CC=1.C(O)C>C(O)(=O)C.Cl.O>[OH:8][NH:9][CH2:15][CH2:16][CH2:17][P:18](=[O:19])([OH:29])[OH:24]
Reactant: CCCCOP(=O)(CCCN(OCc1ccccc1)C(=O)OCC)OCCCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=P(O)(O)CCCNO
Reaction time: 48 h
Yield: 46.2 %

Procedure:
A solution of dibutyl 3-(N-benzyloxy-N-ethoxycarbonylamino)propylphosphonate (6.72 g.) in acetic acid (70 ml.) and conc. hydrochloric acid (70 ml.) was refluxed with stirring for 48 hours. The reaction mixture was concentrated under reduced pressure to give an oily residue, to which there was added water (30 ml.). The solution was washed with ethyl acetate (20 ml.), treated with activated charcoal and then concentrated under reduced pressure to give an oily residue (2.60 g.). The residue was dissolved in water (5 ml.). To the solution was added pyridine (1.08 g.) and ethanol (2 ml.). The mixture was allowed to stand overnight at ambient temperature to give crystalline 3-(N-hydroxyamino)propylphosphonic acid (1.12 g.).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:30])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Li+]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:30])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Agent: [Li+]
Agent: [OH-]
Product: CCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)s1
Yield: 85.1 %

Procedure:
In a manner similar to that of Example 7j, starting with 0.06 g (0.14 mmol) of methyl 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentylureido)thiazol-5-yl]phenyl}propanoate and 0.2 ml (0.2 mmol) of aqueous 1M lithium hydroxide solution, 0.05 g (86%) of 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentylureido)thiazol-5-yl]phenyl}propanoic acid is obtained in the form of a white solid with a melting point of 114° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH3:4].CC([O-])(C)C.[K+].[C:21]([O:25]C(C)(C)C)(=[O:24])[CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[C:21]([OH:25])(=[O:24])[CH2:22][CH2:23][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCCOCCOCCOCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCOCCOCCOCCOCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4.13 g of triethylene glycol mono-n-butyl ether in toluene (150 mL) are added 264 mg of t-BuOK (potassium tert-butanolate) in portions and then 5.81 g of t-butyl acrylate in toluene (20 mL) at room temperature. The mixture is stirred at room temperature overnight, and toluene is removed in vacuo. To this residue are added 40 mL of 0.5 N KOH ethanol solution, and the reaction mixture is heated to reflux for 2 h (hours). After acidifying to pH 3 with diluted HCl aq. solution, EtOAc (ethyl acetate) is added to the mixture. The extract with EtOAc is concentrated, and the residue is applied to silica gel column with CH2Cl2-MeOH (methylene chloride-methanol) mixture as eluent. I1 is obtained as colorless oil, 5.34 g.
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cc4)cc3)(CC1)CO2

Procedure:
The title compound was prepared analogous to Example 4, Step 4, starting from methyl 2-(4-(4′-(5-cyclobutyl-1,3,4-oxadiazol-2-ylamino)biphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (252 mg, 0.53 mmol) and NaOH (1.60 ml, 1.60 mmol). After acidification with 1N HCl, the slurry was filtered and washed with water to afford the title compound as white solid after drying (226 mg, 92% yield). HR/MS (M+H)+ found 460.2221. calc. 476.2236. RT: 2.68 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H) 7.62 (s, 4H) 7.57 (d, J=8.59 Hz, 2H) 7.38 (d, J=8.59 Hz, 2H) 3.89 (s, 2H) 3.62-3.73 (m, 1H) 2.22-2.41 (m, 6H) 1.82-2.11 (m, 10H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[C:15](OCC)(=[O:17])C>>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:15]=[O:17])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])#[N:13]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: Cl
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F

Procedure:
5-Amino-2-cyanobenzotrifluoride (0.07 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL) and dry hydrogen chloride in ethyl acetate (3.5 M, 5.5 mL) was added. After 15 min the solution was concentrated to dryness and co-evaporated three times from toluene (3×5 mL). The residue was added toluene (2.5 mL) and flushed with nitrogen for about 10 min. before diphosgene (0.43 mL) was added. Then the mixture was gently refluxed for 1 hour under a nitrogen atmosphere. The mixture was cooled and concentrated to dryness in vacuo and then co-evaporated twice from toluene to remove excessive diphosgene to afford 4-cyano-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[F:5][C:6]1[CH:36]=[CH:35][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)([OH:11])[CH2:2][CH3:3])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCCN2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCCCN2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a Grignard reactant prepared from 2.4 g. of magnesium turnings and 11 g. of ethyl bromide in 40 ml. of dry ether a solution of 10.8 g. of 4-fluoro-4'-[3-(4-benzyl-piperazin-1-yl)-propoxy]-benzophenone in 200 ml. of dry ether is added dropwise, at -30° C. The reaction mixture is stirred at 0° C. for additional 30 minutes, and is then refluxed for one hour. After cooling the reaction mixture is poured onto a solution of ammonium chloride in ice water. The ethereal phase is separated. The aqueous phase is extracted with ether. The ethereal phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate, the solution is evaporated in vacuo. The residue is crystallized from isopropyl ether. 5.3 g. of the end product are obtained, melting at 119° to 121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].[K+].[Br-]>>[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH:34][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:23])[CH:31]([CH3:33])[CH3:32]
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1)C(C)C
Yield: 84.2 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 84.2% yield. Mass (ES+): 455 (M++1); IR (KBr): 3310, 1742, 1672, 1553 (br), 1506, 1434; 1H NMR (DMSO-d6) δ: 0.92 (2×d, 6H), 2.18 (m, 1H), 3.65 (s, 3H), 4.29 (t, 1H), 7.11 (t, 2H), 7.59 (d, 2H), 7.66 (s, 1H), 7.82 (d, 2H), 8.77 (s, 1H), 8.94 (s, 1H), 9.16 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].Cl.N1C=CC=CC=1>[OH-].[Na+]>[N+:13]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[OH:2])[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:15])=[O:14]
Reactant: COc1cc2ncccc2cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc2cccnc2cc1O
Temperature: 150 °C
Yield: 92.3 %

Procedure:
A mixture of 7-methoxy-6-nitro-quinoline (1.5 g, 7.35 mmol) and pyridine hydrochloride (2.6 g, 22.58 mmol) was heated at 150° C. for ca. 5 hours. The residue was dissolved in an aqueous solution of sodium hydroxide (3 M) and extracted twice with ethyl acetate. The combined organic extract were washed twice with an aqueous solution of sodium hydroxide (3 M) and then discarded. The combined aqueous layers were neutralized (pH 7) by addition of concentrated hydrochloric acid and extracted 4 times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow solid residue was purified on a silica gel plug to give 1.29 g (69% yield) of 6-nitro-quinolin-7-ol as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[N:25][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[N:13]([C:21]3[CH:26]=[N:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CNC(=O)O2
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CN(c1ccc([N+](=O)[O-])nc1)C(=O)O2
Yield: 92.4 %

Procedure:
Following general N—C coupling procedure 1, 2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester (0.510 g, 1.887 mmol) (Reference: German Patent DE10 2005 030051A1 (28 Dec. 2006)) was combined with 5-bromo-2-nitropyridine (0.400 g, 1.971 mmol, 1.05 eq) which gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a brown solid (0.684 g, 1.743 mmol) in 92% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (br. s., 9H) 1.54-1.72 (m, 1H) 1.86-2.16 (m, 3H) 3.30 (d, J=8.03 Hz, 1H) 3.66 (br. s., 2H) 3.81 (d, J=9.03 Hz, 1H) 3.94 (d, J=7.53 Hz, 1H) 8.33 (d, J=9.03 Hz, 1H) 8.52 (br. s., 1H) 8.60 (dd, J=9.03, 3.01 Hz, 1H). MS m/z 337.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[C:21](=[O:22])[N:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])[C:19](=[O:30])[NH:18]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN([P+]([O:41][N:42]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.ON.Cl.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH2:16][CH:17]3[C:21](=[O:22])[N:20]([CH:23]([CH:27]([CH3:28])[CH3:29])[C:24]([NH:42][OH:41])=[O:25])[C:19](=[O:30])[NH:18]3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NO)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the compound obtained in step c above (20c) (166 mg, 0.401 mmol) in DMF (5 mL) was added BOP reagent (213 mg, 0.481 mmol) at 0° C. After stirring for 30 min, HONH2×HCl (50 mg, 11.38 mmol) and N-methylmorpholine (0.15 mL, 1.34 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between EtOAc and saturated NH4Cl solution. The aqueous layer was extracted with EtOAc, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (60 mg, 35%).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:21])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:10]=[C:9]([I:20])[CH:8]=1>O.C1COCC1>[I:20][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:10]=1)[C:6]([OH:21])=[O:5]
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(I)cc(C(=O)O)c2)nc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (526 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid (470 mg, 93%). MS (M+H)=340.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1F>>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Fc1ccccc1Br
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccccc2Br)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 1-bromo-2-fluoro-benzene were converted to yield {4-[1-(2-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([NH:17][C:18]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[C:31]1([CH3:34])[CH:32]=[CH:33][C:28]([S:25]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18]([NH:17][C@H:4]([C:3]([OH:35])=[O:2])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][CH:7]=2)=[O:19])(=[O:26])=[O:27])=[CH:29][CH:30]=1
Reactant: COC(=O)C(Cc1ccc(NS(C)(=O)=O)cc1)NC(=O)C1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(NS(C)(=O)=O)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a solution of 3-(4-methanesulfonylamino-phenyl)-2-{[1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonyl]-amino}-propionic acid methyl ester (0.250 g, 0.477 mmol) in THF (1.0 mL) was added 1H LiOH (955 mL, 0.955 mmol) and the clear solution was stirred at 25° C., under nitrogen, for 16 h. The reaction solution was then diluted with additional water (50 mL) and washed with diethyl ether (25 mL). The aqueous layer was lyophilized to afford a fluffy white solid (0.216 g, 87%). MS (=ESI): 508 [M−1]−
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[OH:28][CH2:27][C:26]1[CH:30]=[CH:31][C:23]([C:22]([NH:20][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:21])=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(CO)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-hydroxymethyl-benzoic acid. MS: 408.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1>[Ir+].ClC1CCC=CCCC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([B:9]([OH:13])[OH:10])[CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCCl
Product: OB(O)c1cc(Cl)nc(Cl)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
To a mixture of 2,6-dichloropyridine (3.28 g, 22.2 mmol) and bis(pinacolato)diboron (6.2 g, 24.4 mmol) was added 1,10-phenanthroline (0.24 g, 1.3 mmol) and chloro-1,5-cyclooctadiene iridium (I) dimer (0.44 g, 0.66 mmol) under nitrogen followed by anhydrous 1,2-dichloroethane. Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 15 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto diethylether/4N sodium hydroxide (50 ml 200 ml) and the phases separated. The aqueous phase was acidified with 6N hydrochloric acid and the resulting solid was filtered, washed with water and dried on the sinter to yield the pinacol ester of 2,6-dichloropyridin-4-ylboronic acid (3.5 g, 58%) as a grey solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)(=[O:6])=[O:5].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH3:3][S:4]([C:7]1[N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1nc2cnccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cnccc21

Procedure:
NaH (122 mg) (60% in mineral oil) was added to a solution of 2-(methylsulfonyl)-1H-imidazo[4,5-c]pyridine (500 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.538 mL) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH (2 mL), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-c]pyridine (330 mg) as a light brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:26])[C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[N:18][N:19]([CH3:25])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])[S:14][CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:15]1[S:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([CH3:25])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])=[N:12][C:11]=1[CH:10]([F:9])[F:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(-c2nc(C(F)F)cs2)cnn1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2nc(C(F)F)c(Br)s2)cnn1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 106.3 %

Procedure:
N-bromosuccinimide (391 mg) was added to an N,N-dimethylformamide (3.6 ml) solution of the methyl 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (200 mg) obtained in (Example 1.3) <Step 1>, and the obtained mixture was then stirred in a nitrogen atmosphere at 80° C. for 40 minutes. Thereafter, N-bromosuccinimide (391 mg) was further added to the reaction solution, and the obtained mixture was then stirred in a nitrogen atmosphere at 80° C. for 15 hours. Thereafter, a sodium thiosulfate aqueous solution (40 ml) and a saturated sodium hydrogen carbonate aqueous solution (60 ml) were successively added to the reaction solution, and the reaction mixture was then extracted with ethyl acetate (60 ml) twice. Organic layers were gathered. The gathered organic layer was washed with a saturated saline (100 ml) three times, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then dried under reduced pressure, so as to obtain the title compound (274 mg) in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][CH2:41]Cl)(=[O:39])[CH2:37][CH3:38]>CN(C=O)C>[C:36]([O:40][CH2:41][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:39])[CH2:37][CH3:38]
Reactant: CCC(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of chloromethyl propionate (75 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1), and recrystallized in methanol to afford the title compound as a white solid (145 mg, 41.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCC1CCCO1
Product: N=C(OCC1CCCO1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethyl-tetrahydrofuran, there is obtained 2-tetrahydrofurylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 322 (14), 237 (66), 194 (100), 85 (36), 71 (12);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[C:9]2[C:14]([CH:15]3[C:20]=1[CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][CH:10]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:17]1[CH2:18][CH2:19][C:20]2=[C:8]([CH3:7])[C:9]3[C:14]([CH:15]2[CH2:16]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)CBr
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC2=C(C)c3ccccc3C2C1

Procedure:
A solution of 15.3 g of bromoacetic acid methyl ester in 50 cc of dimethyl formamide is added dropwise at 60° while stirring to a mixture of 18.5 g of 1,3,4,9b-tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 41.4 g of potassium carbonate in 200 cc of dimethyl formamide. The reaction mixture is allowed to react at 60° for 1 hour, is poured on ice water and is extracted thrice with chloroform. The extracts are dried and completely concentrated by evaporation, the residue is dissolved in 50 cc of methanol, and the calculated amount of hydrochloric acid in ethanol is added. After the addition of ether, 1,3,4,9 b-tetrahydro-5-methyl-2H-indeno [1,2-c]pyridine-2-acetic acid methyl ester crystallizes as hydrochloride and is recrystallized twice from ethanol for further purification. The hydrochloride has a M.P. of 184°-185°.