Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)(Cl)/[C:3](=N\[H])/[O:4][CH:5]1[O:10][CH:9]([CH3:11])[CH:8]2[O:12][CH2:13][C:14](=C)[CH:7]2[CH2:6]1.[Cl:20][CH:21]1[CH:32]([CH3:33])[CH:31]2[CH:23]([C@@:24]3([CH:51]=[O:52])[CH2:36][C@H:28]4[C@@](CO)([CH2:30]2)[C@:25]3([C:40]([O:42]COC(=O)C(C)(C)C)=[O:41])[C:26]([CH:37]([CH3:39])[CH3:38])=[CH:27]4)[CH2:22]1>C(Cl)Cl.CCOCC.CO.[Cl-].[Cl-].[Zn+2]>[Cl:20][CH:21]1[CH:32]([CH3:33])[CH:31]2[CH:23]([C@@:24]3([CH:51]=[O:52])[CH2:36][C@H:28]4[C@@:2]([CH2:3][O:4][CH:5]5[O:10][C:9](=[CH2:11])[CH:8]6[O:12][CH2:13][CH2:14][CH:7]6[CH2:6]5)([CH2:30]2)[C@:25]3([C:40]([OH:42])=[O:41])[C:26]([CH:37]([CH3:38])[CH3:39])=[CH:27]4)[CH2:22]1
Reactant: [H]/N=C(/OC1CC2C(=C)COC2C(C)O1)C(Cl)(Cl)Cl
Reactant: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CO)[C@]13C(=O)OCOC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: C=C1OC(OC[C@@]23CC4C(C)C(Cl)CC4[C@@]4(C=O)C[C@@H]2C=C(C(C)C)[C@@]34C(=O)O)CC2CCOC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of imidate 37 prepared above in CH2Cl2 (5 mL) was added 42 (16 mg, 0.033 mmol) in CH2Cl2 (1 mL), followed by ZnCl2 (0.6 mL of a 1M solution in ether, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. After aqueous work-up (CH2Cl2) and purification by PTLC, about 12.6 mg of crude product 43 (•- and •-isomers) was obtained. To a solution of this crude product 43 (4 mg) in CH3OH (2 mL) was added K2CO2 (20 mg). The mixture was stirred at room temperature for about two hours. After aqueous work-up (CH2Cl2) and purification by HPLC, about 1 mg of 44 was obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromo-3-methylpyridine
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)c(F)c(C)c1-c1cccc(CO)c1
Reaction time: 2 h

Procedure:
3′-Fluoro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde 19a (700 mg, 2.87 mmol, prepared by a method disclosed in PCT patent application WO2008001931) was dissolved in 10 mL of methanol, followed by addition of sodium borohydride (130 mg, 3.44 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water and extracted with ethyl acetate (50 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (700 mg) as a white solid, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:7]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:22](=[O:23])[C:21]2[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=2)[CH:7]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cc(Cl)ccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(5-chloro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 70:30) for the chromatographic purification. Colorless solid (35%). MS (ESI): m/z=473.084 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13]>C1COCC1>[CH3:9][C:10]([CH3:15])=[CH:11][C:12]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: CC(C)=CC(=O)Cl
Reactant: Sc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Sc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice bath cooled solution of 1.92 g (80 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3×15 ml hexane wash) in 30 ml of dry THF was added slowly under argon a solution of 15.1 g (80 mmol) of 4-bromothiophenol in 60 ml of dry THF over 1 h. The mixture was stirred at 0 degrees C. for a further 30 min and then treated with a solution of 10.1 g (85 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture then stirred at room temperature for 40 h. The reaction mixture was poured into 200 ml of water containing 2 ml of glacial acetic acid and the organic layer was separated. The organic layer was washed with 2×75 ml of water and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDCl3): & 1.91 (3 H, s), 2.14 (3 H, s), 6.03-6.06 (1 H, m), 7.28 (2 H, d, J~8.6 Hz), 7.53 (2 H, d, J~8.6 Hz).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:9]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:8]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:7]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.O.[OH-].[Na+]>CO.C(OCC)(=O)C>[OH2:16].[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([Br:24])[C:6]2[O:16][C:9]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:8]([CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:7]=2[CH:23]=1
Reactant: CN(C)CCCC1c2cc(Br)ccc2OC12CCCCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(C)CCCC1c2cc(Br)cc(Br)c2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a stirred solution of 8.4 g of 5-bromo-3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] hydrochloride in 57 ml of methanol, at room temperature under nitrogen, was added 7.44 g of N-bromosuccinimide. All solid dissolved as the pot temperature rose to 37° C. After stirring overnight at room temperature under nitrogen, the mixture was poured into 250 ml of water, made basic by addition of 100 ml of 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with water (100 ml) and saturated sodium chloride solution (100 ml) and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a mixture of oil and solid. This material was taken up in 100 ml of ethyl acetate and gravity-filtered, and the filtrate was stirred and treated dropwise with 10 ml of hydrogen chloride-saturated ether solution. The precipitated salt was filtered off, washed with ether and dried in vacuo to afford 2.85 g of a solid, m.p. sinters 200°, 202°-204° C. A second crop which had precipitated out of the filtrate was filtered off and washed with ether to afford, without drying, an additional 1.2 g of a solid, m.p. sinters 200°, 201°-202.5° C. The two crops of crude salt were combined and dissolved in 50 ml of absolute ethanol and gravity-filtered, and the filtrate was treated dropwise with ether (350 ml) with stirring. After stirring the mixture for a short period of time, the recrystallized solid was filtered off, washed with ether and dried to afford 2.2 g of a solid, m.p. 203.5°-206° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[NH4+]=[S:11]>CO>[O:1]=[C:2]1[C:7]([C:8](=[S:11])[NH2:9])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: N#Cc1ccc[nH]c1=O
Solvent: CO
Product: NC(=S)c1ccc[nH]c1=O
Temperature: 130 °C

Procedure:
To a suspension of 2-oxo-1,2-dihydropyridine-3-carbonitrile (0.211 g) in methanol (14 mL) was added a 40% aqueous solution of ammonium sulfide (0.50 mL). The reaction mixture was heated at 130° C. in a microwave reactor for 2 hours. The reaction mixture was concentrated. The residue obtained was triturated with methanol and the solid filtered to obtain the title compound (0.174 g) having the following physical data.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCN(c2ncc(-c3ccccc3)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cnc(N3CCNCC3)nc2)cc1

Procedure:
0.04 mol of ethyl 1-(5-phenyl-2-pyrimidinyl)-4-piperazinecarboxylate are boiled under reflux with 0.78 mol of KOH in 400 ml of C2H5OH and 40 ml of H2O under N2 protective gas for 15 hours. The mixture is evaporated to dryness, water is added and the residue is taken up in CH2Cl2. After washing with water, the organic phase is separated off and evaporated to dryness, whereupon the amine is obtained as crystals.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](OC(=O)C)(=[O:8])[CH3:7].[NH2:13][CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]>O1CCOCC1.O>[NH:13]([CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16])[C:6]([CH3:7])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC(/C=C/CP(=O)(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
At 0°, 170 mg of sodium hydrogen carbonate and, within a period of 5 minutes, 50 microliters of acetic anhydride are added to a solution of 100 mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/water (1:1). The whole is stirred for 30 minutes at 0°, approximately 2 ml of Dowex 50 H+ are added and filtration is carried out. The filtrate is concentrated by evaporation and purified by ion exchange chromatography (Dowex 50 H+). Lyophilisation of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 155°.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH:16]([C:18]1[CH:19]=[CH:20][C:21](O)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]>C(Cl)Cl>[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C=O)ccc1O
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
Triflic anhydride (7.74 mL) was added to methyl 5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH2Cl2 at 0° C., and the reaction was stirred and allowed to warm to room temperature over 3 hours. The reaction was diluted with CH2Cl2 (150 mL), washed with 3× brine, dried over Na2SO4, and concentrated. The product was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=2)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CN(C=O)C>[N:1]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:12])=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(CBr)cc1)C1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
Add sodium azide (441 mg, 6.785 mmol) to a stirred solution of 4-(cyclohexanecarbonyl)-benzyl bromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mL) and heat the mixture to 90° C. for 2 h. Cool the mixture to room temperature, add water and extract the aqueous solution with diethyl ether. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as oil (310 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:4](=O)[CH:3]=1.O.[NH3:16].O.CCOCC>C1(C)C=CC=CC=1>[NH2:16][C:4]1[CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:2](=[O:1])[CH:3]=1
Reactant: N
Reactant: CCCCCCC1CC(=O)C=C(O)C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC1CC(=O)C=C(N)C1
Temperature: 130 °C
Reaction time: 3.5 h

Procedure:
A suspension of 3-hydroxy-5-n-hexyl-2-cyclohexene-1-one (29.7 g) in toluene (200 ml) was combined with conc. ammonia water (100 ml), and the mixture was stirred at 130° C. for 3.5 hours in an apparatus equipped with a water separator. After completion of the reaction, ether was added. The precipitate was collected by filtration, and was recrystallized from a solvent mixture of chloroform-ether. 17.0 g of 3-amino-5-n-hexyl-2-cyclohexene-1-one was obtained as pale yellow needles having a melting point of 113° C. (57.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](#[N:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22]>CC(O)C>[C:19]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:27]
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Reactant: N#Cc1ccccc1N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1ccccc1C#N
Yield: 64.6 %

Procedure:
The reaction mixture of 102.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 53.0 mg (0.44 mmol) of anthranilonitrile in 2.0 mL of 2-propanol was refluxed for 2 h and cooled down. The yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 40° C. overnight to give 84.5 mg (65%) of the title compound.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:53]=[CH:52][CH:51]=[CH:50][C:10]=1[CH2:11][NH:12][C:13]([C@@H:15]1[C:19]([CH3:21])([CH3:20])[S:18][CH2:17][N:16]1[C:22](=[O:49])[C@@H:23]([OH:48])[C@@H:24]([NH:32][C:33](=[O:47])[C@H:34]([CH2:43][C:44](=[O:46])[NH2:45])[NH:35]C(OC(C)(C)C)=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]>>[CH3:8][C:9]1[CH:53]=[CH:52][CH:51]=[CH:50][C:10]=1[CH2:11][NH:12][C:13]([C@@H:15]1[C:19]([CH3:20])([CH3:21])[S:18][CH2:17][N:16]1[C:22](=[O:49])[C@@H:23]([OH:48])[C@@H:24]([NH:32][C:33](=[O:47])[C@H:34]([CH2:43][C:44](=[O:46])[NH2:45])[NH:35][C:7]([C:6]1[O:5][C:4]2[CH:3]=[CH:52][CH:53]=[CH:9][C:10]=2[CH:11]=1)=[O:2])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:14]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CSC1(C)C
Reactant: C1COCCO1
Agent: Cl
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)c2cc3ccccc3o2)CSC1(C)C
Reaction time: 2 h

Procedure:
4N HCl/dioxane (2 ml) was added to Boc-Asn-Apns-Dmt-NHBzl(2-Me) (197 mg) obtained in the step 1 of Example 6 and the mixture was stirred for two hours. After concentration, the reaction mixture was dissolved in DMF (3 ml) and neutralized with Et3N (0.042 ml). 2-benzofurancarboxylic acid (54 mg), HOBt (45 mg), and EDC.HCl (69 mg) were added to this solution, and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% NaHCO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (108 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[C:6]([C:16]([O:18]C)=[O:17])=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)=[O:4].[Li+].[OH-]>C1COCC1>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[C:6]([C:16]([OH:18])=[O:17])=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(-c2ccccc2)nc1C(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
A solution of methyl 5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate (0.195 g, 0.71 mmol) in THF (3.6 mL) at 23° C. was treated with LiOH (1 M aq., 3.6 mL, 3.6 mmol). The resulting suspension was stirred for 15 min at 23° C. and partitioned between ether and water. The aqueous layer was acidified to pH 1 with HCl (conc.). The resulting white solid was collected by filtration, washed with water, and air-dried to provide 0.164 g (89%) of 5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (330 mg, 0.84 mmol), (1R,2R)-2-aminocyclohexanol (192 mg, 1.27 mg) and DIEA (327 mg, 2.54 mmol) in DMA (15 mL) was stirred at 135° C. for 1 h. The reaction mixture was cooled to rt, poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:6 petroleum ether/ethyl acetate to give (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (373 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 5.48 (s, 2H), 4.68 (s, 3H), 3.37 (br s, 2H), 1.92 (br s, 2H), 1.62 (br s, 2H), 1.23 (br s, 4H). LCMS (ESI) m/z 441 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH2:8]O.[CH2:14]([N:16](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(OCC)(=O)C.O.CN(C)C=O.C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:8][C:14]#[N:16])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: COCOc1cc(CO)ccc1C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(CC#N)ccc1C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-(methoxymethoxy)-4-methylbenzyl alcohol described in WO2004/022551 (9.80 g; 53.78 mmol), triethylamine (7.90 ml; 56.47 mmol) and anhydrous THF (50 ml) was added dropwise methanesulfonyl chloride (4.40 ml; 56.47 mmol) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected and condensed under reduced pressure. Then, to the residue were added sodium cyanide (7.91 g; 0.161 mol) and anhydrous N,N-dimethylformamide (50 ml). The mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give [3-(methoxymethoxy)-4-methylphenyl]acetonitrile as blackish brown oil (7.87 g; 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:10]([CH3:12])=[CH2:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:5]=2[N:6]([C:10]([CH3:12])=[CH2:11])[C:7]1=[O:9]
Reactant: C=C(C)n1c(=O)[nH]c2cc(C)ccc21
Reactant: ClCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C=C(C)n1c(=O)n(CCCCl)c2cc(C)ccc21

Procedure:
To a stirred and hot (±50° C.) mixture of 34 parts of 1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 300 parts of a sodium hydroxide solution 50% are added 57 parts of 1-bromo-3-chloropropane (exothermic reaction: temperature rises to 70° C.). The whole is stirred for one hour at 65°-70° C. The reaction mixture is cooled and poured onto crushed ice. The product is extracted with methylbenzene. The extract is washed three times with water, dried, filtered and evaporated. The oily residue is distilled, yielding 3-(3-chloropropyl)-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one; bp. 140° C. at 0.02 mm. pressure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([O:24][C:25]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=[CH:33][C:25]=3[O:24][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:19]([N:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:9]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)N1CCCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCN(Cc2ccccc2)CC1
Yield: 80.9 %

Procedure:
Potassium carbonate (0.80 g) was added to a solution of 0.86 g of ethyl 1-homopiperazinecarboxylate and 0.90 g of benzylbromide in 5 ml of tetrahydrofuran, and the mixture was refluxed for 4 hours. Thereafter, water was added, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (2:1) mixture gave 1.06 g of ethyl 4-benzylhomopiperazine-1-carboxylate.