Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[OH2:39]>Cl>[NH2:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:21])[OH:18])[C:6]([OH:39])=[O:7]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: O
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 2-acetamido-2-(1-benzylpiperidin-4-yl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (510 mg, 0.97 mmol) in 6 N HCl (15 mL) was heated to a gentle reflux for 16 h. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (15 mL) and washed with dichloromethane (3×25 mL). The aqueous layer was concentrated to give an off-white solid that was purified by HPLC (5-95% acetonitrile in water). The fractions containing product were concentrated, redissolved in deionized water (15 mL), frozen in liquid nitrogen and lyophilized to give 2-amino-2-(1-benzylpiperidin-4-yl)-6-boronohexanoic acid (210 mg, 62%) as its dihydrochloride salt and trihydrate. 1H NMR (D2O, 500 MHz) δ 7.37-7.43 (m, 5H), 4.21 (s, 2H), 3.51 (brt, J=10 Hz, 2H), 2.92-2.99 (m, 2H), 2.02-2.10 (m, 2H), 1.66-1.84 (m, 4H), 1.41 (dq, J1=13.0 Hz, J1=4.0 Hz, 1H), 1.29-1.35 (m, 2H), 1.23-1.28 (m, 1H), 1.08-1.12 (m, 1H), 0.68 (t; J=8.0 Hz, 2H). ESI MS found for C18H29BFN2O4 m/z [331.6 (M+1−18) 13%, 313.6 (M+1−2×18) 100%, 329.6 (M−1−18) 100%]. Anal. Calcd for C18H29BN2O4×2HCl×3H2O: C, 45.49; H, 7.85; N, 5.89. Found C, 45.60; H, 7.10; N, 5.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)C(F)(F)F
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (793 mg, 4.15 mmol), 2-bromo-3,3,4,4,4-pentafluorobut-1-ene (1.0 g, 4.57 mmol), K2CO3 (1.14 g, 8.3 mmol) and Pd(PPh3)2Cl2 (58 mg, 0.08 mmol) in THF (4 mL) and H2O (2 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (800 mg; 66% yield) as colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:25][C:26]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCC1)C2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 45 min. Cyclopentyl acetic acid 0.36 ml and WSC 0.59 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with 10% sodium hydroxide and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclopentylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hours. The reaction mixture was cooled, then added ether, water and 10% aqueous sodium hydroxide thereto, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After filtering the drying agent, a residue obtained by concentrating the filtrate in vacuo was purified by means of flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-chloroform:acetone=20:1) to obtain the product.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:54])[C:47]1[CH:52]=CC(N)=[CH:49][N:48]=1.O1CCN(CCOC2N=CC(N)=CC=2)CC1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:49]=[N:48][C:47]([N:46]([CH3:54])[CH3:45])=[CH:52][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN(C)c1ccc(N)cn1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Agent: Nc1ccc(OCCN2CCOCC2)nc1
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N(C)C)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(2-morpholinoethoxy)pyridin-3-amine N2,N2-dimethylpyridine-2,5-diamine as the aniline component. (5%, MS=514.3 (M+H))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:25])=[C:16]([C:20]([F:24])=[C:21]([F:23])[CH:22]=2)[C:17](O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[F:25][C:15]1[C:16]([CH2:17][OH:18])=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(C(=O)O)c2F)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CO)c2F)CC1
Yield: 37 %

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5,6-trifluorobenzoic acid (0.84 g) was reacted in the standard reduction conditions with Borane in THF (see Example 179, Step i). The crude product was purified by Flash chromatography using a gradient of Hexane/Ethyl acetate (from 9:1 to 1:4) to give tert-butyl 4-(2,4,5-trifluoro-3-(hydroxymethyl)phenyl)piperazine-1-carboxylate as a white solid (0.18 g, 37% yield from beginning of step ii)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.[Cl-].[NH4+]>CN(C=O)C.C1COCC1>[CH2:28]([NH:34][C:12]([C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:14])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCC1CCCO1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCO1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
To a solution of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (95 mg, 0.5 mmol) in a 4:1 mixture of THF:DMF (2.5 mL) and triethylamine (146 μL, 1.05 mmol) at 0° C. is added ethyl chloroformate (98 μL, 1.03 mmol). The reaction mixture is allowed to stir for 1 h before tetrahydrofurfurylamine (155 μL, 1.5 mmol) is added. The reaction mixture is stirred for ¾ h and then allowed to warm to ambient temperature for 20 h. The mixture is subsequently poured into aqueous ammonium chloride, the THF is removed in vacuo, and the mixture is extracted with ethyl acetate. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is treated with 1N NaOH (2 mL) and ethanol (0.5 mL) at reflux for 1 h. The reaction mixture is cooled, diluted with aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic layers are dried (Na2SO4), filtered, and concentrated to give 65 mg of N-tetrahydrofurfuryl 4-oxo-1,4-dihydro-quinoline-3-carboxamide (compound 1) as a cream solid; m.p. 205-209° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.O>C1COCC1>[OH:14][CH2:15][C@H:16]1[N:21]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)=[O:4])[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cccc([N+](=O)[O-])c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (1.01 g, 4.14 mmol) was dissolved in THF (20 mL) and added (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.074 g, 4.97 mmol) followed by Hunig's base (1.45 mL, 8.28 mmol) then stirred at room temperature overnight. The reaction was poured into water and extracted with ETOAC (2×). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography through a 120 g ISCO Redi-sep column eluting with 0-70% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1ncccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncccc1O

Procedure:
To a stirred solution of 3-hydroxypicolinic acid (0.7122g, 5.1 mmol) in CH3OH (32 mL) at room temperature was added concentrated H2SO4 (4 mL). The mixture was heated to reflux for 18 hrs then concentrated. The residue was diluted with saturated aqueous Na2CO3 (45 mL) and extracted with CH2Cl2 (4×30 mL). The combined organic phases were dried (Na2SO4) and concentrated to give 0.73 g 3-hydroxypicolinic acid methyl ester as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.CC(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)C>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[C:13](/[CH:15]=[CH:24]/[N:25]([CH3:27])[CH3:26])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(-c2c(C)cccc2C)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C

Procedure:
To a solution of the 2-(2,6-dimethyl-phenyl)4-methyl-5-nitro-pyridine (8 g, 33.0 mmol) in anhydrous DMF (30 mL), Bredereck's reagent (20 mL, 99.0 mmol) is added, and the mixture is heated for 1 h at 90° C. The mixture is concentrated under reduced pressure, and the residue is dissolved a mixture of EtOAc-hexane-DCM (1:1:1, 200 mL) and filtered over small pad of silica gel. Removal of the solvent under reduced pressure gives the crude {(E)-2-[2-(2,6-dimethyl-phenyl)-5-nitro-pyridin-4-yl]-vinyl}-dimethyl-amine which is used in the following step.
Reaction SMILES: C([S:4][C:5]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][C:5]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)Sc1c(C)cccc1C(=O)N(CC(=O)O)C1CCCC1
Agent: N
Product: Cc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1S
Reaction time: 3 h

Procedure:
To a chilled solution of methanolic ammonia (30 ml) was added 2.6 g (0.0078 mole) of N-(2-acetylthio-3-methylbenzoyl)-N-cyclopentylglycine. The reaction was covered with a nitrogen atmosphere and stirred three hours while warming slowly from 0° C. to room temperature.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6]
Reactant: CC(C)(CF)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
157 g (0.79 mol) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were added dropwise to a stirred mixture of 129 g (0.79 mol) of 2,4-dichlorophenol and 110 g (0.79 mol) of powdered potassium carbonate in 500 ml of acetone at 20° to 30° C., while cooling. The mixture was subsequently stirred at 20° C. for 2 hours, the inorganic salt was filtered off and the filtrate was concentrated. 199.3 g (90% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were obtained as an oil, which was further reacted directly. ##STR82##
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:36][C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1

Procedure:
5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme 183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound 619, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](C(O[Si](C(C)(C)C)(C)C)C([O-])=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[C:39](=[O:42])([O-])[OH:40].[Na+].[O:44]1CCC[CH2:45]1>>[OH:44][CH2:45][C:39]([O:40][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:42]
Reactant: O=C([O-])O
Reactant: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(O[Si](C)(C)C(C)(C)C)C(=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Product: CCC(OC(=O)CO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl{[tert-butyl(dimethyl)silyl]oxy}acetate (137.1 mg, 0.235 mmol) in tetrahydrofuran (5.0 mL) was added 1N hydrogen chloride (1.0 mL, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate (4.0 mL) was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (88.0 mg, 0.188 mmol, 80%) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38][N:39]([CH3:48])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[N:39]([CH3:48])[CH3:38])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3N(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(dimethylamino)benzyl chloride (0.51 g) as starting materials, 5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)(C)(C)C.[ClH:21].CO>>[ClH:21].[NH2:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCc1ccccc1
Agent: Cl
Solvent: CO
Product: NCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of 3-tert-butoxycarbonylaminopropanoic acid (2 g, 10.6 mmol.) and HOSu (1.22 g, 10.6 mmol.) in 40 mL DCM/Dioxane (2:1) was cooled in an ice bath. To this solution was added DCC (2.4 g, 11.6 mmol.), and the mixture was stirred at room temperature for 1 h. To the resulting mixture was added benzylamine (1.7 g, 15.8 mmol.), the mixture was stirred for 4 h at room temperature. The solid that formed in the mixture was removed by filtration and washed with EtOAc. The filtrate and washings were combined and washed with 1N HCl and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford 3-tert-butoxycarbonylamino-N-benzylpropionamide (2.4 g, 82%). 3-tert-Butoxycarbonylamino-N-benzylpropionamide was dissolved in cooled HCl/MeOH (20 mL) and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed to afford 3-amino-N-benzylpropionamide hydrochloride (1.8 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:15][CH2:16][CH:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])[CH2:12][CH2:13]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: N#Cc1cc(F)ccc1OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3C#N)CC2)CC1

Procedure:
The title compound was prepared analogously to example 1 (1.3) starting from 5-Fluoro-2-(piperidin-4-yloxy)-benzonitrile; hydrochloride and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester with sodium triacetoxyborohydride in 1,2-dichloroetane. MS (m/e): 446.3 (M+H+)
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:13]([C:14]2[CH:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[N:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:47]3[CH2:49][CH2:48]3)[CH:43]=2)[C:38]1=[O:50])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:47]1([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:50])[N:37]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]4[CH:19]=[C:18]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[O:28])=[CH:23][N:22]=5)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=4)[C:8]=2[CH2:7][OH:6])[CH:46]=[CH:45]3)[CH2:48][CH2:49]1
Reactant: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one (56 mg, 0.078 mmol) was dissolved in 3 mL anhydrous THF. Added a 1.0 M solution of tetrabutylammonium fluoride (466 μL, 466 mmol) in THF and stirred at room temperature for 15 min. Partitioned the reaction mixture between 8 mL of water and 10 mL of CH2Cl2 and separated phases. Washed the organic phase with 8 mL of 1.0 M KHSO4 and 8 mL of saturated aqueous NaHCO3. Dried over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one as an off-white solid. (29 mg, 0.048 mmol). MS (ESI) 604 (M+H)+.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(CC)=[C:8]([N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:9]=1)(=O)C.[CH:22]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:32])[C:26]=2[CH:25]=[CH:24][N:23]=1.[CH2:33]([OH:35])[CH3:34]>>[C:33]([C:13]1[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:11][N:10]([CH2:8][CH3:9])[C:15](=[O:16])[C:14]=1[NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[CH:25]=[CH:24][N:23]=[CH:22]2)(=[O:35])[CH3:34]
Reactant: CCc1cc([N+](=O)[O-])c(C(C)=O)cc1-n1ncccc1=O
Reactant: Nc1cccc2cnccc12
Reactant: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3cnccc23)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.4 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of 5-isoquinolinamine was added. The resulting mixture was stirred at room temperature for three days. The final product was collected by filtration and purified by column chromatography (silica gel, ethyl acetate/hexane 7:3) to yield the title compound (20 mg, 12.4% yield).