Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH:14]([OH:32])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:33])[C:4]1=[O:34].[OH:35]O>O.C(Cl)Cl.CO.[NH4+].[OH-]>[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH:14]([OH:32])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:35])[CH2:18][CH2:17]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:33])[C:4]1=[O:34]
Reactant: OO
Reactant: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCS(=O)c3ccccc3)CC2)n(C)c1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
0.1 Moles of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylthio-propyl)piperazine hydrochloride was dissolved in 200 ml demineralized water and maintained at 20° C. 120 ml hydrogen peroxide in 250 ml water was added dropwise. The mixture was stirred for four hours at room temperature. Completion of the reaction was checked by TLC using a mixture of 80/20/1 CH2Cl2 /methanol/NH4OH as eluent. When the reaction was completed, the reactive mixture was alkalinized, extracted with methylene chloride, washed with water, dried, and the solvent evaporated under vacuum to give the free base form of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylsulfinylpropyl)piperazine. The dihydrochloride salt was prepared in the manner indicated in Example III, m.p. 260°-265° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][CH:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:19]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(N=C=O)c1ccccc1
Product: CC(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)c1ccccc1
Yield: 97.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) α-methylbenzyl isocyanate, 24.0 mg (97%) of the title compound were recovered.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: NCc1cncc(Br)c1
Reaction time: 8 h

Procedure:
To a solution of 3-azidomethyl-5-bromo-pyridine 250 (1.49 g, 7.00 mmol, 1.00 equiv) in 1,4-dioxane (12 mL) was added water (1 mL) and triphenylphosphine resin (2.08 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-(5-bromo-pyridin-3-yl)-methylamine 251.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Cl[C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1.Br[C:29]1[CH:30]=C2C(=C[CH:37]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH2:37]([N:1]1[CH:5]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH:3]=[N:2]1)[CH2:29][CH3:30]
Reactant: OB(O)c1cc[nH]n1
Reactant: O=C(Nc1ccc(Cl)nc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Product: CCCn1cc(-c2ccc(NC(=O)N3Cc4ccccc4C3)cn2)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and N-(6-chloropyridin-3-yl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.90-8.92 (bs, 1H), 8.84 (d, J=2.5 Hz, 1H), 8.39 (s, 1H), 8.25 (dd, J=8.8, 2.5 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.31-7.41 (m, 4H), 4.79-4.83 (bs, 4H), 4.13 (t, J=6.9 Hz, 2H), 1.77-1.89 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI(+)) m/e 348 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:44]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]=[O:44])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C=O)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate (0.63 g, 1.06 mmol) was dissolved in dioxane (10 mL), SeO2 (0.6 g, 5.4 mmol) and water (0.096 mL) were added and the reaction mixture heated at 100° C. for 3.5 hours. The reaction mixture was concentrated in vacuum and the mixture loaded on to a column of silica gel and eluted with MeOH, dichloromethane as eluent, to give the desired compound (0.52 g). 1HNMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.53 (s, 1H), 8.56 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.26 (m, 4H), 2.35 (m, 4H)), 1.39 (s, 9H), 1.36 (t, J=6.8 Hz, 3H); MS m/z 636.5 (M+1).
Reaction SMILES: B.CSC.O=[C:6]1[NH:24][CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:8][CH2:7]1>C1COCC1>[CH2:10]1[C:9]2([CH2:22][CH2:23][NH:24][CH2:6][CH2:7][O:8]2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC(=O)CO2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC2(CCNCCO2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Borane-methyl sulfide complex (2M in THF, 2.88 mL) was added to a solution of tert-butyl 9-oxo-7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step d) (0.41 g) in dry THF (40 mL) and the reaction mixture then heated at 70° C. for 30 minutes under nitrogen. The mixture was cooled to room temperature and quenched with methanol. The solvents were removed under reduced pressure and the residue dissolved in methanol (100 mL). N1,N2-dimethylethane-1,2-diamine (1.0 g) was added and the mixture heated at reflux under nitrogen for 16 h. Further N1,N2-dimethylethane-1,2-diamine (1.0 g) was added and refluxing continued for 16 h. The solvents were evaporated under reduced pressure and the residue azeotroped with toluene. The crude product was purified by flash silica chromatography using 6% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.176 g.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2].[Se](=O)=O.O.[C:20](=[O:23])(O)[O-].[Na+].C[N:26](C)C=O>>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:26][O:23][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)=[O:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1nccc(NC=O)n1
Reactant: O=C([O-])O
Agent: O=[Se]=O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=NOC)c1nccc(NC=O)n1
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(4-formamidopyrimidine-2-yl)acetate (50.0 g) and selenium dioxide (31.87 g) in N,N-dimethylformamide (240 ml) was stirred for an hour at 70° to 75° C. and cooled to ambient temperature. The precipitated solid was filtered off and the filtrate was evaporated in vacuo to give an oily product. The oil was added to water (750 ml) under stirring, adjusting to pH7 with an aqueous solution of sodium bicarbonate. The precipitated yellow substance was filtered off and washed with water. The filtrate and washings were combined and thereto was added methoxyamine hydrochloride (19.95 g). The mixture was adjusted to pH4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at ambient temperature. The aqueous reaction mixture was extracted with ethyl acetate and the extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (31 g) as a brownish oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:20][CH:21]=3)[C:8]=2[CH:9]=1)=O.[Br:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.ClCCl.C([O-])(O)=O.[Na+]>CC(O)C>[Br:28][C:29]1[S:33][C:32]2=[N:34][C:3]([C:5]3[O:6][C:7]4[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]5[N:18]=[C:19]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[S:20][CH:21]=5)[C:8]=4[CH:9]=3)=[CH:2][N:31]2[N:30]=1
Reactant: O=C(CBr)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 150 °C
Yield: 43.8 %

Procedure:
In a 2-5 mL microwave pressure vial was added 2-bromo-1-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone (Example 36E, 35 mgs, 0.078 mmol) in propan-2-ol (2 mL) followed by 5-bromo-1,3,4-thiadiazol-2-amine (16.2 mgs, 0.09 mmol). The reaction was heated to 80° C. overnight and to 150° C. for 1 h in microwave oven. The reaction mixture was then poured into a mixture of dichloromethane (8 mL) and saturated NaHCO3 (2 mL) and this was extracted twice with dichloromethane. The organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (ISCO 12 g gold column using 100% dichloromethane, then 1% ethyl acetate and then 2% ethyl acetate in dichloromethane) to give the title material (18 mgs, 43%) as a yellowish solid. LC (Method B): 2.754 min. LCMS (APCI) calcd for C22H13BrFN4O2S2 [M+H]+ m/z 526.96. found 527.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[N:2]1.[Cl:11][C:12]1[C:17]([C:18](O)=[O:19])=[C:16]([F:21])[C:15]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:11][C:12]1[C:17]([C:18]([NH:10][C:8]2[CH:9]=[C:4]3[CH:3]=[N:2][NH:1][C:5]3=[N:6][CH:7]=2)=[O:19])=[C:16]([F:21])[C:15]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:14][CH:13]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
1H-Pyrazolo[3,4-b]pyridin-5-amine (1.55 g, 11.6 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (3.59 g, 12.1 mmol), EDCI (2.44 g, 12.7 mmol), and HOBt (0.25 g, 0.16 mmol) were dissolved in DMF (30 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was diluted with ethyl acetate (500 mL), and the organic layers were washed with water (3×50 mL). The organic layers were dried, filtered and concentrated. The crude solids were washed with DCM (3×50 mL) to give 6-chloro-2-fluoro-3-(propylsulfonamido)-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (2.7 g, 58%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=410.2, 412.2.
Reaction SMILES: [Br:1][C:2]1[C:11](O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:17][CH2:16]1.C(N(CC)CC)C.[OH2:33]>CC(N(C)C)=O>[CH2:19]([O:18][CH2:14][C@H:15]([OH:17])[CH2:16][O:33][C:5]1[C:6]([CH3:13])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: Cc1ccc2c(Br)c(O)ccc2n1
Reactant: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1nc2cccc(Br)c2cc1OC[C@@H](O)COCc1ccccc1
Yield: 73 %

Procedure:
A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200 mL) was heated in a 95-98° C. oil bath for 2 days. The solution was cooled and poured into water (300 mL) while stirring. The tan precipitate formed was filtered, washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the title compound as a tan solid. Rf=0.35 (ethyl acetate); 1H NMR (DMSO) δ 8.31 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.25-7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m, 2H), 4.08-4.15 (m, 1H), 3.61-3.73 (m, 2H), 2.66 (s, 3H); Specific rotation=+6.2° (c=1, CH3OH);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]3[CH:32]=[CH:33][C:18]([F:17])=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: Fc1ccc(COc2ccc(CS)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccc(F)cc3)cc2)CC1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
5.84 g (23.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester were added to a solution of 6.0 g (24.2 mmol) 4-(4-fluoro-benzyloxy)-phenyl-methanethiol in 14.6 ml pyridine. The solution was heated to 100° C. for 3.5 h, then cooled to rt, 10 ml of water added and the volume reduced to a third. The resulting precipitate is collected, washed with water and dried. The crude product is re-crystallized from hexane/AcOEt. Flash chromatography on silica gel provided 4.90 g 4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl ester as colourless powder, mp: 123–124° C. 1H-NMR (CDCl3): 1.46 s, 9H; 3.38–3.60 m, 8H; 4.13 s, 2H; 5.00 s, 2H; 6.89 d, 2H, 7.06 t, 2H, 7.28 d, 2H and 7.40 dd, 2H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-hydroxypiperidine (0.65 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) to give 3-(4-Hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.34 g, 23%). 1H NMR (CDCl3, 400 MHz) δ 3.92 (t, J=7.8 Hz, 2 H); 3.87-3.72 (m, 3 H); 3.07 (m, 1 H); 2.68-2.63 (m, 2 H); 2.09-2.03 (m, 2 H); 1.96-1.91 (m, 2 H); 1.69-1.55 (m, 2 H); 1.43 (s, 9 H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4].[CH3:27]S(C)=O.CI>O>[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH3:27])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CS(C)=O
Reactant: CN1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1c(C(C)(C)C)cc(C=C2CCON(C)C2=O)cc1C(C)(C)C
Reaction time: 50 h
Yield: 71 %

Procedure:
Sodium hydride (0.33 g, 8.3 mmol), 60% in mineral oil dispersion, kept under nitrogen purge, was washed twice with 20 ml portions of hexane. Dimethyl sulfoxide (10 ml) was added, followed by the addition of 2.5 g (7.6 mmol) of dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one. Gas evolution was observed and the mixture became yellow following which an additional 5 ml of dimethyl sulfoxide was added. One hour later, 1.1 g (7.7 mmol) of methyl iodide was added and the mixture was stirred for 50 hours. The reaction mixture was diluted with 75 ml of water and precipitation occurred in the form of crystals which were collected and air dried to yield 3.3 g of crude product. Recrystallization from acetone-hexane afforded 1.85 g (5.4 mmol, 71%) of dihydro-4-(3,5-di-tert-butyl-4-methoxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one having a melting point of 119°-121° C.
Reaction SMILES: Br.Br.[CH3:3][C:4]([NH2:9])([CH3:8])[CH2:5][CH2:6][NH2:7].C[O-].[Na+].[Br:13][C:14]#[N:15]>CO.O>[BrH:13].[CH3:3][C:4]1([CH3:8])[CH2:5][CH2:6][NH:7][C:14]([NH2:15])=[N:9]1
Reactant: CC(C)(N)CCN
Reactant: N#CBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCNC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 195.8 %

Procedure:
1.95 g of 3-methylbutane-1,3-diamine dihydrobromide are suspended in 20 mL of MeOH, 1.2 g of sodium methanolate are added. The mixture is stirred at RT for 2 h. The mixture is filtered and then dry evaporated. The reaction crude is solubilized in 20 mL of water, cooled with an ice bath. 0.78 g of BrCN are added and stirred at RT for 12 h. The mixture is dry evaporated, 3 g (quantitative yield) of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide are obtained as a translucent oil which will be used as such for the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(F)ccc4F)cc3)c2cc1OC
Yield: 87 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,5-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 132 mg of the title compound (yield: 87%).
Reaction SMILES: [Br:1][C:2]1C=C[S:4][C:3]=1C(O)=O.Cl.C(N=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C)C.O.[OH:23]N1C2C=CC=CC=2N=N1.N>CN(C=O)C.O>[Br:1][C:2]1[CH:16]=[C:17]([C:18]([NH2:19])=[O:23])[S:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1sccc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cs1

Procedure:
In the same way as described for Compound 179, step 2, using 4 bromo-thiophene-2-carboxylic acid (2.0 g, 9.66 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.04 g, 10.63 mmol), 1-hydroxybenzotriazole hydrate (1.44 g, 10.63 mmol) and aq. NH3 (1 ml, 17.3 mmol) in DMF (20 ml). Water is added to the reaction mixture and the resultant precipitate is collected by filtration and washed with 1M NaOH, H2O and petrol. The title compound is isolated as a white solid (1.56 g, 78%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(F)cc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-4-fluoro-benzoic acid (44.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 26 mg (21.0% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-4-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.27%, 1H NMR: (CDCl3) δ 7.94 (d, 2H), 7.74-7.6 (q, 4H), 7.54-7.46 (t, 2H), 7.44-7.38 (t, 1H), 7.38-7.3 (m, 2H), 7.24-7.2 (m, 1H), 7.16-7.06 (tt, 1H), 4.4-4.26 (td, 2H), 4.1-3.84 (m, 2H), 3.78-3.6 (m, 3H), 3.54-3.24 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C.C1COCC1>C(Cl)(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)=[O:28]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)CCCCCBr)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
A 25-mL RB-flask, charged with tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.00 mmol, 0.553 g), 6-bromohexanoyl chloride (0.427 g, 2.00 mmol, 1.0 eq.), triethylamine (0.404 g, 4.00 mmol) and THF (8.00 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with chloroform (50 mL) and washed with water (100 mL), brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, hexanes/EtOAc 10:1) to yield the desired product (0.921 g, 95.8%). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.28-7.22 (m, 2H), 7.11 (s, 1H), 6.5 (d, 1H, J=7.0 Hz), 3.45-3.39 (m, 2H), 2.85-2.70 (m, 2H), 2.68-2.58 (m, 1H), 2.37 (t, 2H, J=7.4 Hz), 1.96-1.71 (m, 7H), 1.68-1.50 (m, 5H), 1.48 (s, 9H); ESMS m/e: 355.4, 476.6.