Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:3]1.[N+:19]1([O-])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.CS(NC1C=CC(CC(O)=O)=CC=1)(=O)=O.CC1(C)OC(=O)CC(=O)O1>C(OC(=O)C)(=O)C>[O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)/[C:3]/1=[C:20]1/[NH:19][C:28]2[C:23]([CH:22]=[CH:21]/1)=[CH:24][CH:25]=[CH:26][CH:27]=2
Reactant: [O-][n+]1cccc2ccccc21
Reactant: CS(=O)(=O)Nc1ccc(CC2=NNC(=O)C2)cc1
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)Nc1ccc(CC2=NNC(=O)/C2=C2/C=Cc3ccccc3N2)cc1

Procedure:
The tile compound was synthesized using N-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide and quinoline N-oxide in acetic anhydride according to the procedure described in Example 23. The N-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide was synthesized using 2-(4-(methylsulfonamido)phenyl)acetic acid and Meldrum's acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 3H) 4.08 (s, 1H) 4.43 (s, 1H) 7.10 (d, J=3.79 Hz, 2H) 7.24-7.37 (m, 2H) 7.46 (d, J=6.06 Hz, 1H) 7.67-7.77 (m, 2H) 7.82-7.94 (m, 2H) 8.17-8.29 (m, 1H) 9.60 (s, 1H) 11.40 (s, 1H); ESI-MS: m/z calc'd for C20H18N4O3S 394.45. found 395.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:29](OC1C=CC(C(OC)=O)=CC=1)[CH2:30]CCCCCCCCCC.[OH-].[K+].C(Cl)(=O)C(Cl)=O.OC1C=CC(C=O)=CC=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:29][CH3:30]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1

Procedure:
Synthesized as described above for compound 10. Quantities: 2 (9.58 g, 30 mmol), KOH (2.34, 42 mmol), oxalyl chloride (12 mL, 140 mmol), p-hydroxybenzaldehyde (4.38 g, 36 mmol), triethylamine (32 mL, 0.23 mol), DMAP (0.19 g, 1.6 mmol). Yield 11.6 g (97%). 1H NMR: δH (CDCl3; 300 MHz): 0.89 (3 H, t, 3J=6.9 Hz, CH3), 1.21-1.51 (18 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 4.05 (2 H, t, 3J=6.6 Hz, O—CH2), 6.99 (2 H, d, 3J=9.0 Hz, Ar—H), 7.40 (2 H, d, 3J=8.5 Hz, Ar—H), 7.97 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=9.0 Hz, Ar—H), 10.0 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.6, 29.7, 32.2, 68.8, 114.8, 121.2, 123.0, 131.6, 132.8, 134.3, 156.3, 164.3, 164.6, 191.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2].CO.[OH-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethylacetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol 40/1) to give the title compound (0.61 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(N(CC)CC)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2ccccc2c1
Yield: 100.5 %

Procedure:
Propionic acid chloride (17 g, 184 mmol) was added at ambient temperature to a solution of 25 g (174 mmol) 3-aminoquinoline and 26 ml triethyl amine in 400 ml dichloromethane. After stirring for 2 hours in 200 ml 10% sodium carbonate was added and the mixture was shaken and separated. The aqueous phase was extracted 3 times with dichloromethane and 3 times with ethyl acetate. The combined organic phases where dried (magnesium sulfate), filtered and evaporated to yield 35.0 g (100%) of the desired product.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=O)[CH:9]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1([CH3:21])[CH3:20])[CH3:10])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[CH3:1][C:2]1([CH3:6])[C:3](=[O:4])[O:5][C:8]([CH:9]([O:11][N:12]2[C:13]([CH3:20])([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]2([CH3:18])[CH3:19])[CH3:10])=[N:7]1
Reactant: CC(ON1C(C)(C)CCCC1(C)C)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(ON1C(C)(C)CCCC1(C)C)C1=NC(C)(C)C(=O)O1
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a stirred mixture of 2-methyl-2-[2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-propionylamino]-propionic acid (0.50 g; 0.0016 mol), triethylamine (0.16 g; 0.0016 mol) and acetone (5 ml) there was added ethyl chloroformate (0.17 g; 0.0016 mol). After 2 hours, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was mixed with hexane (5 ml) and the solution was decanted from the precipitated solid. The decanted solution was concentrated under vacuum to give 0.30 g (64% yield) of 4,4-dimethyl-2-[1-(2,2,6,6-tetramethylpiperidin-1-yloxy)-ethyl]-4H-oxazol-5-one (AzTEMPO) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:16]=[C:15]([Cl:17])C=C[C:9]=1[C:10](O)=O.CN(C)C=O>C(Cl)Cl>[Cl:17][C:15]1[N:16]=[C:8]([Cl:7])[CH:9]=[CH:10][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (2M solution, 20 mL) (Aldrich, Milwaukee, Wis.) was added to a mixture of 2,6-dichloronicotinic acid (6.2 g) and N,N-dimethylformamide (DMF) (0.5 mL) in DCM (100 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction was concentrated to give 2,6-dichloro-nicotinoyl chloride (used directly in the next step).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:23]4[CH2:25][CH2:24]4)[CH2:28][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: C1CN(CC2CC2)CCN1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CC2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 83%. White crystals, m.p. 254–255° C.; IR (KBr): ν 1728 (C═O) cm−1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:26][CH2:25][N:24]3[C:17](=[CH:18][C:19]4[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]=43)[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1B(O)O)(=[O:3])[CH3:2].Br[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:26][CH2:25][N:24]3[C:17](=[CH:18][C:19]4[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]=43)[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccn(C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (595 mg, 1.5 mmol), 290a (282 mg, 1.0 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (164 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (82 mg, 0.1 mmol), and acetonitrile/water (15/1 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (30 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 50/1) to 290b (300 mg, 54%) as yellow solid. MS-ESI: [M+H]+ 556.1
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9](=[O:18])[NH:10][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:19][C:20]1[C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=2)[NH:22][N:21]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([C:29]([N:15]3[CH2:16][CH2:17][C:11]4([NH:10][C:9](=[O:18])[C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][C:7]=5[CH2:12]4)[CH2:13][CH2:14]3)=[O:30])[CH:27]=2)[NH:22][N:21]=1
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Reactant: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(C)cc(C(=O)N3CCC4(CC3)Cc3cnn(C(C)C)c3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7 (1′H)-one hydrochloride salt (Intermediate 2, 430 mg, 1.3 mmol) and 3,7-dimethyl-1H-indazole-5-carboxylic acid (306 mg, 1.6 mmol) in dimethylformamide (2 mL) was added triethylamine (0.75 mL, 5.4 mmol), 4-dimethylaminopyridine (33 mg, 0.37 mmol), and 1-propanephosphonic acid cyclic anhydride (0.52 mL, 1.74 mmol, 50% solution in ethyl acetate), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to a solid. The solid was purified via flash column chromatography (0-15% methanol/dichloromethane) to afford a glassy solid. The glassy solid was stirred in ethyl acetate for 16 hours and the resulting solid collected by vacuum filtration to afford the desired product as a white solid (138 mg). +ESI (M+H) 421.0; 1H NMR (400 MHz, CD3OD, δ): 7.65 (s, 1H) 7.42 (s, 1H) 7.21 (s, 1H) 5.50 (m, 1H) 3.95 (br. s., 1H) 3.50-3.62 (br. s., 3H) 2.97 (s, 2H) 2.56 (m, 6H) 1.83 (br. s., 4H) 1.44 (d, 6H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)[C:6](N)=[N:5]1)([CH3:3])[CH3:2].C(ON=O)CC(C)C.C(I)[I:27]>>[I:27][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)=[CH:8][N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: CSc1nccc(-c2cn(C(C)C)nc2N)n1
Reactant: ICI
Agent: CC(C)CCON=O
Product: CSc1nccc(-c2cn(C(C)C)nc2I)n1
Temperature: 100 °C

Procedure:
A mixture of Intermediate 1-isopropyl-4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine (4.0 g, 16.0 mmol), isopentylnitrite (13.2 g, 112 mmol), and methylene iodide (30 mL) was heated at 100° C. for 3 h. Removal of the volatiles under vacuum provided a dark residue, which was purified by silica gel chromatography (2:1 hexane/ethyl acetate eluant) to afford the title compound as a solid; MS m/z: 361.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:1][CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)=[CH:3][C:4]([C:14]3[N:15]=[CH:16][S:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(O)cc(-c3cscn3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1

Procedure:
The title compound was prepared from 4-hydroxy-7-methoxy-2-(thiazol-4-yl)quinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=591 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([OH:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccccc2COc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2COc2cc(F)ccc21
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 2.0 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-one in 20 ml of methanol is added 0.5 g of sodium borohydride with ice-cooling and then the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into water and the resultant is extracted with toluene. The extract is washed with water and then dried over magnesium sulfate. Toluene is distilled off to give 1.9 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ol (crystals). Mass spectrum m/z: 230(M+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH2:26][OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl.O>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1[CH:26]=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOc1cc(I)ccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCOc1cc(I)ccc1C=O
Reaction time: 0.25 h

Procedure:
A solution of dimethyl sulfoxide (DMSO) (41.4 mmol, 3 ml) in dichloromethane (10 ml) is added to a solution of 1.8 ml of oxalyl chloride (20.7 mmol) in 55 ml of dichloromethane, dropwise, at −78° C. After stirring for 15 minutes, a solution of (2-heptyloxy-4-iodophenyl)methanol obtained in Step b (6.55 g, 18.8 mmol) in 25 ml of dichloromethane is added dropwise. After stirring for 20 minutes, 14 ml of triethylamine are added. After stirring for 2 hours, the reaction medium is hydrolysed by addition of water. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. After evaporation of the solvents, 6.49 g (100%) of the expected compound are recovered in the form of a yellow solid.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([N:11]1[C:16](=[O:17])[C:15]([NH:18]C(OC(C)(C)C)=O)=[CH:14][N:13]=[C:12]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:9]=[CH2:10]>CO>[CH2:8]([N:11]1[C:16](=[O:17])[C:15]([NH2:18])=[CH:14][N:13]=[C:12]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:9]=[CH2:10]
Reactant: C=CCn1c(-c2ccccc2)ncc(NC(=O)OC(C)(C)C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C=CCn1c(-c2ccccc2)ncc(N)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride/dioxane (31 ml, 122.2 mmol) was added to a solution of 1-allyl-5-t-butyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine (2 g, 6.11 mmol) in methanol (12 ml) under cooling on ice and stirred at 0° C. for 30 minutes and at room temperature overnight. The reaction solution was concentrated under reduced pressure whereby the title compound (1.49 g, 93%) was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Reaction time: 0.08 h

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridine (200 mg) was dissolved in N,N-dimethylformamide (5 ml). 55% Sodium hydride (53 mg) was added at 0° C., and the mixture was stirred at the same temperature for five minutes and then stirred at room temperature for 20 minutes. 2-(Chloromethoxy)ethyltrimethylsilane (0.213 ml) was added and the mixture was stirred at 0° C. for 2 hours. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (0.224 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:19])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.SC[CH2:22][OH:23].C1CCN2C(=NCCC2)CC1.ClCCl.CCCCCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:19][CH2:22][OH:23])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCS
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1ccc(F)cc1)c1cnc(SCCO)nc1
Yield: 47 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (39 mg, 0.14 mmol) in THF (1 mL) was added β-mercaptoethanol (20 μL, 0.28 mmol) followed by DBU (43 μL, 0.28 mmol). After 15 min the reaction was quenched with 40 mL 1% HCl, resulting in the formation of solids. The solids were collected by filtration and washed with water. The filtrate was extracted with dichloromethane to afford a white solid after concentration. These were combined with the solids isolated from the filtration and passed through a plug of SiO2 using 60% ethyl acetate/hexane to afford a white solid. After trituration with dichloromethane/hexane, 19.3 mg (47% yield) of titled product was obtained. API-MS m/z 294 (MH+), 292 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1>CO.[Pd]>[CH3:33][O:32][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20]2)[CH:30]=[CH:31][C:9]=1[OH:8]
Reactant: COc1cc(CCN2CCN(CCCc3ccccc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCN2CCN(CCCc3ccccc3)CC2)ccc1O

Procedure:
1-(4-(Benzyloxy)-3-methoxyphenethyl)-4-(3-phenylpropyl)piperazine is hydrogenated in 10 mL methanol with 10% Pd/C. The resultant product is then purified by column chromatography, eluting with dichloromethane-methanol (9:1) to afford 95 mg of 1-[2-(3-methoxy-4-hydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([NH2:38])=[CH:14][C:15]2[O:35][C:19]3([CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)[CH2:18][C:17](=[O:36])[C:16]=2[CH:37]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:50].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[ClH:50].[ClH:50].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][C:19]3([O:35][C:15]4=[CH:14][C:13]5[N:38]=[CH:1][NH:11][C:12]=5[CH:37]=[C:16]4[C:17](=[O:36])[CH2:18]3)[CH2:20][CH2:21]2)=[CH:28][CH:29]=1)#[N:34]
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(N)c(N)cc2O3)cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc4[nH]cnc4cc2O3)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Triethyl orthoformate (75 ml, 67 mg, 0.45 mmol) was added to a stirred suspension of 6,7-diamino-3,4-dihydro-1'-[2-(4-cyanophenyl)ethyl]spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (56 mg, 0.15 mmol) and p-toluensulfonic acid (monohydrate, 10 mg) in ethyl acetate (5 ml). The mixture was heated under reflux for 1 hour, further triethyl orthoformate (75 ml) was added and the mixture was heated under reflux for 1.5 hour. The mixture was cooled and aqueous HCl (1N, 5 ml) was added. The mixture was stirred for 15 minutes, poured into aqueous sodium hydrogen carbonate (saturated, 25 ml) and extracted with dichloromethane (3×25 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (95:5:0.5) to give a yellow solid which was suspended in ethanol (1 ml) and treated with ethanolic HCl (6M, 0.2 ml). The mixture was stirred for 1 hour, cooled and the precipitate was collected and dried in vacuo to give the title compound as a tan solid (40 mg, 55%), m.p >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1N
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (150 mL) at 0° C. was treated sequentially with o-anisidine (6 mL), triethylamine (6.7 mL) and N,N-dimethylaminopyridine (440 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14 g).