Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4])=[CH2:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH:1]=[CH2:2]
Reactant: C=CC(O)c1cccc2ccccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C=CC(=O)c1cccc2ccccc12

Procedure:
Vinyl-1-naphthylcarbinol (184 mg) was oxidized with pyridinium chlorochromate (214 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 46.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-thienylmethoxy)benzyl]-3-pyrrolyl]propionate (620 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 7 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-thienylmethoxy)benzyl]-3-pyrrolyl]propionic acid (272 mg, yield: 47%). This was recrystallized from ethyl acetate-hexane. Melting point: 127–128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[CH2:26][NH:27][CH2:28][CH2:29][CH3:30].[N:31]#[C:32]Br>C(O)C>[NH2:31][C:32]1[N:27]([CH2:28][CH2:29][CH3:30])[CH2:26][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([S:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:4]=2)[N:1]=1
Reactant: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(S(=O)c3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(4-amino-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide (0.00090 mol) and cyanogen bromide (0.00094 mol) in ethanol (30 mL) was stirred overnight at room temperature, and then the solvent was evaporated. The residue was triturated under diisopropyl ether, and the solids were filtered off. The residue was converted into the free base with a NaOH solution. The mixture was extracted with CH2Cl2, but the product stayed in the aqueous layer so the mixture was desalted with NaCl to yield an oil. The solvent was decanted, and the remaining oil was triturated under CH3CN. The resulting solids were filtered off, washed with diisopropyl ether, and dried to yield the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=2[F:24])[CH:10]=1)[CH3:7])C.[F:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:7][N:6]([CH2:5][C:4]([OH:3])=[O:26])[C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=3[F:27])=[CH:19][C:18]=2[F:24])[CH:10]=1
Reactant: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1
Reactant: OB(O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2F)c1
Temperature: 150 °C

Procedure:
A mixture of {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester (600 mg, 1.51 mmol), 2,4,5-trifluorophenylboronic acid (400 mg, 2.27 mmol), Pd(dppf)Cl2 methylene chloride complex (37 mg, 0.045 mmol), potassium carbonate (520 mg, 3.8 mmol), DMF (12 mL) and water (3 mL) was degassed, flashed with nitrogen, heated at 150° C. for 60 minutes in microwave reactor. The mixture was acidified by conc. HCl and diluted with water. Solvent was then removed by decantation and the sticky residue was purified by preparative HPLC to afford {{methyl-[3-(3,2′,4′,5′-tetrafluoro-biphenyl-4-yloxymethyl)-benzoyl]-amino}-acetic acid, 171 mg (25%). LC-MS (ES) calculated for C23H17F4NO4, 447; found m/z 448 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.[CH3:7][N:8]([CH3:12])[C:9]([NH2:11])=[S:10]>>[CH3:7][N:8]([CH3:12])[C:9](=[NH:11])[S:10][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CN(C)CCO
Reactant: CN(C)C(N)=S
Product: CN(C)CCSC(=N)N(C)C
Yield: 128 %

Procedure:
A mixture of 2-dimethylaminoethanol (2.23 g), N,N1 -dimethylthiourea (2.6 g) and aqueous hybrobromic acid (48%, 20 ml) was boiled under reflux for 50 hours and evaporated to dryness. The residue was recrystallised from a mixture of methanol and ethanol to give the dihydrobromide of the title compound (5.6 g) m.p. 198°-199°.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:25]1[S:29][N:28]=[C:27]2[C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:32]=[CH:33][C:26]=12>>[N:25]1[S:29][N:28]=[C:27]2[C:30]([S:34]([NH:22][C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[C:13]([NH:12][CH:4]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:24])=[O:23])(=[O:35])=[O:36])=[CH:31][CH:32]=[CH:33][C:26]=12
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(Cl)c(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
This compound was prepared from 2-(2-amino-4,5-dichloro-benzoylamino)-3-phenyl-propionic acid methyl ester and benzo[1,2,5]thiadiazole-4-sulfonyl chloride as in EXAMPLE 2, Parts D and E. HPLC: RT=10.10 min. MS (ESI−): mass calcd. for C22H16Cl2N4O5S2, 551.4; m/z found, 550 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.11 (s, 1H), 8.33 (dd, J=7.1, 0.9, 1H), 8.20 (dd, J=8.8, 0.8, 1H), 7.83 (s, 1H), 7.70 (dd, J=8.8, 7.1, 1H), 7.28 (m, 3H), 7.20 (s, 1H), 7.13 (dd, J=7.4, 1.7, 2H), 6.42 (d, J=7.5, 1H), 5.00 (dd, J=13.3, 6.0, 1H), 3.32 (dd, J=14.1, 5.7, 1H), 3.23 (dd, J=14.1, 6.1, 1H).
Reaction SMILES: C(OCC(C1C=CC(Cl)=CC=1)=O)(=O)C.II.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Cl.[Cl:27][CH2:28][C:29](Cl)=[O:30].Cl>CN(C)C(=O)C.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:27][CH2:28][C:29](=[O:30])[CH2:21][C:20]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=1
Reactant: O=C(Cl)CCl
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)OCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
The organozinc species was generated as described by S. Huo (Organic Letters 2003, 5 (4), 423-5). In a flame-dried 25 mL 2-necked round-bottomed flask, under an inert atmosphere, iodine (65 mg, 0.26 mmol) was taken up in 6 mL anhydrous N,N-dimethylacetamide. Zinc dust (0.502 g, 7.67 mmol) was added, and the suspension stirred until the red color of the iodine disappeared. Then, 3,4-dichlorobenzyl chloride (0.71 mL, 1.0 g, 5.1 mmol) was added via syringe, and the mixture heated at 80° C. until the t.l.c. of a hydrolyzed aliquot (5% ethyl acetate in hexanes, visualized by cerium molybdate staining) showed that the starting material had been consumed. The reaction vessel was placed in a water bath to cool it, and Pd(PPh3)4 (0.118 g, 0.102 mmol) was added, followed by dropwise addition, via syringe, of chloroacetyl chloride (0.61 mL, 0.87 g, 7.7 mmol). The brown suspension was allowed to stir overnight at room temperature. To work up the reaction, 12 mL 1 M HCl was added, and the mixture extracted into ethyl acetate (4×12 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (1-30% ethyl acetate in hexanes), to give material of sufficient purity to be used in the next step (0.545 g, 45% yield): 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 2H) 4.13 (s, 2H) 7.06 (dd, J=8.2, 2.6 Hz, 1H) 7.33 (d, J=2.0 Hz, 1H) 7.42 (d, J=8.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH:19]([C:21]4[C:29]5[C:24](=[N:25][CH:26]=[C:27]([CH3:30])[CH:28]=5)[NH:23][CH:22]=4)O)=[C:13]([F:31])[CH:12]=3)=[N:8][C:4]=2[CH:3]=1.ClC1C=CC2NC(COC3C=C(F)C(C(OC)C4C5C(=NC=C(C)C=5)NC=4)=CC=3OC)=NC=2C=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:12]=[C:13]([F:31])[C:14]([CH2:19][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[C:27]([CH3:30])[CH:28]=5)[NH:23][CH:22]=4)=[CH:15][C:16]=3[O:17][CH3:18])=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(O)c2c[nH]c3ncc(C)cc23)c(F)cc1OCc1nc2cc(Cl)ccc2[nH]1
Agent: CC[SiH](CC)CC
Agent: COc1cc(C(OC)c2c[nH]c3ncc(C)cc23)c(F)cc1OCc1nc2cc(Cl)ccc2[nH]1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(C)cc23)c(F)cc1OCc1nc2cc(Cl)ccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
[4-(5-chloro-1H-benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-phenyl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (228a) and 5-chloro-2-{5-fluoro-2-methoxy-4-[methoxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenoxymethyl}-1H-benzoimidazole (228b) were dissolved in acetonitrile. Triethylsilane was added followed by trifluoroacetic acid. The reaction was stirred for one hour at 60° C. The solvent was removed under reduced pressure, Ethyl acetate was added and the organic layer was washed with sodium bicarbonate saturated solution and brine, then dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography, eluting with a gradient of methanol (2-25%) in dichloromethane, provided the desired compound P-2184. MS (ESI): [M+H+]+=451.0, [M−H+]−=449.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:26])([F:25])[C:22]([CH3:24])=[O:23].[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:22]([OH:23])([CH3:24])[C:21]([F:26])([F:25])[F:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(F)(F)F
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#CC(C)(O)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of prop-2-ynyl-carbamic acid tert-butyl ester (0.646 g, 4.16 mmol) in 15 mL of tetrahydrofuran at −78° C. was added lithium diisopropylamide (2.0 M solution in heptane/THF/EtPh, 4.6 mL, 9.2 mmol) all at once. The orange solution was stirred at −78° C. for 2 h, at which point it is a cloudy yellow mixture. 1,1,1-Trifluoroacetone (0.5 mL, 5 mmol) was added all at once, and the yellow mixture was stirred, allowing to slowly warm to RT, for 17.5 h. A sat. aq. NH4Cl solution (30 mL) was added, and the mixture was extracted with 30 mL of ether. The organic layer was sequentially washed with 30 mL of water and 30 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to an orange cloudy oil. Column chromatography (20->40% EtOAc/hexanes) afforded 0.687 g (62%) of slightly impure (5,5,5-trifluoro-4-hydroxy-4-methyl-pent-2-ynyl)-carbamic acid tert-butyl ester as a yellow oil that was used without further purification.
Reaction SMILES: [CH:1]1[C:2](Cl)=[CH:3][C:4]([N+:19]([O-])=O)=[C:5]([OH:18])[C:6]=1[C:7]1[CH:8]=[C:9](Cl)[CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=1[OH:13]>O1CCCC1.C(N(CC)CC)C.[Pd]>[OH:13][C:12]1[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=1[C:6]1[CH:1]=[CH:2][CH:3]=[C:4]([NH2:19])[C:5]=1[OH:18]
Reactant: O=[N+]([O-])c1cc(Cl)cc(-c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cccc(-c2cccc(N)c2O)c1O
Reaction time: 40 h

Procedure:
10 g of niclofolan (1) are dissolved in 100 ml of tetrahydrofuran (THF) and 17.6 g of triethylamine. After addition of 4 g of palladium on carbon 5% and a further 4 g after 40 hours, hydrogenation is carried out to saturation over a total period of about 88 hours. The solution is filtered through Hyflo and is immediately processed further without evaporation. Assumed yield of (2): 100%. Rf 0.11 (CH2Cl2/methanol/NH4OH 25% (60:10:1))
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12](N)=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N([O-])=[O:23].[Na+].O>C(O)(=O)C>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12]([OH:23])=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1ccc2oc3cc(C#N)c(N)nc3c(=O)c2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc2oc3cc(C#N)c(O)nc3c(=O)c2c1
Temperature: 70 °C

Procedure:
To a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid was added gradually 1.0 g of sodium nitrite at 70° C. After one hour period, 3 ml of water was added to the mixture which was heated at 70° C. for a further one hour. The solvent was distilled off under reduced pressure and then, to the residue, water was added. The yellow precipitate was collected by filtration, rinsed with water and recrystallized from ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals, m.p.>300° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:5]1[N:6]=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: COc1ccc(CNc2ccc(Cl)nn2)c(OC)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(CNc2cccnn2)c(OC)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-chloro-N-(2,4-dimethoxybenzyl)pyridazin-3-amine (7.5 g, 26.9 mmol) in ethanol (250 mL) was added ammonium formate (5.94 g, 94.15 mmol) and the mixture was degassed with nitrogen three times. Palladium on charcoal (10 wt %, 2.14 g) was added and the mixture was degassed and recharged with nitrogen and stirred at 80° C. for 90 minutes under a nitrogen atmosphere. The mixture was filtered, concentrated to 15 mL and partitioned between DCM (200 mL) and water (150 mL). The organic layer was washed with brine (150 mL) and concentrated in vacuo. The residue was recrystallised from EtOAc to afford the title compound as cream coloured solid (4.5 g, 68%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O>[CH3:20][N:19]1[C:15]([NH:14][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[N:16][N:17]=[N:18]1
Reactant: Cn1nnnc1N
Reactant: O=C(O)c1cccc2cccnc12
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1nnnc1NC(=O)c1cccc2cccnc12
Temperature: 70 °C

Procedure:
A mixture of 2.4 g. (0.020 mole) of 8-quinolinecarboxylic acid and 3.0 g. (0.030 mole) of 5-amino-1-methyltetrazole is stirred in 30 ml. of pyridine at 20° C. while adding 2.0 ml. of thionyl chloride dropwise. The mixture is heated at 70° C. for one hour. The reaction mixture is evaporated to provide a residue which is diluted with water. The solid is separated by filtration and recrystallized from acetic acid with decolorizing charcoal. The product is recrystallized a second time from acetic acid to provide 8-(1-methyl-1H-tetrazole-5-yl-carbamoyl)quinoline, m.p. 224°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccccc1Br
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccccc1Br
Reaction time: 0.75 h

Procedure:
To a solution of o-bromo-benzaldehyde (4 g, 21.6 mmol) and nitromethane (1.32 g, 21.6 mmol) in methanol (5 mL) was added NaOH (0.908 g, 22.7 nmol) in 1 mL of H2O. After 45 minutes, the precipitate was dissolved in 10 mL of H2O. The product precipitated out after the addition of 6N HCl. The product was recrystallized from ethanol; 0.312 g (6%).
Reaction SMILES: C(OC(=O)C)C.Cl.[CH2:8]([O:10][C:11](=[O:34])[C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=1)[CH3:9].[H][H]>C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@H:12]1[CH2:13][CH2:14][C@@H:15]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)[NH:26]1)=[O:34])[CH3:9]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 16 h

Procedure:
3,4,5-Trifluorophenyl magnesium bromide (0.35 M diethylether solution, 55 mL) was dropwise added to a tetrahydrofuran solution (100 mL) of (R)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS Register No. 128811-48-3, 4.1 g) over 20 min at −40° C. This reaction solution was stirred at −40° C. for 5 hr. To this solution, a saturated ammonium chloride aqueous solution and ethyl acetate were added. The reaction solution was heated to room temperature. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane ethyl acetate=1:0 to 1:1) to give 4.8 g of (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. A 4 N hydrochloric acid ethyl acetate solution (30 mL) was added to an ethyl acetate solution (30 mL) of the obtained (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. This solution was stirred for 16 hr. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To an ethyl acetate solution (50 mL) of the residue, 10% palladium-carbon (100 mg) was added. The resulting reaction solution was stirred under 1 atm of hydrogen atmosphere for 6 hr. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give 2.91 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][C:14](=[O:29])[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])[C:16]([CH3:18])=O>>[CH3:12][O:13][C:14]([C:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([CH3:11])[C:8]=2[NH:10][C:16]=1[CH3:18])=[O:29]
Reactant: CCCCc1cc(N)n(C)n1
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Product: CCCCc1nn(C)c2c1C(c1ccccc1[N+](=O)[O-])C(C(=O)OC)=C(C)N2

Procedure:
Starting from 3-butyl-1-methyl-5-pyrazolamine and methyl-2-(2-nitrobenzyliden)acetoacetate in equimolar proportions.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].N1C=CC=CC=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>ClCCl.O>[C:14]([C:13]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(O)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(O)CCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a mixture of 13.2 ml (0.15 mol) of (±)-1,3-butandiol 24 and 17.8 ml (0.23 mol) of pyridine in 200 ml of dry dichloromethane is added a solution of 22.2 ml (0.18 mol) of pivaloyl chloride in 50 ml of dry dichloromethane dropwise over 20 minutes under ice cooling. Then, the mixture is stirred for additional 30 minutes at room temperature. Ice-cooled water is added and the mixture is stirred for 5 minutes and then 1N hydrochloric acid is added thereto. The mixture is extracted with dichloromethane twice. The extract is washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (250 g of silica gel, ethyl acetate:n-hexane=1:9 to 1:4) to give 20.4 g of the desired monopivaloyl ester 25 as an oil in 78.2% yield.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16].N#N.B(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)=[O:16]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Agent: ClB(Cl)Cl
Agent: N#N
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Dissolve (2,6-Dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone in CH2Cl2 (10 volume equivalents) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stirbar, and N2 source. Cool the flask in an ice/brine bath and add 1.0 M BCl3 solution in CH2Cl2 (1.2 equivalents) dropwise. The reaction solution turns dark red and the temperature initially increases to 5° C. Within one hour, all starting material is consumed, as determined by TLC (1:1, Ether:Petroleum Ether). Quench the reaction with methanol (5 equivalents) and allow to warm to room temperature. Dilute the organic solution with CH2Cl2 (one volume equivalent) and add to a 1.0 M NaHCO3 solution (5 volume equivalents) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH2Cl2 (one volume) and the combine organic layers, wash with saturated NH4Cl and dry over Na2SO4. Purify the product via column chromatography (50/1 silica gel) eluting with CH2Cl2/Hexanes (3/1) to yield (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (typical yield 87%).