Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: N#Cc1ccccc1CBr
Product: N#Cc1ccccc1COc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-benzonitrile using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(CO)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N#N
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(COC2CCCCO2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), to a mixture of 5-hydroxymethyl-2-furaldehyde (100 g, 0.79 mol) and pyridinium toluene-4-sulfonate (10 g, 0.04 mol) in CH2Cl2 (1 L) was added 3,4-dihydro-2H-pyran (150 mL, 1.62 mol) while keeping the internal temperature below 28° C. (water bath). The reaction mixture was stirred at rt for 5 h. Water (1 L) was added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:11][C:8]3[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by two-fold alkylation of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](N)[CH2:22][NH2:23]>C(=S)=S.O>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1[NH:23][CH2:22][CH2:21][N:16]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCCN
Reactant: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Solvent: S=C=S
Solvent: O
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1C1=NCCN1

Procedure:
2-(α,α,β,β-Tetrafluorophenethyl)benzonitrile, 2.06 g. (0.0074 mole), together with 1.2 g. (0.02 mole) of ethylenediamine and 3 drops of carbon disulfide, is heated in a sealed tube at 160°-165° C. for 18 hours. After cooling in an ice-bath, the tube is opened and the contents are poured into water. The orange gum that separates is washed with water by decantation and then dissolved in ethyl acetate. The ethyl acetate solution is extracted with 3N hydrochloric acid. The combined, ice-cold, acid extracts are rendered strongly alkaline with 40% aqueous sodium hydroxide and the oily base is extracted into ethyl acetate. The washed and dried ethyl acetate extract is concentrated under reduced pressure to a volume of about 25 ml. and 0.6 ml. of 8N ethanolic hydrogen chloride is added. Dilution with an equal volume of absolute ether precipitates the white crystalline hydrochloride salt of the product, m.p. 263°-266° C., sintering at 258° C. Recrystallization from acetone gives a purified sample, m.p. 266°-267° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.C([Li])CCC.CC(O)C.C(=O)=O.CN(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:39][C:32]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]2[C:6](=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7](=[O:8])[N:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Combined under Ar 108 (3.00 g, 13.2 mmol) and tetrahydrofuran. Cooled in an IPA/dry ice bath. Added dropwise n-butyllithium solution (2.5M in hexanes, 11.1 mL, 27.8 mmol). Stirred 0.5 h with cooling then warmed over 0.5 h to −15° C. Recooled using IPA/dry ice and added a tetrahydrofuran solution of N,N-dimethylbenzamide (2.38 g, 15.8 mmol). Warmed to room temperature and quenched with water. Removed solvent in vacuo; added sat. sodium bicarbonate and extracted with ethyl acetate (3×). Dried combined organic portions with sodium sulfate (anh.), filtered, removed solvent in vacuo. A solid resulted which was triturated with ether to give 109 as a white solid (3.11 g, 9.39 mmol, 71.2%).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CO.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: NC1CC1
Agent: N
Solvent: CCO
Solvent: CO
Product: OCC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 18 h

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL) and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution was refluxed under nitrogen for two hours. Additional cyclopropylamine (0.66 mL) was added and reflux continued for an additional 18 hours. The solution was cooled and methanol saturated with ammonia at 0° C. (5 mL) was added. After two days at ambient temperature, volatiles were removed in vacuo and the residue chromatographed on silica gel. (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 7% methanol-chloroform and solidified from ethyl acetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; 1H-NMR(DMSO-d6)δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH of cyclopentane), 0.80-0.50 (m, 4, 2 CH2 of cyclopropyl); mass spectrum (CI): 372(M+1).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([C:30]3[N:35]=[C:34]4[CH2:36][O:37]C(C5C=CC=CC=5)[O:39][C:33]4=[CH:32][CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>O.C(O)(=O)C>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([C:30]3[N:35]=[C:34]([CH2:36][OH:37])[C:33]([OH:39])=[CH:32][CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNCC(O)c2ccc3c(n2)COC(c2ccccc2)O3)c1)C1CCCC1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNCC(O)c2ccc(O)c(CO)n2)c1)C1CCCC1

Procedure:
A solution of 2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (61 mg) in water (5 ml) and glacial acetic acid (5 ml) was heated under reflux for 0.5 h. The reaction mixture was concentrated in vacuo to afford the title compound. LCMS RT=2.63 min 548(M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.C[CH2:24][N:25](CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([NH:25][CH3:24])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.20 g, 0.63 mmol), methylamine hydrochloride (0.13 g, 1.88 mmol) and Et3N (0.30 mL) 2.19 mmol) in EtOH (15 mL) is heated at 100° C. in a pressure vessel for 18 h. The solvent is removed under reduced pressure, and the residue is partitioned between EtOAc and water. Workup of the organic layer gives 4-(3-bromoanilino)-7-(methylamino)pyrido[2,3-d]pyrimidine (0.16 g, 77%). 1H NMR (DMSO) δ 9.53 (1H, s), 8.54 (1H, s), 8.41 (1H, d, J=8.1 Hz), 8.17 (1H, t, J=1.8 Hz), 7.83 (1H, dd, J=8.0, 1.9 Hz), 7.66 (1H, brs), 7.32 (1H, t, J=8.0 Hz), 7.24 (1H, dd, J=8.0, 1.8 Hz), 6.77 (1H, d, J=8.1 Hz), 2.92 (3H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:29][CH2:28][CH2:27][O:5]1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C2OCCO2)c(F)c1
Temperature: 25 °C

Procedure:
2-Fluoro-4-(hexadecylamino)benzaldehyde (1.7 g.) is dissolved in toluene (20 ml), and ethylene glycol (2.5 ml.) and p-toluenesulfonic acid (10 mg.) are added. The reaction mixture is heated under reflux for 16 hours while water is removed using a Dean-Stark trap. The reaction mixture is then cooled to room temperature, diluted with toluene (70 ml.), washed with aqueous sodium bicarbonate and then with water. The organic layer is separated dried over mangnesium sulfate, decolorized with charcoal and filtered through anhydrous magnesium silicate. Removal of the solvent in vacuo gives a light yellow solid which is recrystallized from hexane to yield 2-[2-fluoro-4-(hexadecylamino)phenyl]-1,3-dioxolane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]([F:23])([F:22])[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[CH3:19]>[Cu]I>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:4]1[CH:3]=[C:2]([C:18]([CH3:20])([CH3:19])[CH2:17][C:16](=[O:21])[C:15]([F:23])([F:22])[F:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: Brc1cccc(C2OCCCO2)c1
Agent: [Cu]I
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the Grignard reagent derived from 2-(3-bromophenyl)-[1,3]dioxane (52.6 mL of 0.25M in THF, 13.1 mmol) at 0° C. was added copper (I) iodide (25 g, 13.1 mmol). After 45 minutes, 1,1,1-trifluoro-4-methylpent-3-en-2-one (2 g, 13.1 mmol) was added and the reaction mixture slowly warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, and concentrated in vacuo. The residue was triturated with hexanes and filtered. The filtrate was concentrated in vacuo to give 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzonitrile (1.08 g, 6.50 mmol, 1 equiv), 1-isopropylpiperazine (1.0 g, 7.80 mmol, 1.2 equiv), and K2CO3 (2.69 g, 19.50 mmol, 3 equiv) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between excess water and EtOAc, and then the layers were separated. The aqueous layer was extracted with EtOAc 2×, and the combined organic layer was washed with brine 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 2-(4-isopropylpiperazin-1-yl)-5-nitrobenzonitrile (1.76 g, 99% yield) as a brown oil that was used without further purification.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](Cl)=[O:12].[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH:19]1([CH2:25][NH:26][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([F:7])[C:16]([F:17])=[C:15]([F:18])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: NCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To 10 ml of ethyl acetate were added 0.50 g of 3,4,5-trifluorobenzoyl chloride, 0.32 g of cyclohexylmethylamine and 0.50 g of triethylamine and the mixture obtained was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Crystals obtained were washed with a mixture of hexane and MTBE to obtain 0.70 g of N-cyclohexylmethyl-3,4,5-trifluorobenzamide. N-cyclohexylmethyl-3,4,5-trifluorobenzamide:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([C:21]#[N:22])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]([N:13]1[C:14]2=[N:15][C:16]([C:21]#[N:22])=[CH:17][CH:18]=[C:19]2[NH:20][C:29]1=[O:30])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1N)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C#N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To a stirred solution of (R)-3-(3-amino-6-cyano-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (600 mg, 1.93 mmol) in THF (20 ml) was added CDI (630 mg, 3.87 mmol) and DBU (0.12 ml, 0.77 mmol). The resulting solution was stirred at room temperature for 18 hours after which time the reaction appeared complete. Added silica gel and concentrated. The remaining solid was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-60% EtOAc/hexanes) to give 120 mg (19%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]COC)=[C:9]2[C:4]=1[C:5](=[O:25])[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:7][NH:8]2.O.[Na]>C(O)C>[F:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]2[C:4]=1[C:5](=[O:25])[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:7][NH:8]2
Reactant: COCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3c(O)ccc(F)c3c2=O)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
2N Hydrochloric acid (6.0 ml) was added to an ethanol solution (18 ml) of 5-fluoro-8-methoxymethoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (350 mg, 1.06 mmol). The mixture was stirred at 55° C. for 1 hour. The stirred mixture was cooled to room temperature, and 1N sodium hydrate (11.6 ml) was added thereto to obtain a pH of 3 to 4. The mixture in which pH was adjusted was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol=50:1→20:1). The purified product was concentrated under reduced pressure, and the residue was crystallized from ethanol, collected by filtration, washed with ethanol, and dried to thereby obtain 165 mg of powdery pale dark brown 5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(Br)c1
Yield: 43.9 %

Procedure:
3-Bromo-4-methylbenzoic acid (10 g), N-bromosuccinimide (8.7 g) and 2,2′-azobisisobutyronitrile (0.4 g) were suspended in carbon tetrachloride (50 ml) and then heated to reflux for 2 hours. The mixture was returned to room temperature and added a 15% aqueous solution of citric acid (20 ml), and stirred for some time. Resulting crystals were filtered and washed with the 15% aqueous solution of citric acid (20 ml), and then dried, to obtain 3-bromo-4-(bromomethyl)benzoic acid (6 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClC1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1)=[O:17]
Reactant: COc1cc(SC)ccc1C(=O)Cl
Reactant: Nc1cc(=O)[nH]cc1[N+](=O)[O-]
Solvent: Clc1ccccc1
Product: COc1cc(SC)ccc1C(=O)Nc1cc(=O)[nH]cc1[N+](=O)[O-]

Procedure:
A mixture of 0.45 g of 4-amino-5-nitro-1H-pyridin-2-one and 0.87 g of 2-methoxy-4-methylmercapto-benzoyl chloride was refluxed for 8 hours in 10 ml of chlorobenzene. The precipitated product was suction-filtered off, washed with methylene chloride and used in the next step as the crude product without further purification.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]3([CH:57]([F:59])[F:58])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]3([CH:57]([F:59])[F:58])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([OH:42])=[O:41])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2(C(F)F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6, and making variations as required to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 5-cyclopropyl-4-((1-(difluoromethyl)-cyclohexyl)methoxy)-2-fluorobenzoate, the title compound was obtained as a beige solid (0.16 g, 96%): MS (ES+) m/z 343.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)C(C)(C)CCC2=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCC2=O
Yield: 93.7 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 3,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Intermediate 172, 5.04 g, 15 mmol), triethyl amine (20 mL), copper(I)iodide (0.6 g, 3 mmol), trimethylsilyl acetylene (5.3 mL, 37.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (2.2 g, 3 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluent, the title compound (4 g, 93%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N+:16]=[N-:17].[Na]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:18]([N:15]=[N+:16]=[N-:17])[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxybenzaldehyde (992 mg) and methyl azidoacetate (2.91 g) were dissolved in dry methanol (2 mL), and a dry methanol solution (10 mL) of sodium (582 mg) was added dropwise to the solution at 0° C. over 2 hours under an argon atmosphere. After stirring the reaction mixture for 30 minutes as it is, it was concentrated under reduced pressure, and water was added to the residue to collect crystals deposited by filtration. The crystals were washed with water and dried to obtain the title compound.
Reaction SMILES: Cl.OC1CNC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH:25]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([OH:32])=[O:31])=[O:26]>ClCCl.O>[OH:26][CH2:25][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:37])([F:38])([F:39])[F:40])[CH:35]=1)[C:30]([OH:32])=[O:31]
Reactant: O=Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: OC1CNC1
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54 mg (0.49 mmol) of 3-hydroxyazetidine hydrochloride, 97 mg (0.46 mmol) of sodium triacetoxyborohydride and 0.13 ml (2.35 mmol) of acetic acid were added in succession to a solution of 90 mg (0.32 mmol) of the compound of Example 36A in 3.2 ml of dichloromethane, and the mixture was stirred at RT for 1 h. A little water was then added, and the mixture was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 18). Evaporation of the appropriate fractions and drying of the residue under high vacuum gave 60 mg (66% of theory) of the title compound as the product of the reaction.