Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25].O>CN(C=O)C>[Br:7][C:8]1[C:18]([O:19][CH2:22][C:23]([CH2:24][CH3:25])=[O:26])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(=O)CC)c1Br
Temperature: 80 °C

Procedure:
0.853 g (6.20 mmol) of K2CO3, 0.154 g (0.90 mmol) of KI and 1.000 g (3.10 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were initially charged in 10 ml of DMF. At RT, 0.621 g (3.70 mmol) of 1-bromo-2-butanone was added, and the mixture was then heated at 80° C. for 4 h. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness. Drying under oil pump vacuum gave ethyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[CH:15]=3)=[CH:12][NH:11][N:10]=2)[C:5]([F:8])=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[F:22][C:3]1[C:4]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[CH:15]=3)=[CH:12][NH:11][N:10]=2)=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:31]([C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[F:23])(=[O:33])=[O:32]
Reactant: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N)c2F)ccn1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[3-(3-amino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine (144 mg, 0.48 mmol) in anhydrous pyridine (0.2 M), 2,5-difluoro-benzenesulfonyl chloride (64 μL, 0.48 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and filtered. The product was isolated by silica gel column chromatography eluting with methanol 5% in methylene chloride (58%).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.Cl.[CH3:19][NH:20][O:21][CH3:22].C([Mg]Cl)(C)C>O1CCCC1>[CH3:22][O:21][N:20]([CH3:19])[C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)([CH3:8])[CH3:9]
Reactant: CNOC
Reactant: CCOC(=O)CCC(C)(C)c1ccc(F)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CCC(C)(C)c1ccc(F)cc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(4-fluoro-phenyl)-4-methyl-pentanoic acid ethyl ester (3.97 g) and N,O-dimethylhydroxylamine hydrochloride (2.44 g) in tetrahydrofuran (40 ml) at −18° C. was added dropwise a solution of isopropylmagnesium chloride (25.0 ml, 2 M solution in THF). The mixture was stirred for 30 min at −15° C. and then quenched by addition of saturated ammonium chloride solution. The mixture was then acidified to pH 1 by addition of 1 M aq. hydrochloric acid and taken up in ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a colourless oil, (3.91 g, 93%); MS (ISP): 254.2 ([M+H]+).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:5]1
Reactant: COc1ccc2c(c1OC)CC(C1CCCCC1)C=C2CN
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1OC)C[C@@H](C1CCCCC1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
1-Aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-dimethoxy-naphthalene hydrochloride (1 g, 3.3 mmol), from Step 2 of Example 6, was dissolved in 20 mL of ethanol and 0.25 g of 10% palladium on carbon was added to the ethanol solution. The reaction mixture was sealed under a blanket of one atmosphere of hydrogen gas and shaken at ambient temperature for 24 h. The reaction mixture was filtered to remove the catalyst and concentrated to give 1 g (100% yield) of the title compound, m.p. 282°-283° C. 1H NMR (d6 -DMSO) delta 1.0-1.5 (m, 8H), 1.5-1.9 (m, 5H), 2.0-2.2 (m, 2H), 2.7-3.1 (m, 3H), 3.3-3.4 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4-6.8 (m, 2H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14]C(=O)OC(C)(C)C)[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O>[C:2]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccccc2)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccc2)ccn1
Temperature: 60 °C

Procedure:
A stream of HCl gas was bubbled into a suspension of tert-butyl 4-phenylpyridin-2-ylcarbamate (1–2, 0.93 g, 3.4 mmol, 1 equiv) in EtOAc (50 mL) at 0° C. for 2 min. The acidified solution was then heated at 60° C. for 3 h. The reaction mixture was cooled then concentrated to give 4-phenylpyridin-2-amine (1-3) as an off-white solid. LRMS m/z (M+H) Calcd: 171.2, found 170.9.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([NH:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16]>ClCCl.C(O)(C(F)(F)F)=O>[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:4]=3)[N:9]=[N:8][CH:7]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cnnc3ccc(C(F)(F)F)cc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1cnnc2ccc(C(F)(F)F)cc12)NC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(6-(trifluoromethyl)cinnolin-4-ylamino)acetamido)azetidine-1-carboxylate (140 mg, 0.33 mmol,) in dichloromethane (10 ml) and CF3COOH (1 ml). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to give the title compound as yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(CC(C)C(=O)N(C)C)c2ccc(C(=O)NCC3CCCC3)cc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1Cn1cc(CC(C)C(=O)N(C)C)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 69 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N,N-dimethylcarbamoyl)propyl]indol-1-ylmethyl]-3-methoxybenzoate (0.53 g) in dioxane (3 ml) was treated with triethylamine (0.31 ml) and trimethylsilyl trifluoromethanesulfonate (0.38 ml). The solution was heated under nitrogen at reflux for thirty minutes, allowed to cool, and then diluted with water to give a precipitate which was collected by filtration and dried under vacuum to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N,N-dimethylcarbamoyl)propyl]indol-1-ylmethyl]-3-methoxybenzoic acid (0.33 g, 66%) as a yellow powder; mp 120°-122°; partial NMR (250 MHz, DMSO-d6): 1.04(d, 3H, CHCH3), 2.07-2.24(m, 1H, CH3CH), 2.71(s, 3H, NCH3), 2.80(s, 3H, NCH3), 3.93(s, 3H, OCH3), 5.42(s, 2H, NCH2), 6.58(d, 1H, Ar), 7.30(s, 1H, H2 -indole), 7.40(d, 1H, H5 -indole), 7.90(br s, 1H, H7 -indole), 8.33(br t, 1H, NH).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[C:18](/[CH3:26])=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Pd]>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH:18]([CH3:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C/C(=C\c1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Yield: 94.1 %

Procedure:
(±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-methyl-3-phenyl-2-propenamide (0.0144 mol) in methanol (200 ml) was hydrogenated with palladium-on-charcoal 10% (0.52 g) as a catalyst at RT over a 5 hour period under a 1 bar pressure in a Parr apparatus. After uptake of hydrogen, the catalyst was filtered through celite and the solvent was evaporated. The residue was crystallized from 2-butanone/DIPE, yielding 4.9 g (94%) of (±)—N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-α-methyl-benzenepropanamide (compound 164).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br.Br[C:26]1[S:30][C:29]([NH2:31])=[N:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[C:9]([C:26]3[S:30][C:29]([NH2:31])=[N:28][CH:27]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: Nc1ncc(Br)s1
Reactant: CC1(C)OB(c2cccnc2Oc2ccc(N)cc2)OC1(C)C
Agent: [Pd]
Agent: Br
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ncccc2-c2cnc(N)s2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a 20 mL sealed tube was added dioxane (1.0 mL), purged solvent with nitrogen for 5 minutes and the tube was sealed. 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine (0.144 g, 0.462 mmol), 5-bromothiazol-2-amine hydrobromide (0.100 g, 0.385 mmol), 2.0M aqueous sodium carbonate (0.385 mL) was added and the tube was purged flask with nitrogen, and again sealed. Tris(dibenzylideneacetone)dipalladium (0) (0.026 g, 0.029 mmol), tri-t-butylphosphonium tetrafluoroborate (0.025 g, 0.087 mmol) was added and the tube was purged with nitrogen, sealed and heated to 100° C. while stirring for 5 hours. The mixture was cooled to RT, passed through pad of silica, washing with 90:10:1 (CH2Cl2:MeOH:NH4OH). The eluent was concentrated and the product was purified by silica gel chromatography eluting with 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated to yield 5-(2-(4-aminophenoxy)pyridin-3-yl)thiazol-2-amine as tan solid. MS m/z=285 [M+1]+. Calc'd for C14H12N4OS: 284.34.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][S:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:16][CH2:15][CH2:14][S:13][CH3:12]
Reactant: CSCCN
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCNc1c(C)cccc1[N+](=O)[O-]
Temperature: 220 °C
Yield: 157.4 %

Procedure:
A mixture of 2-chloro-3-nitrotoluene (1.3 g, 7.3 mmol), 2-(methylthio)ethylamine (1.4 mL, 15 mmol) and N,N-diisopropylethylamine (5.0 mL, 29 mmol) in 1-methyl-2-pyrrolidinone (3.7 mL) was heated to 220° C. by microwave for 1 h. The mixture was diluted with ethyl acetate (0.10 L) and washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, filtered and concentrated to give a crude material. The another batch starting from 1.3 g of 2-chloro-3-nitrotoluene was combined to this crude material and the combined crude products were purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1) to afford 2.6 g (77%) of the title compound.
Reaction SMILES: [Sn](Cl)Cl.[C:4]([O:8][C:9]([N:11]([C:19]1[C:24]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)[CH:26]=2)=[N:23][C:22]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:21][N:20]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[C:25]([C:24]3[C:19]([N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:18])[C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[N:20][CH:21]=[C:22]([C:39]4[CH:40]=[CH:41][C:42]([S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[CH:43][CH:44]=4)[N:23]=3)[O:29][N:28]=2)=[CH:35][CH:34]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([N+](=O)[O-])cc4)no3)n2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(N)cc4)no3)n2)cc1
Temperature: 60 °C
Yield: 61 %

Procedure:
Tin (II) chloride (499.4 mg, 2.213 mmol) was added to a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-[3-(4-nitrophenyl)isoxazol-5-yl]pyrazin-2-yl]carbamate (491 mg, 0.7376 mmol) in ethanol (15 mL) and the resulting solution heated at 60° C. for 16 h. The reaction mixture was cooled rt and concentrated in vacuo. The residue was partitioned between ethyl acetate (10 mL) and 1M NaOH(aq) (5 mL) and the residue that formed was filtered off. The layers were then separated and the aqueous layer was extracted further with ethyl acetate (2×10 mL) and the combined organic extracts were washed with brine (1×10 mL), dried over MgSO4 and concentrated in vacuo. The material was purified by column chromatography on silica (ISCO Companion, 12 g column) eluting with 0-100% EtOAc with petroleum ether. The product fractions were combined and concentrated in vacuo to leave the title compound as a yellow/orange solid (286 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ 1.37 (m, 6H), 1.42 (s, 18H), 3.28 (m, 1H), 3.95 (br s, 2H), 6.79 (m, 2H), 7.30 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 8.10 (m, 2H), 8.36 (m, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 636.3 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][C:12]([O:14]CC)=O)=[O:10])=[CH:4][CH:3]=1.[ClH:17].[NH2:18][OH:19].[Na]>CO>[ClH:17].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][C:12]([NH:18][OH:19])=[O:14])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1ccc(NC(=O)CC(=O)NO)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 17.8 g (0.08 mol) of ethyl 4-amino-phenylcarbamoylacetate, 7 g (0.1 mol) of hydroxylamine hydrochloride and 4.6 g (0.2 gram atom) of sodium in 250 ml of anhydrous methanol is left in contact for 2 hours at 20° C. The methanol is evaporated in vacuo, the residue is taken up in 100 ml of water and acidified with 6 N HCl and the product is filtered off. Recrystallisation from 80 ml of water gives CRL 40,472. Melting point 164°-165° C. (with decomposition). Yield: 64%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:9]([O:33][CH3:34])=[C:10]([O:31][CH3:32])[C:11]2[O:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=O)([CH3:16])[CH2:13][C:12]=2[C:29]=1[CH3:30].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[OH:7][C:8]1[C:9]([O:33][CH3:34])=[C:10]([O:31][CH3:32])[C:11]2[O:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)([CH3:16])[CH2:13][C:12]=2[C:29]=1[CH3:30]
Reactant: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)N1CCOCC1)C2
Agent: O=S([O-])S(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCCN1CCOCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Lithium aluminum hydride (0.50 g) was added to a solution (30 ml) of 4-[5-(2,3-dihydro-5-hydroxy-6,7-dimethoxy-2,4-dimethylbenzofuran-2-yl)pentanoyl]morpholine (2.6 g) in tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into an aqueous sodium hydrosulfite solution, and the insoluble materials were filtered off. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol =95:5) to obtain the title compound (2.2 g, 88%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)cc3)ccn2c1=O
Yield: 94.3 %

Procedure:
Methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.42 mmol) and 4-cyano-phenyl-boronic acid (132 mg, 0.90 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (142 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=N)[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:14]3)=[CH:4][CH:3]=1.Cl.C([O-])(O)=[O:32].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:14]3)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccccc1CNc1ccc2c(C(=N)c3ccc(F)cc3)cccc2n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2c(C(=O)c3ccc(F)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 88 %

Procedure:
A mixture of {5-[(4-fluoro-phenyl)-imino-methyl]-quinolin-2-yl}-(2-methoxy-benzyl)-amine (130 mg, 0.34 mmol), 2N HCl (4 ml) and THF (1 ml) was stirred at room temperature for 23 h, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow gum (115 mg, 88%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][C:17]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[CH:18][CH:13]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc(C)cc2)cc1
Yield: 42.5 %

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 2.85 g (20 mmol) of chloroanisole, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 3.37 g (60 mmol) calcium oxide and 60 ml of N-methyl-2-pyrrolidone were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours. After the completion of the reaction, the reaction mixture was analyzed by means to high performance liquid chromatography. The analysis showed that 46% of sodium p-toluenesulfinate was converted and 8.5 mmol (yield 42%) of 4'-methoxy-4-methylbiphenyl was formed in the reaction mixture solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH-])(C)C.[Li+].C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:42](C1NC=CN=1)(=[O:45])[CH2:43][CH3:44].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:42](=[O:45])[CH2:43][CH3:44])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CCC(=O)c1ncc[nH]1
Agent: CC(C)[NH-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)C(C(=O)OC)[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A solution of 2.61 g (10 m mol) of dimethyl (R)-N-tert-butoxycarbonylaspartate in 10 ml of tetrahydrofuran was added dropwise to a lithium isopropylamide solution [prepared from 4.62 ml (33 m mol) of diisopropylamine and 21 ml (33 m mol) of butyllithium hexane solution, in 30 ml of tetrahydrofuran]at -78° C. in a stream of nitrogen. The mixture was stirred for 10 minutes and a solution of 2.48 g (20 m mol) of propionylimidazole in 15 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred for 10 minutes at -78° C. and further stirred in a dry ice-acetone bath of -40° C. Stirring was continued until the temperature of the mixture reached -20° C. Then a saturated ammonium chloride aqueous solution was added and the mixture was stirred at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was subjected to a silica gel column (2.5×40 cm) chromatography (ethyl acetate:hexane=1:3→1:2) to obtain 2.93 g (92%) of dimethyl (R)-N-tert-butoxycarbonyl-3-propionylaspartate as colorless oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].[I-:17].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.S(=O)(=O)(O)O>[C:15]([CH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[I:17])[C:10]#[N:11])#[N:16]
Reactant: N#CCc1cc(C#N)ccc1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: O
Product: N#CCc1cc(C#N)ccc1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 mmol of Sodium nitrite in 5 ml water is added dropwise over 10 minutes to a stirred solution of 2 mmol of 4-amino-3-cyanomethyl-benzonitrile in 6 ml of water and 3 ml of conc. sulphuric acid at 0° C. After a further 15 minutes at 5° C., a solution of 3.9 mmol of potassium iodide in 6 ml of water is quickly added and the mixture allowed to warm to room temperature. 10% Aqueous sodium thiosulphate is added, the mixture is extracted with ethyl acetate, the extract is dried over magnesium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.