Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O-:7][N+:8]1[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[N:9]=1.[BH3-]C#N.[Na+].CC(O)=O>CO.CN(C=O)C>[N:1]1([CH2:23][CH2:22][CH2:21][C:10]2[N:9]=[N+:8]([O-:7])[C:13]3[CH:14]=[C:15]4[CH2:20][CH2:19][O:18][C:16]4=[CH:17][C:12]=3[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCO3
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Morpholine (0.22 mL, 2.52 mmol) was added to a solution of aldehyde 214 (220 mg, 0.90 mmol) in MeOH (10 mL) and DMF (10 ml), and the solution stirred for 30 min. NaCNBH3 (176 mg, 2.80 mmol) was added, followed by HOAc (0.12 mL) and the mixture stirred at 20° C. for 30 min. The solvent was evaporated and the residue partitioned between DCM (40 mL) and water (40 mL). The aqueous phase was extracted with DCM (2×40 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 215 (210 mg, 74%) as a pale brown solid, mp 96-99° C.; 1H NMR δ 8.27 (t, J=1.6 Hz, 1H, H-9), 7.11 (s, 1H, H-5), 4.80 (t, J=8.4 Hz, 2H, H-8), 3.59 (t, J=4.6 Hz, 4H, 2×CH2O), 3.43 (dt, J=8.4, 1.6 Hz, 2H, H-7), 2.97-3.01 (m, 2H, CH2), 2.44-2.48 (m, 2H, CH2), 2.41 (t, J=4.5 Hz, 4H, 2×CH2N), 2.03-2.11 (m, 2H, CH2); 13C NMR δ 167.1, 166.4, 150.5, 134.8, 128.9, 116.2, 103.9, 73.0, 67.0 (2), 58.3, 53.5 (2), 53.4, 27.0, 24.9. Anal. calcd for C16H20N4O3: C, 60.8; H, 6.4; N, 17.7. Found: C, 60.7; H, 6.5; N, 17.7%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[CH2:19][C:18](=[O:30])[NH:17][C:9]=2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(c1)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
Prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K74) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (33 mg).
Reaction SMILES: CC(O)C.[Na].[N:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@@H:8]([OH:14])[CH2:7]2.CC([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)C>CC(C)[O-].[Na+].CN(C=O)C.C1(C)C=CC=CC=1>[CH:34]1[CH:35]=[CH:36][C:31]([C@@H:22]2[N:21]([C:19]([O:14][C@@H:8]3[CH:9]4[CH2:12][CH2:13][N:6]([CH2:11][CH2:10]4)[CH2:7]3)=[O:18])[CH2:30][CH2:29][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)=[CH:32][CH:33]=1
Reactant: CC(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 64.7 %

Procedure:
In a mixture of sodium isopropoxide prepared from 0.20 g of 2-propanol and 0.08 g of metallic sodium with 20 ml of toluene and 2.5 ml of DMF, 2.58 g of (R)-quinuclidin-3-ol was allowed to react with 5.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid propan-2-yl ester for 8 hours while evaporating the solvent, thereby obtaining 3.97 g of a solifenacin-containing composition.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@H:10]([O:11][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.3 %

Procedure:
To a solution of (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.5 g) in N,N-dimethylformamide (40 ml) were successively added imidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and the solution was stirred at room temperature for 14 hours. The reaction mixture was quenched by the addition of water (100 ml) and extracted with ethyl acetate (100 ml×1). The extract was washed with water (100 ml×2), brine (100 ml×1), and dried over magnesium sulfate. Filtration followed by evaporation gave a colorless oil, which was chromatographed on silica gel (eluent:hexane/ethyl acetate) to give (2R)-N-benzyl-N-[2-(4-bromophenyl)ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (21.0 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2-Methyl-3-nitrobenzylchloride (1.0 g, 5.4 mmol) was dissolved in 30 ml of THF, and to this was added 1-methylpiperazine (0.65 g, 6.5 mmol) and sodium bicarbonate (2.26 g, 26.9 mmol). The reaction mixture was stirred at 65° C. for 16 hours. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with saturated NH4Cl, H2O, brine and dried over MgSO4. Solvent evaporation afforded 1-(2-methyl-3-nitrobenzyl)-4-methylpiperazine.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:16])[OH:15])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[OH:3][CH:1]([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:15])[OH:16])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(C(C)=O)c2sc(NC(=O)O)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)O)c2sc(NC(=O)O)nc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
0.05 g of (7-acetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (0.00018 Mol) were dissolved in ethanol (30 ml) and 0.028 g of NaBH4 (0.00072 Mol) were added. After stirring at 40° C. for 24 hrs. the reaction mixture was diluted with water, extracted with CH2Cl2, the organic phase washed with brine and dried over MgSO4. After chromatography on silicagel with CH2Cl2/MeOH 97:3 the title compound was obtained as a white solid (38%); F.p.: 179° C. (dec.).
Reaction SMILES: CO.[C:3]1([N:9]2[C:17](=[O:18])[C:16]3[C:15]([CH3:19])=[CH:14][C:13](=[O:20])[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C1(N=[CH:35][CH:36]=[CH:37][CH:38]=[CH:39][NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(N(CC)CC)C>[C:47]([N:40]([CH2:39][CH:38]=[C:37]=[CH:36][CH:35]=[C:14]1[C:13](=[O:20])[N:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]2=[N:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:17](=[O:18])[C:16]2=[C:15]1[CH3:19])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(=O)n(-c2ccccc2)c2[nH]n(-c3ccccc3)c(=O)c12
Reactant: C(=CC=Nc1ccccc1)C=CNc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N(CC=C=CC=c1c(C)c2c(n(-c3ccccc3)c1=O)=NN(c1ccccc1)C2=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a solution prepared by adding methanol (50 ml) and triethylamine (2.8 ml) to 2,7-diphenyl-4-methylpyrazolo(3,4-b) pyridine-3,6-dione (3.17 g), 1,7-diphenyl-1,7-diaza-1,3,5-heptatriene hydrochloride (2.85 g) was dissolved and then acetic anhydride (1.88 ml) was added, and the mixture was stirred at room temperature for one hour. The resulting precipitate was collected by filtration, washed with methanol and dried to obtain 5-[5-(N-acetylanilino)-2,3-pentadienylidene]-2,7-diphenyl-4-methylpyrazolo(3,4-b)pyridin-3, 6-dione (1.9). To these crystals (1.5 g), N,N-dimethylformamide (60 ml), 2,7-diphenyl-4-methylpyrazolo(3,4-b)pyridin-3,6-dione (0.95 g) and triethylamine (0.42 g) were added, and stirred at 50° C. for 2 hours. After a trace amount of insoluble matters were removed by filtration, ethyl acetate of 10-fold the volume of the filtrate was added thereto while stirring for crystallization. The resulting crystals were redissolved in a small amount of N,N-dimethylformamide, and a 10-fold volume of ethyl acetate was added thereto for crystallization. The resulting crystals were collected by filtration and dried to obtain compound II-2 (1.3 g). Gold crystals, melting point 300° C. or more, λmaxDMF 792 nm
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[C:14]([F:23])[CH:13]=1>C(COC)OC.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>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[CH:10]=2)=[C:14]([F:23])[CH:13]=1
Reactant: COc1cc(B(O)O)c(F)cc1Cl
Reactant: Brc1cn2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: COc1cc(-c2cn3ccccc3n2)c(F)cc1Cl
Yield: 61.7 %

Procedure:
A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz); δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][N:23]([CH:31]([CH3:33])[CH3:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:15]([C:34]3[C:35]4[CH:42]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:31]([N:23]([CH2:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[N:15]([C:34]3[C:35]4[CH:42]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:14][C:11]3([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:21]=12)[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN(C(=O)OC(C)(C)C)C(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C(C)C)cccc43)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 783.4 %

Procedure:
A solution of tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl(isopropyl)carbamate (0.088 g, 0.14 mmol) in MeOH (1 mL) was treated with ammonium formate (0.027 g, 0.43 mmol) and Pd/C (0.0077 g, 0.0072 mmol) and heated to reflux for 7 hours and stirred at room temperature overnight. The reaction was filtered through glass filter paper, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (5% MeOH/DCM, then 5% 7N N1—I4 in MeOH/DCM) to yield pure tert-butyl isopropyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.57 g, 76%). LCMS (APCI+) m/z 520.2 [M+H]+; Rt=3.80 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@H:5]2[CH2:11][C@H:10]([CH:12]3[CH2:14][CH2:13]3)[O:9][CH2:8][C@:6]2([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[F:23])[C:18]#[N:19])[N:7]=1.[NH3:24].[C:25](#[N:27])C>>[F:23][C:22]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C@H:6]([CH3:5])[CH2:8][O:9][CH3:10])=[CH:16][C:15]=1[C@:6]12[CH2:8][O:9][C@@H:10]([C:12]3[CH:13]=[N:24][N:27]([CH3:25])[CH:14]=3)[CH2:11][C@H:5]1[CH2:4][S:3][C:2]([NH2:1])=[N:7]2
Reactant: N
Reactant: CC#N
Reactant: N#Cc1ccc(F)c([C@]23CO[C@@H](C4CC4)C[C@H]2CSC(N)=N3)c1
Product: COC[C@@H](C)NCc1ccc(F)c([C@]23CO[C@@H](c4cnn(C)c4)C[C@H]2CSC(N)=N3)c1

Procedure:
Compound C87 was converted to the product according to the method described for synthesis of 13 in Example 13. In this case, reversed phase HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B) afforded the product as a white gum. By 1H NMR analysis, this was judged to consist of a mixture of the expected diastereomers. Yield: 37 mg, 83 μmol, 25%. LCMS m/z 448.3 [M+H+]. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 7.60 (s, 1H), 7.33 (s, 1H), 7.24-7.32 (m, 2H), 7.12 (dd, J=12, 8 Hz, 1H), 6.14 (br s, 2H), 4.55 (d, J=11.0 Hz, 1H), 4.46 (br s, 1H), 4.06 (d, J=11 Hz, 1H), 3.79 (s, 3H), 3.58-3.75 (m, 3H), 3.21 and 3.22 (2 s, total 3H), 2.80-2.88 (m, 1H), 2.63-2.79 (m, 3H), 1.85-1.98 (m, 1H), 1.71-1.80 (m, 1H), 0.96 (d, J=6.3 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)=O.C(OCC)(=O)C>O1CCCC1>[F:19][C:16]([F:17])([F:18])[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([NH2:7])[CH2:10][CH2:11]1
Reactant: O=NN1CCN(CC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NN1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of lithium aluminum hydride (2.22 g, 58.5 mmol) in tetrahydrofuran (100 mL) that cooled with ice bath, a solution of 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine (5.43 g, 27.5 mmol) in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature, then stirred for 5 days. The reaction mixture was cooled with ice bath, ethyl acetate was added until cease bubbling up, and water (2.1 mL) was added then the mixture was stirred for 20 min. To this mixture, 15% w/v sodium hydroxide solution (2.1 mL) and water (6.3 mL) were added, then the suspension mixture was allowed to warm to ambient temperature and then the mixture was stirred vigorously for 1 h. Magnesium sulfate was added to the mixture and stirred for a while, then the suspension was filtered. The filtrate was concentrated to afford 4-(2,2,2-trifluoroethyl)piperazine-1-amine as oil (4.72 g, y. 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N+:6]([O-:28])[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1cc(-c2c(CC)cccc2CC)[n+]([O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester (2.1 g, 7.1 mmol) and 3-chloroperoxybenzoic acid (77%, 1.9 g) in CH2Cl2 (50 mL) is stirred at room temperature overnight. The mixture is diluted with ether (600 mL) and washed with saturated Na2CO35 then brine, and dried. Concentration at reduced pressure gives 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester N-oxide. 1H NMR (CDCl3) 8.89 (s, 1H), 7.26 (t, 1H), 7.19 (m, 3H), 3.95 (s, 3H), 3.02 (q, 2H), 2.04 (m, 2H), 2.30 (m, 2H), 1.26 (t, 3H), 1.11 (t, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C-:6]#[N:7].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.O>Cl.CO>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:6]#[N:7])=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: NCCCO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(NCCCO)c1ccc(F)cc1

Procedure:
to a cold solution (0° C.) of 30.2 g. of 3-amino-1-propanol dissolved in 161.2 ml of 2.5 N hydrochloric acid, add 19.8 g of sodium cyanide followed by a solution of 50.0 g of 4-fluorobenzaldehyde in 160 ml of methanol. Stir the reaction mixture at room temperature (20° C.) for twenty four (24) hours, then treat with 500 ml of water and extract with ethyl ether. Dry the ether extract over sodium sulfate and concentrate to an oily residue which subsequently crystallizes. Recrystallize from isopropyl ether to obtain thereby the title compound which melts at 69°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[C:17](=[O:20])(O)[O-].[Na+].C1(OC(Cl)=O)C=CC=CC=1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>C1COCC1>[O:35]1[CH:36]=[CH:37][C:33]([NH:32][C:17](=[O:20])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([B:8]3[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]3)=[CH:4][CH:3]=2)=[N:34]1
Reactant: Nc1ccon1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C([O-])O
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccon3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Aminophenyl)boronic acid pinacol ester (1 g) was dissolved in dry THF (30 mL), sodium bicarbonate (576 mg) added followed by the dropwise addition of phenylchloroformate (0.575 mL). The mixture was stirred at RT for 1 hour then. 3-aminoisoxazole (0.506 mL) added and the reaction left to stir at 40° C. for 16 h. More 3-aminoisoxazole (0.506 mL) and sodium bicarbonate (576 mg) were added and the reaction heated to 75° C. for 8 h. before the mixture was concentrated in vacuo and partitioned between DCM (50 mL) and water (50 mL). The organic layer was dried over magnesium sulphate, filtered and vacuumed to dryness. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (1.05 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.O.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>[CH:10]1([C:2]2[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=2)[NH2:7])[CH2:12][CH2:11]1
Reactant: Nc1cc(Br)ccc1F
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C2CC2)ccc1F
Yield: 54.3 %

Procedure:
Stir the mixture of 5-bromo-2-fluoroaniline (800 mg, 4.26 mmol), cyclopropylboronic acid (434 mg, 5.05 mmol), tetrakis(triphenylphosphine)palladium(0) (242 mg, 0.21 mmol), cesium carbonate (2.7 g, 8.28 mmol) in dioxane (5 mL) and water (0.3 mL) under N2 atmosphere at 100° C. for 17 hrs. TLC (EtOAc:PE=1:3) shows the reaction is complete. Filter off the solid, concentrate the filtrate. Purify by flash chromatography (silica gel, EtOAc:PE=3:7) to afford the title compound (350 mg, 55%). MS: (M+1): 152.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][N+:11]([O-:13])=[O:12].[ClH:14].CNC.[F-].[K+]>O>[Cl:14][C:10]([N+:11]([O-:13])=[O:12])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: O=[N+]([O-])CBr
Reactant: O=Cc1ccccc1
Agent: CNC
Agent: [F-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])C(Cl)=Cc1ccccc1
Temperature: 25 °C
Yield: 79 %

Procedure:
The title compound was prepared by the method of Dauzonne, D.; Demerseman, P. Synthesis 1990, 66-70. Benzaldehyde 158 (3.59 g, 33.8 mmol), bromonitromethane 159 (9.0 g, 64.3 mmol), dimethylamine hydrochloride (24.8 g, 304.2 mmol), potassium fluoride (spray-dried, 0.3 g, 5.08 mmol) and m-xylenes (85 mL) were combined in a 250 mL round bottom flask. The flask was then connected to a Dean-Stark trap and reflux condenser and the mixture was heated at reflux with azeotropic removal of water for 24 h. After cooling to room temperature, the reaction solution was decanted from the excess dimethylamine hydrochloride solids, rinsing with dichloromethane. The dichloromethane and xylenes were then removed under reduced pressure. The crude brown oil was taken up in CH2Cl2 and washed with water. The dimethylamine hydrochloride solids were taken up in 1:1 CH2Cl2/water. After removal of the organics, the aqueous fraction was extracted three times with CH2Cl2. The combined organics were dried over MgSO4 and concentrated. Purification by flash chromatography (SiO2, gradient eluent: 5% CH2Cl2/hexanes to 10% CH2Cl2/hexanes to 15% CH2Cl2/hexanes) afforded pure 160 as a yellow solid (79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:17][CH:18]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:19])=[C:8](\[C:15]#[N:16])/[C:9]([O:11]CC=C)=[O:10].N1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.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>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:17][CH:18]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:19])=[C:8](\[C:15]#[N:16])/[C:9]([OH:11])=[O:10]
Reactant: C=CCOC(=O)/C(C#N)=C(\NC(C)c1nccs1)c1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(N/C(=C(/C#N)C(=O)O)c1sccc1Br)c1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Allyl (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylate (0.1 g, 0.212 mmol, 1 eq.) was dissolved in 5 ml of DCM under Argon and cooled to 0° C. Pyrrolidine (0.018 g, 0.255 mmol, 1.2 eq.) added followed by triphenylphosphine (0.010 g, 0.038 mmol, 0.18 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.011 mmol, 0.05 eq.). The reaction was stirred at 0° C. for 2 h at which point no starting material remained. The reaction medium was quenched with aqueous HCl 1N (5 ml) and diluted with water. The organic layer was basified with aqueous 1N NaOH until pH 9 and was extracted again with aqueous 1N NaOH. The aqueous layers were combined, acidified with aqueous 1N HCl and extracted with DCM (CH2Cl2). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to give (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylic acid (0.075 g, 87% yield) as a white solid and a mixture of atropoisomers.