Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC(C=O)=C[CH:10]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:40])=[C:31]([N:34]4[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35]4)[CH:32]=3)[C:27](=[O:41])[C:26]([C:42]([OH:44])=[O:43])=[CH:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:40])=[C:31]([N:34]4[CH2:38][CH2:37][CH:36]([N:39]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][CH:3]=5)[CH2:35]4)[CH:32]=3)[C:27](=[O:41])[C:26]([C:42]([OH:44])=[O:43])=[CH:25]2)=[CH:20][CH:19]=1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Reactant: O=Cc1ccccc1
Reactant: O=Cc1ccncc1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with 4-pyridinecarboxaldehyde and using the acid (1) (R=ethyl) described in Example 13 one obtains 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(4-pyridylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=ethyl, Z=4-pyridine).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:14]1([N:19]2[C:23](N)=[C:22]([C:25]([NH2:27])=O)[C:21]([CH2:28][CH3:29])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C[N:31](C=O)C.[H-].[Na+]>C(O)(=O)C>[CH:14]1([N:19]2[C:23]3=[N:9][C:8]([C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[N:27][C:25]([NH2:31])=[C:22]3[C:21]([CH2:28][CH3:29])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: N#Cc1ccccc1-n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nn(C2CCCC2)c2nc(-c3ccccc3-n3ccnc3)nc(N)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(1-imidazolyl)benzonitrile (3.14 g), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.75 g, 16.59 mmol) and DMF (75 ml) was added 60% NaH (0.78 g, 60% dispersion in mineral oil). The reaction mixture was stirred at room temperature overnight, poured into ice/water (600 ml) and treated with acetic acid until a pH of 7 was obtained. The product was collected by filtration, and recrystallized from EtOAc/hexane to afford 2.82 g of 1-cyclopentyl-3-ethyl-6-[2-(1-imidazolyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine.1/4 hydrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
To a mixture of 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2 g, 5.25 mmol) and 4-chlorophenyl boronic acid (1.17 g, 7.5 mmol)in toluene (20 ml) was added a 2M sodium carbonate solution (7.5 ml). The reaction mixture was stirred under a nitrogen atmosphere, then tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. After allowing to cool the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. Purification by flash chromatography using hexane/ethyl acetate as eluant gave the title compound as an oil (0.7 g, 39%); δH (CDCl3) 1.5 (9H, s, C(CH3)3), 2.89 (2H, t, J 8.3 Hz, CH2), 3.68 (2H, t, J 8.3 Hz, CH2), 4.61 (2H, s, CH2), and 7.15-7.5 (7H, m, ArH).
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])/[CH:24]=N/O)=[CH:18][CH:17]=1)([CH2:11][CH2:12][CH:13]([F:15])[F:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(=O)(=O)(O)[OH:30]>>[F:14][CH:13]([F:15])[CH2:12][CH2:11][C:5]([C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:23](=[O:27])[C:24]2=[O:30])([CH2:4][CH2:3][CH:2]([F:1])[F:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc(NC(=O)/C=N/O)cc1
Product: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
3.0 g of ethyl 2-(3,3-difluoropropyl)-5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate are added in portions to 20 ml of sulfuric acid (98%) at 50° C., during which the temperature rises to 60° C. When the addition is complete, the mixture is stirred at 50° C. for a further 120 min and subsequently poured into 400 ml of ice-water. The mixture is washed three times with 200 ml of dichloromethane/ethanol (9:1) each time, the combined organic phases are dried over sodium sulfate, filtered off and evaporated to dryness in vacuo. The crude product obtained is employed in the next reaction without further purification. Yield: 1.9 g (66%) of ethyl 2-(3,3-difluoropropyl)-2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate obtained; LC-MS retention time: 2.17 min.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
150 mg (91%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (80 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1O.[CH:27](C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.CN1C=CN=C1.Cl>O1CCCC1.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([O:16][CH2:27][CH:22]2[O:21][CH2:25][CH2:24][CH2:23]2)=[O:15])[N:6]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: OC1CCCO1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCC2CCCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.55 Gram of 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid, 0.21 g of tetrahydrofuryl alcohol and 0.85 g of 2,4,6-triisopropylbenzenesulfonyl chloride were dissolved in 5 ml of tetrahydrofuran. Subsequently, 0.45 g of 1-methylimidazole was added to the mixture. After stirring the resulting solution at room temperature for 1 hour in order to carry out the reaction, the reaction solution was poured into diluted hydrochloric acid, and exracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merch & Co., Inc., solvent: chloroform) to obtain 0.30 g of tetrahydrofurfuryl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (III-9)].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:32](=[O:34])[CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 4-((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (Example 1, 80 mg, 0.242 mmol) in chloroform (5 mL) was added triethylamine (0.067 mL, 0.484 mmol) followed by acetyl chloride (0.022 mL, 0.315 mmol). The solution was stirred for 1 hour, and then water (5 mL) was added. The layers were separated and the organic layer was washed with brine, dried over MgSO4 and filtered. The solution was then evaporated. tert-Butyl 4-((N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate (80 mg, 0.198 mmol, 82% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30-7.37 (m, 2H), 7.21-7.28 (m, 1H), 7.08 (d, J=7.07 Hz, 2H), 4.03-4.25 (m, 2H), 3.53 (dd, J=7.58, 13.64 Hz, 1H), 3.06-3.25 (m, 1H), 2.78-2.87 (m, 1H), 2.61-2.77 (m, 2H), 2.22 (td, J=2.65, 4.86 Hz, 1H), 2.18 (s, 3H), 1.82-1.98 (m, 1H), 1.54-1.72 (m, 2H), 1.47 (s, 9H), 1.36-1.45 (m, 2H), 1.06-1.25 (m, 2H); LC-MS Rt=1.09 min; MS (ESI): 373.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N+:17]=[N-:18]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of intermediate 46, 2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) in dimethylformamide (4 mL) was stirred at 55–60° C. for 30 min after which the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic phase was washed with water, dried (Na2SO4), filtered and concentrated to provide 670 mg (Yield 87%) of the title compound as a yellow oil; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.78 (2H, s) 7.29–7.34 (1H, m) 7.59–7.64 (2H, m).
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]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:46]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCO)cc2)cc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOC(=O)c3ccccc3)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzoyloxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 736 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Reactant: O=C=NCC1CCCCC1
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.5 mg, 34%) having the following characteristics.
Reaction SMILES: CON(C)[C:4](=[O:23])[C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1.[CH3:25][Mg]Br.Cl>C1COCC1.O>[N:17]1([C:7]2[CH:6]=[C:5]([C:4](=[O:23])[CH3:25])[CH:10]=[C:9]([S:11]([F:12])([F:16])([F:15])([F:13])[F:14])[CH:8]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CON(C)C(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-3-morpholin-4-yl-5-(pentafluorosulfanyl)benzamide (2.38 g) was dissolved in THF (50 ml), methylmagnesium bromide (4.22 ml, 3 M in ether) was added dropwise at 0° C. and then the mixture was stirred at RT for 2 h. Then 1N hydrochloric acid (100 ml) was added, and the mixture was diluted with water and extracted by shaking three times with EA. Thereafter, the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-70% within 40 min). 1.1 g of the title compound were obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][CH2:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)[CH3:26]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (90 mg, 0.29 mmol), glycine ethyl ester hydrochloride (162 mg, 1.16 mmol), and triethylamine (0.16 mL, 1.16 mmol) in 1,2-dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (129 mg, 0.58 mmol). The mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4 and concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give product (64 mg, yield: 55%). ESI-MS: 420.30 (M+23)+; 1H NMR (400 MHz, CDCl3) δ=7.66-7.70 (m, 3H), 7.41 (dd, 1H), 7.11-7.14 (m, 2H), 4.26 (m, 1H), 4.19 (q, 2H), 3.93 (s, 2H), 3.43 (s, 2H), 2.28 (d, 4H), 1.89 (d, 2H), 1.44 (q, 2H), 1.27 (t, 3H), 1.09-1.20 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:29])[CH:22](Br)[C:23](OCC)=[O:24])[CH3:19].Cl>C(O)C.O>[CH2:18]([O:20][C:21]([C:22]1[C:23](=[O:24])[NH:1][C:2]2[C:3](=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[N:4]=1)=[O:29])[CH3:19]
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
2-Amino-4-methoxy aniline (5.0 g, 36.2 mmol) was dissolved in 50 mL of ethanol and triethylamine (5.08 mL, 69.1 mmol) added. The mixture was cooled to 0° C. and diethylbromomalonate (8.02 mL, 47.0 mmol) in 8 mL of ethanol was added dropwise over 30 minutes. Mixture is stirred at 0° C. for 30 minutes and 16 h at room temperature. The resulting solid was isolated and stirred in 200 mL water and 50 mL 1N HCl for 1 h. The solid was filtered, suspended in toluene and evaporated to dryness to give the 6-methoxy-3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid ethyl ester as a solid (5.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>CC(O)=O>[Br-:13].[CH2:23]([N+:1]1[CH:2]=[CH:3][CH:4]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:6]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCCCCCBr
Reactant: CN1CCC[C@H]1c1cccnc1
Solvent: CC(=O)O
Product: C=CCCCCCCCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 60.6 %

Procedure:
To a stirred solution of (S)-nicotine (0.52 g, 3.2 mmol) in AcOH (10 ml) was added 10-bromo-dec-1-ene (1.66 g, 7.58 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.74 g (61%) of (S)-1-dec-9-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide (NDNB-9e) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.65 (1H, d, J=5.1 Hz), 9.14 (1H, s), 8.41(1H, d, J=8.1 Hz), 8.09 (1H, dd, J=8.1, 5.1 Hz), 5.75 (1H, m), 4.88–5.10 (4H, m), 3.54 (1H, t, J=8.1 Hz), 3.23 (1H, m), 2.45 (2H, m), 2.22 (3H, s), 1.70–2.10 (6H, m), 1.61 (1H, m), 1.10–1.40 (10H, m); 13C NMR (75 MHz, CDCl3) δ 146.46, 144.39, 143.74, 142.97, 139.07, 128.50, 114.33, 67.17, 62.25, 56.92, 40.74, 36.11, 33.93, 32.35, 29.42, 29.24, 29.15, 29.03, 26.35, 23.41.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[N:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][NH:13][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccncc1[N+](=O)[O-]
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A mixture of 3-nitroisonicotinic acid (1.75 g, 10.1 mmol), 1-amino-2-methylpropan-2-ol (968 ul, 10.1 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (4.86 g, 15.1 mmol) and triethylamine (4.9 ml, 35.3 mmol) in tetrahydrofurane (60 ml) was stirred over the week-end at rt. The reaction mixture was diluted with ethyl acetate, washed with water, with brine, dried with magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography using a CH2Cl2/MeOH gradient as eluent, providing the title compound as off-white solid (255 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(Cl)c(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 29.8 %

Procedure:
3,4-Dichlorobenzeneboronic acid (49.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (19 mg, 30%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:16][C:3]1[C:4](=[O:15])[NH:5][C:6](=[O:14])[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2ccco2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 53.4 %

Procedure:
6-Amino-1-furfuryluracil (3.0 g, 14.5-mmol) was dissolved with heating in 30% aqueous acetic acid (30 ml) and then a solution of sodium nitrite (1.7 g, 24.6 mmol) in water (5 ml) was added dropwise. The reaction was heated to 70° C. for 30 min and then cooled to 0° C. The solids were collected by filtration and rinsed with cold water (20 ml). The solids were dissolved into concentrated aqueous ammonium hydroxide solution (10 ml) and then a solution of sodium hydrosulfite (9.8 g, 47.8 mmol) in water (30 ml) was added in one portion. After heating at 80° C. for 1 hour, the slurry was cooled to ambient temperature. The solids were collected by filtration, rinsed with water (4×50 ml) and vacuum dried over phosphorus pentoxide to give 5,6-diamino-1-furfuryluracil (1.72 g, 53% yield) as a brown solid.