Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH2:8])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H),1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, 1H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H).7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100w) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[C:10]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile, and acetic anhydride (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was then stirred overnight in an ice-water bath. The solvent was evaporated, and water (50 mL) was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:9]1[C:13](=[O:14])[C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:10]1(=[O:33])=[O:32])[CH2:6][CH2:7][CH3:8].CCOC(C)=O>C1COCC1>[C:1]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([NH:15][C:12]3[C:13](=[O:14])[N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[S:10](=[O:32])(=[O:33])[C:11]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)[CH2:22]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCN1C(=O)C(Nc2ccc3c(c2)CCNC3)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)CCN(C(C)=O)C3)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.4 %

Procedure:
Acetyl chloride (0.020 ml, 0.243 mmol) was added to a solution of 2-butyl-5-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)isothiazol-3(2H)-one 1,1-dioxide (example 60) (0.100 g, 0.243 mmol) and TEA (0.040 mmol, 0.267 mmol) in dry THF (2 ml) and the reaction mixture was stirred at rt for 40 mins. EtOAc was added and the mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 1:5 mixture of EtOAc/petroleum ether 40-60° C. mixture as eluent, to give the title compound (0.071 g, 64%). 1H NMR (500 MHz CDCl3); δ 7.30-7.22 (m, 2H), 7.22-7.14 (m, 4H), 6.88, 6.68 (dd, 1H), 6.68 (td, 1H), 6.36, 6.31 (d, 1H), 4.58, 4.47 (s, 2H), 3.79 (t, 2H), 3.63, 3.48 (t, 2H), 2.43, 2.39 (t, 2H), 2.16, 2.15 (s, 3H), 1.94-1.84 (m, 2H), 1.56-1.44 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz CDCl3): δ 169.8, 159.6, 135.8, 134.4, 131.0, 130.8, 129.6, 129.4, 128.3, 127.0, 126.2, 126.0, 122.6, 122.2, 120.4, 120.0, 111.4, 111.2, 47.8, 43.9, 40.5, 39.4, 30.5, 29.3, 26.8, 22.0, 21.8, 20.3, 13.8; Mass Spectrum M+H+ 454.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[S:13](Cl)(Cl)(=[O:15])=[O:14]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:13]1(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: OCCNCc1ccccc1Cl
Product: O=S1(=O)OCCN1Cc1ccccc1Cl

Procedure:
contacting N-hydroxyethyl-2-chlorobenzylamine with sulfuryl chloride and an organic base to give N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine, and
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3I)=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH2:38]([NH2:40])[CH3:39]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[NH:40][CH2:38][CH3:39])=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Product: CCNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Yield: 76.9 %

Procedure:
Using the procedure of Example 7, 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(2-acetylamino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-amide (90 mg, 0.145 mmol) and a methanolic solution of ethylamine (10 mL) were combined to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (60 mg, 76.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 10.58 (s, 1H), 10.49 (m, 1H), 8.47 (dd, J=12.9, 7.2 Hz, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.65 (m, 1H), 7.52 (dd, J=11.2, 7.4 Hz, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 6.70 (dd, J=5.8, 2.5 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H), 3.42 (m, 2H), 2.03 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 538.0 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:24][C:25](=[O:27])[CH3:26])[CH3:20]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1

Procedure:
Potassium carbonate (200 mmol, 27.6 g) was added to a solution of ethyl benzoylacetate (100 mmol, 19.2 g) and potassium iodide (20 mmol, 3.3 g) in dry acetone (100 mL). The resulting solution was refluxed, and chloroacetone (110 mmol, 10.7 g) was added dropwise. Analysis of the reaction mixture by GC/MS indicated the presence of Intermediate 2. Solid material was filtered from the reaction mixture, then washed with 200 mL acetone. The resulting filtrate was concentrated under vacuum, redissolved in ether, then washed three times with water (100 mL). The organic layer was separated from the aqueous layer, and dried over MgSO4. The solids were separated, and the organic solvents removed under vacuum to yield a yellow/orange oil. The crude oil was purified by Kugelrohr distillation (b.p. 175-185 at 0.65 Torr.).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)C>O1CCCC1>[CH3:50][O:49][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[CH:45][C:44]=1[O:47][CH3:48]
Reactant: COc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1OC
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2cc(O)c(=O)[nH]n2)cc1OC

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3,4-dimethoxyphenyl)ethynyl]pyridazine (Intermediate 30) except that the solvent mixture used for the hydrogenation was ethanol and tetrahydrofuran (1:1) and the final material was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([Cl:18])[C:12]=1[Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(Cl)cc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 54.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,3,5-trichlorophenylboronic acid (Aldrich; 751 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-methyl-N′-(2,3,5-trichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (592 mg, 53%) as a colorless oil that solidified on standing.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCCCc1ccccc1
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCCCCCc1ccccc1

Procedure:
A solution of 10 g (80.56 mmol) of 2-hydroxybenzyl alcohol in 200 ml of dry acetonitrile is mixed with 27.45 g (120.83 mmol) of (5-bromopentyl)benzene and 12.25 g (88.61 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 18.7 g (81% of theory) of a colorless solid are obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH:26]=O)=[O:19])[CH3:16].[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O)(=O)C>ClCCCl>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH2:26][NH:47][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:19])[CH3:16]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Yield: 55.4 %

Procedure:
Sodium triacetoxyborohydride (32 mg, 0.152 mmol) was added to a solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-oxo-ethyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5h (34 mg, 0.084 mmol), cyclopentylamine (12 μl, 0.118 mmol), and acetic acid (5 μl, 0.09 mmol) in 1,2-dichlorethane (2 ml) at room temperature. The reaction mixture was quenched with 1N NaOH and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with sat'd aq NaCl, dried, and concentrated in vacuo. The crude residue was purified on a 1 mm chromatotron plate using 100% EtOAc to give I-5i as a colorless oil (22 mg): +APCI MS (M+1) 472.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8]([OH:10])=[N:13][CH:11]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: NC=O
Product: Oc1ncnc2cccnc12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
3-Aminopicolinic acid (A-1) (30 g, 217 mmol, 1.0 eq) is suspended in formamide (75 mL, 1.88 mol, 8.66 eq). The resulting mixture is stirred at 140° C. for 1 h and at 170° C. for 1 h and then at 180° C. for an additional 1 h. The mixture is cooled to RT and filtered. The filter cake is washed with water, and dried in vacuo to afford the product, pyrido[3,2-d]pyrimidin-4-ol (A-2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=2)=[O:25])[CH2:13][CH2:14]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a stirred solution of 0.34 g (1 mmol) of N-(3-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide (Example 11) and 0.16 ml (2 mmol) of pyridine in 10 ml of dichloromethane 0.16 ml (2 mmol) of methanesulfonyl chloride in 2 ml of dichloromethane is added dropwise below 10° C., and the reaction mixture is stirred at room temperature for 10 hours. Then 50 ml of 8% sodium hydrogencarbonate solution is added to the mixture, the organic layer is separated and the water phase is extracted three times with 10 ml of dichloromethane. The combined organic layers are dried over sodium sulfate, concentrated, the residue is treated with diethylether and the crystals are filtered to yield 0.25 g (30%) of the title compound. Melting Point: 128-130° C. (diethylether)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.ClCCl.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>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1cccnc1
Yield: 76.5 %

Procedure:
A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 minutes with argon, and 3 g (4,3 mmol) of bis(triphenylphosphine)palladium(II)chloride and 450 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2CO3), concentrated and bulb-to-bulb distilled (b.p. 120°-130° C./0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 500 ml of ethyl acetate and af ter addition of 15 ml of quinoline is hydrogenated f or 5 h over 6 g Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parrhydrogenator. The crude product is evaporatively distilled (b.p. 120°-130° C./0.05 mbar), yielding 61 g (73%) of (Z)-6-(3-pyridyl)hex-5-enol as a colourless viscous liquid. (C11H15NO; F.W. 177.3).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=O)[CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(=O)[nH]cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Yield: 95 %

Procedure:
A mixture of 4-methyl-5-nitro-1H-pyridine-2-one (5.00 g, 32.44 mmol), thionyl chloride (20 ml), and two drops of dimethylformamide was heated atreflux under nitrogen for 52 hours. The resultant orange colored solution was evaporated under reduced pressure, and a small amount of anhydrous toluene was added and then removed via evaporation under reduced pressure to remove traces of thionyl chloride. The residual oil then passed througha silica gel filter (dried at 150° C. under vacuum overnight, approximately 100 g) followed by methylene chloride (1 1). This filtrate was evaporated under reduced pressure to afford 2-chloro-4-methyl-5-nitropyridine (5.30 g, 30.71 mmol, 95%) as an orange oil, which crystallized below 0° C.; IR (CHCl3) 1605, 1550, 1520, 1450, 1360, 1345 cm-1 ; 1H NMR (CDCl3) δ 9.03 (s, 1H), 7.83 (s, 1H), 2.60 (s, 3H); LRMS (m/z, relative intensity) 174 (25), 173 (19), 172 (M+, 68), 157 (74), 155 (100), 128 (27), 101 (47), 100(55], 99 (74), 90 (43), 75 (36).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10]([OH:19])(=[O:18])[CH:11]([CH:13]([C:15]([OH:17])=[O:16])[OH:14])[OH:12]>C(O)C.O>[C:15]([CH:13]([CH:11]([C:10]([OH:19])=[O:18])[OH:12])[OH:14])([OH:17])=[O:16].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1CCCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1CCCCN1
Temperature: 80 °C

Procedure:
2-Piperidinecarboxylic acid (26 g, 0.201 mol) and (+)-tartaric acid (31.2 g, 0.208 mol) were suspended in a mixture of ethanol (400 ml) and water (25 ml). The mixture was heated to 80° C., and the solution was allowed to cool to room temperature. The precipitated solid was filtered off, washed with ethanol and dried to give 25.4 g (45%) (R)-(+)-2-piperidinecarboxylic acid (+)-tartrate. The mother liquor was evaporated in vacuo, and the residue was dissolved in water (120 ml). A solution of potassium hydroxide (6.5 g, 116 mmol) in water (13 ml) was added, and the precipitated mono potassium tartrate was removed by filtration. Evaporation of the filtrate in vacuo afforded 19.5 g crude (S)-(-)-2-piperidinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:3]1=[CH2:4].[N:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[OH:26])=O>C(O)C>[CH3:12][N:5]1[C:3]2([O:26][C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[N:14]=[CH:4]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:2]([CH3:13])([CH3:1])[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=Nc1c(O)ccc2ccccc12
Solvent: CCO
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A mixture 1,3-dihydro-1,3,3-trimethyl-2-methyleneindoline (3.62 g; 0.021 mol) and 1-nitroso-2-naphthol (3.46 g; 0.02 mol) in ethanol (80.0 ml) was heated under reflux for 2 h. The solution was evaporated and the residue flash-chromatographed over silica (dichloromethane) to give 1,3-Dihydro-1,3,3-trimethylspiro[2H-indole-2,3'-3H-naphtho[2,1-b][1,4]oxazine] as a pale yellow solid (3-96 g; 60%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[CH3:99][NH:100][CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][N:106]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[CH2:105][CH2:104]1>>[CH3:99][N:100]([CH2:101][CH2:102][N:103]1[CH2:108][CH2:107][N:106]([C:109]([O:111][C:112]([CH3:115])([CH3:114])[CH3:113])=[O:110])[CH2:105][CH2:104]1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29](=[O:30])[NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:32]=1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. Tert-Butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate was used as the amine component in this coupling. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.98 (d, J=5.1 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.18˜8.11 (m, 3H), 7.89˜7.53 (m, 8H), 4.72 (s, 2H), 4.00˜3.11 (m, 16H), 3.08 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=5.7 Hz, 2H), 1.49 (s, 9H). MS (ES, m/z): 828 [M+H]+.