Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.B(F)(F)F.[CH3:35]COCC>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15](C3SC=CN=3)=[O:16])=[CH:13][C:12]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].C[C:42]([CH3:45])([O-])C.[K+]>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15](=[O:16])[NH:10][C:6]3[S:7][CH:42]=[CH:45][N:5]=3)=[CH:13][C:12]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:26][CH:27]=3)=[CH:11][C:9]=2[N:10]=1)=[O:40])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(=O)c3nccs3)c2s1
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C(=O)Nc3nccs3)c2s1
Yield: 8 %

Procedure:
Ethyl 1-(5-(2-(3-ethylureido)-7-(thiazole-2-carbonyl)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (185 mg, 0.31 mmol) was dissolved in DMSO (2 ml) with stirring and potassium-t-butoxide (174 mg, 1.56 mmol) was added. The reaction was allowed to stir at rt for 1 h. The reaction was filtered and purified by preparative HPLC to afford Compound 145 as a solid (7 mg, 95% purity by HPCL) (4%) 1H NMR (DMSO-d6): δ 9.00-8.95 (2H, m), 8.63 (1H, s), 8.19 (1H, s), 7.65 (1H, d, J=3.59 Hz), 7.37 (1H, d, J=3.57 Hz), 6.93 (1H, t, J=5.58 Hz), 4.34 (2H, dt, J=13.73, 4.50 Hz), 3.41 (2H, dd, J=11.79, 3.40 Hz), 3.25 (2H, p, J=6.76 Hz), 2.06 (2H, dt, J=13.53, 3.67 Hz), 1.44 (2H, ddd, J=13.50, 9.94, 4.01 Hz), 1.23 (3H, s), 1.15 (3H, t, J=7.18 Hz). MS: 567 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:18]([F:17])[C:19]=1[CH2:20][N:21]([CH3:42])[C:22](=[O:23])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][CH:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CN(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 39.9 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.126 g, 0.51 mmol), 1-(2,6-Difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-methyl-urea (0.5 mmol), glacial acetic acid (0.028 g, 0.49 mmol) and sodium cyanoborohydride (0.031 g, 0.49 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.136 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:25][CH3:26])[C:21]([O:27]C)=[C:20]([C:29]([O:31]C)=[O:30])[C:19]=3OC)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:25][CH3:26])[C:21]([OH:27])=[C:20]([C:29]([OH:31])=[O:30])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(CNC)c(OC)c(C(=O)OC)c3OC)cs2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CNC)c(O)c(C(=O)O)c3)cs2)cc1OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 150 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxy-methoxy-5-methylaminomethylphenyl)thiazole. Thereto was added 0.2 ml of 10% hydrochloric acid. The mixture was stirred at 60° C. for 30 minutes. 2 ml of 10% sodium hydroxide was added, and the mixture was refluxed for 1 hour with heating. The reaction mixture was made neutral with 10% hydrochloric acid and the solvent was removed by distillation. The residue was mixed with ethanol. The insoluble was collected by filtration, washed with water, dried and recrystallized from dimethylformamide to obtain 35 mg of 2-(3,4-diethoxyphenyl-4-(3-carboxy-4-hydroxy-5-methylaminomethylphenyl)thiazole.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH2:6])=[NH:5].[C:7](OC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.[OH-].[Na+].Cl>CCOCC>[Cl:2][CH2:3][C:4]1[N:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[N:5]=1
Reactant: N=C(N)CCl
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cc(O)nc(CCl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetamidine hydrochloride (6.45 g, 0.05 mole), methyl acetoacetate (6.38 g, 0.055 mole) and 2 N aqueous sodium hydroxide solution (50 ml) were mixed and stirred for 1 hour at room temperature. The reaction solution was acidified (pH 4-5) with 6 N hydrochloric acid, followed by extraction with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown crystal. The crystal was stirred in ether and then filtered to obtain 5.1 g (64% of the theoretical yield) of 2-(chloromethyl)-4-hydroxy-6-methylpyrimidine as colorless plate-like crystals (m.p. 157°-159° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:31]([F:34])([F:33])[F:32])=[N:7][C:8]([N:11]2[CH2:16][CH2:15][C:14](=[N:17][O:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].C1COCC1.[OH-].[Na+]>Cl>[CH:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([O:18][N:17]=[C:14]2[CH2:13][CH2:12][N:11]([C:8]3[N:7]=[C:6]([C:31]([F:33])([F:34])[F:32])[C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:20][CH2:21]1)=[O:26])([CH3:30])[CH3:29]
Reactant: COC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)CC2)CC1
Temperature: 50 °C

Procedure:
The crude 57a obtained in the previous step was taken up with THF (3 mL) and 1N NaOH (0.6 mL) and heated to 50° C. for 2 h. The mixture was cooled, diluted with 10 mL of 1N HCl and extracted with DCM (3×5 mL). The combined extracts were dried and concentrate to afford the crude 57b.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11]>O1CCCC1>[OH:11][CH2:10][C:9]1[C:8](=[O:7])[NH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]cccc1CO
Temperature: 0 °C
Yield: 32.4 %

Procedure:
In Example 1, 1.6063 g (42.33 mmol) of lithium aluminum hydride (LAH) was suspended in 100 mL of tetrahydrofuran (THF) in a 250 mL round bottom flask (RBF) under the presence of argon gas (99.999% purity) and was cooled to 0° C. in an ice bath. 5.0946 g (36.62 mmol) of 2-hydroxynicotinic acid was slowly added, and the solution returned to room temperature before being refluxed for 8 h. The reaction was cooled to room temperature and was quenched with 1.6 mL of water, 1.6 mL of 15% NaOH and an additional 4.8 mL of water. The solvent was removed in vacuo and the residue was taken up in 100 mL of refluxing ethanol. The solution was filtered through celite and the solvent removed in vacuo to produce 1.4848 g (32.40% yield) of 3-hydroxymethyl-2-pyridone. Characterization data of the product was consistent with literature.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[C:23]1([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[B-]C#N.[Na+].O>CO>[C:23]1([C@@H:29]2[CH2:31][C@H:30]2[NH:32][CH2:1][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][C:10]3[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=3)[CH2:5][CH2:4]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (6.7 g, 22.08 mmol) in methanol (50 mL) was added (1R,2S)-2-phenylcyclopropanamine (3.53 g, 26.5 mmol). The reaction mixture was refluxed for 5 minutes then cooled down to the room temperature. Sodium cyanotrihydroborate (2.082 g, 33.1 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organics were washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added slowly as a solid crashed out. The solid was filtered and suspended in isopropanol. The suspension was sonicated and filtered. tert-Butyl 4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (5.8 g, 13.65 mmol, 61.8% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.07 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.08 Hz, 2H), 7.28-7.37 (m, 2H), 7.10-7.28 (m, 3H), 4.43 (br. s., 2H), 3.54 (d, J=10.86 Hz, 2H), 3.08-3.26 (m, 4H), 3.03 (dt, J=3.76, 7.39 Hz, 1H), 2.54-2.71 (m, 1H), 2.03-2.29 (m, 3H), 1.67-1.84 (m, 2H), 1.58-1.67 (m, 10H), 1.40 (q, J=6.82 Hz, 1H); LC-MS Rt=0.76 min; MS (ESI): 421.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 75.75 gm. (0.307 mole) of 4-chloro-3,5-dinitrobenzoic acid and 64.0 gm. (0.307 mole) of phosphorus pentachloride is heated at reflux for ninety minutes and cooled to room temperature. The phosphorus oxychloride is removed by distillation in vacuo The residue is washed with Skellysolve "B" and the solvent removed by decantation. The oily residue is recrystallized from benzene-cyclohexane. There is obtained 58.2 gm. (72%) of tan needles melting at 55°-57°.
Reaction SMILES: Cl.[Si]([O:19][CH2:20][C@H:21]([NH:34]C(=O)OC(C)(C)C)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@H:25]2[NH:34][C@@H:21]([CH2:20][OH:19])[CH2:22][O:23][CH2:24]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1ccc(Cl)cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (18 mL) was added to tert-butyl {(R)-1-(tert-butyldiphenylsilanyloxymethyl)-2-[2-(4-chlorophenyl)-2-oxoethoxy]ethyl}carbamate (960 mg) under ice-cooling. The reaction solution was stirred under ice-cooling for 30 minutes and subsequently at room temperature for 30 minutes, and then concentrated under reduced pressure. Platinum oxide (37.4 mg) was added to a solution of the resulting residue in methanol (18 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for one hour. The reaction solution was filtered through celite. A saturated sodium bicarbonate solution and ethyl acetate were added to the filtrate, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain a crude product. A 1 M solution of tetrabutylammonium fluoride in THF (0.947 mL) was added to a solution of the resulting crude product in THF (5 mL), and the reaction solution was stirred at room temperature for one hour. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 86 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:16][CH:5]1[CH2:6][N:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9][N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2cnccn2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(c2cnccn2)CC1Br
Reaction time: 8 h

Procedure:
4-Isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.0 g, 4.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was placed on an ice-bath and brominated according to literature (Tetrahedron 44,10,1988, 2977-2984) in very bad yield. N-Bromosuccinimide (3.45 g, 19.4 mmol) was added slowly at 0° C. and then left overnight at rt. No reaction was observed. An additional 3.45 g of N-bromosuccinimide was added during 8 h, and then the reaction mixture was left at rt for 2 days. Aqueous concentrated Na2CO3 was added and the mixture was extracted with dichloromethane (3×75 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The oily residue was purified on a silica gel column with dichloromethane/MeOH (9:1) as eluent. Yield: 196 mg (28%) of 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(N(CC)CC)C>O1CCOCC1>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: ON=Cc1ccccc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
To a solution of benzaldehyde (2.0 g, 19 mmol) in 1,4-dioxane (6.0 ml) was added hydroxylamine hydrochloride (1.3 g, 19 mmol) and triethylamine (2.6 ml, 19 mmol). The mixture was sonicated for 0.5 h and stirred at room temperature for 116 h and at 35° C. for 24 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water, dried (MgSO4), filtered and evaporated in vacuo affording 1.9 g (84%) of benzaldehyde oxime as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[CH2:10]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2c(c1)CC(CN1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (170 mg, 0.70 mmol), NaBH3CN (84 mg, 1.3 mmol) and HOAc (80 mg, 1.3 mmol) in 50 mL MeOH was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (235 mg, 1.3 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=7.8 Hz, 1H), 7.46˜7.51 (m, 4H), 7.34 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.48 (d, J=7.0 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.21 (s, 2H), 2.69˜3.09 (m, 11H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[C:4]([C:20]#[CH:21])([OH:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:7][CH:6]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[C:4]([CH2:20][CH3:21])([OH:19])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: C#CC(O)(c1ccc(OCCN(CC)CC)cc1)c1cc(C)ccc1C
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cc(C)ccc2C)cc1

Procedure:
10.5 g. of 2,5-dimethyl-4'-[2-(diethylamino)-ethoxy]-α-ethinyl-benzhydrol are dissolved in 110 ml. of methanol, and 0.5 g. of a 10% palladium-on-charcoal catalyst are added to the mixture. The reaction mixture is hydrogenated until the uptake of the calculated amount of hydrogen is complete. Thereafter the catalyst is filtered off, and the solvent is evaporated in vacuo. Recrystallization of the solid residue obtained from a mixture of n-hexane and ethyl acetate yields 9.1 g. of the title compound, melting at 89° to 90° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([S:24]([CH3:23])(=[O:26])=[O:25])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 8 mmol) in dichloromethane (10 mL) was added triethylamine (1.30 mL, 8.8 mmol) followed by methanesulphonyl chloride (0.68 mL, 8.8 mmol). After stirring for 16 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography using 50% ethyl acetate in petroleum ether as the eluent to yield 4-(methanesulfonyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.85 g, 75%). Treatment of this compound with trifluoroacetic acid in dichloromethane yielded N-methyl-N-piperidin-4-yl-methanesulfonamide, which was isolated as the TFA salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([N:16]([CH2:27][CH3:28])[CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:15]>C1COCC1.CC(O)C>[CH2:27]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccc(OCCN(CC)CC)cc2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of 1.013 g (5 mmol) of 2-chloro-4-(ethylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After removal of the solvent, the residue is dissolved in aqueous acetic acid and filtered through celite. The aqueous solution is then basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried to give 1.65 g (95%) of the title compound: mp (MeOH) 134–136° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 1-(4-tert-butylphenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 447.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O.N1C(C)=CC=CC=1C>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Nc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: FCCNc1cccc(F)c1
Yield: 10.1 %

Procedure:
3-Fluoroaniline (1.4 g, 11.6 mmol, 1.2 mL) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) and lutidine (1.24 g, 11.6 mmol) were stirred and heated in DMF (5 mL) at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 184 mg (10%) of (2-fluoro-ethyl)-(3-fluoro-phenyl)-amine (43) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.37 (1H, q, J=6 Hz, NCH2CH2F), 3.46 (1H, q, J=6 Hz, NCH2CH2F), 4.12 (1H, s, br, NH), 4.54 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.31-6.50 (3H, m, NCCHCHCH), 7.10-7.25 (1H, m, NCCHCF).