Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=[N:12][OH:13])=[N:6][CH:7]=1
Reactant: Cc1cc(C=O)ncc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at room temperature. The white solid was filtered off and the solution concentrated in vacuo to afford the crude title product (2.2 g, white solid), which was used directly for the next step. LCMS (Method F) 2.09 min, M+H 564/566.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O.[CH2:9]([N:24]=[C:25]=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCCC>C(O)COCCO>[CH2:9]([N:24]=[C:25]=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCN=C=O
Reactant: OCCCCCCO
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCCN=C=O

Procedure:
Following the procedure described in preparation 4, but using 1,6-hexanediol and n-pentadecylisocyanate, instead of diethylene glycol and n-heptadecylisocyanate respectively, the title compound was obtained in a similar yield.
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N.Cl>C1COCC1.O>[C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:12]2[CH:13]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH2:39])=[O:28])[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:15]=[CH:10][C:11]/1=2)/[CH3:4])#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCc1nc2c(C(=O)O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2c(C(N)=O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
[step 5] (E)-1-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-2-propyl-1H-benzo[d]imidazole-4-carboxylic acid (97 mg, 0.20 mmol) obtained in step 4 was dissolved in THF (1.0 mL), 1,1′-carbonyldiimidazole (130 mg, 0.80 mmol) was added, and the mixture was stirred at 50° C. for 4 hr. After cooling to room temperature, 25% aqueous ammonia solution (55 μL, 0.80 mmol) was added, and the mixture was stirred at room temperature for 17 hr. To the mixture were added 1 mol/L hydrochloric acid and water, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-93/7 v/v) to give the title compound (97 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:20]1([C:23]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.[S].C(O)(=O)C>C(O)C>[CH:20]1([C:23]2[N:28]=[C:27]([C:29]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: O=Cc1cccc(C2CC2)n1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (250 mg, 0.686 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (55 mg, 0.823 mmol), sulfur (43 mg, 1.372 mmol) and acetic acid (1.5 mL) at room temperature. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organics were concentrated under reduced pressure and the crude material was purified via preparative TLC (80% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (180 mg). MS (ES+APCI) (M+H) 392.2; LCMS retention time 3.757 min (Method J).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6](=[NH:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:19][CH:20]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=[CH:20][N:14]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=CCCl
Reactant: COc1cccc(C(=N)Nc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cccc(-c2nccn2-c2ccccc2)c1
Yield: 75.5 %

Procedure:
To a 500 mL round bottom flask was added 3-methoxy-N-phenylbenzimidamide (7.81 g, 34.5 mmol), 2-chloroacetaldehyde solution (50%, 9.4 mL, 69 mmol), sodium bicarbonate (5.80 g, 69 mmol), and 150 mL 2-propanol. The reaction mixture was heated at reflux for 3 h under nitrogen. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 50% and 100% ethyl acetate/hexane to give pure product (6.52 g, 75%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Mg].[CH2:6]([C:9]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8]>CCOCC>[CH2:6]([C:9]1([CH:13]([OH:14])[CH2:3][C:2]#[CH:1])[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: C#CCBr
Reactant: CCCC1(C=O)CCC1
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)C1(CCC)CCC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 250.6 %

Procedure:
Propargyl bromide (0.27 mL, 2.4 mmol) was added to a mixture of magnesium (1.1 g, 45 mmol) and mercuric chloride (30 mg, 0.117 mmol) in Et2O (60 mL). The mixture was warmed to 40° C. until bubbling commenced. The remainder of the propargyl bromide (2.1 mL, 19 mmol) was added in small portions. After −1.5 h the reaction became cloudy white. A solution of the aldehyde 3 (0.8 g, 7 mmol) in Et2O (4 mL) was added and the reaction was stirred for 16 h. The reaction was then quenched by cautiously adding saturated aqueous NH4Cl. The resultant mixture was extracted with Et2O. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 1:1 pentane/CH2Cl2) gave 1.0 g (94%) of the alcohol 4.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:21])[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[C:35]([C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:34]=[C:33]([CH2:43][CH3:44])[CH:32]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:43]([C:33]1[CH:32]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][N:9]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)[CH3:21])=[O:28])[CH:36]=[C:35]([C:37]2[N:41]([CH3:42])[N:40]=[N:39][N:38]=2)[CH:34]=1)[CH3:44]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CN(C[C@@H]1CCCC[C@H]1N)C1CCc2cc(F)ccc2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CN(C)C2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A mixture of N-(2RS)-{[(1S,2R)-2-aminocyclohexyl]methyl}-6-fluoro-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 206 μmol), phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (52 mg, 206 μmol), triethylamine (57 μL, 412 μmol) and acetonitrile (2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium hydroxide (1.0 N), dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (40 mg, 37%) which was a mixture of two diastereomers by NMR.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:12]1[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:7]2=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34](C)C.Cl.NO>O1CCOCC1.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:13]1[C:12]2[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([C:1]1[O:3][N:34]=[CH:33][CH:2]=1)[CH:5]=2
Reactant: CC(=O)c1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4ccno4)ccc3n2Cc2cccc(F)c2)C1
Temperature: 40 °C

Procedure:
Combine (R)-N-[6-Acetyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 191) (0.055 g, 0.14 mmol) and dimethylformamide dimethylacetal (0.81 g, 6.8 mmol) and heat at 100° C. for 82 h. Concentrate in vacuo and treat the resulting residue with hydroxylamine hydrochloride (0.012 g, 0.18 mmol) in dioxane at 23° C. for 1 h before warming to 40° C. briefly. Dilute with water and collect 0.029 g of a solid by filtration. Recrystallize from EtOAc/hexanes to yield a light yellow solid. mp: 238-241° C.; MS (ES): m/z 432 (M+1); HPLC: Rt=2.59 (85%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[CH2:12]([O:19][C:20](=[O:23])[NH:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:22][NH:21][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:23])[CH2:8]2
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: CCO
Product: O=C(NN=C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 101.5 %

Procedure:
Under an argon atmosphere, a solution of 2-adamantanone (1.00 g, 6.70 mmol) in ethanol (40 mL) was added with benzylcarbazate (1.11 g, 6.70 mmol) at room temperature and the resultant was stirred at 80° C. for 12 hours. The reaction solution was concentrated in vacuo, and benzyl 2-(adamantan-2-ylidene)hydrazinecarboxylate (2.03 g, quant.) was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]([NH:11]C(=O)OC(C)(C)C)=[N:9][CH:10]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CCC#N)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-(2-cyanoethyl)pyrazin-2-ylcarbamate (25 mg, 0.101 mmol) in DCM (0.336 mL) was added TFA (0.1 mL, 1.298 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After quenched with sat. NaHCO3, the reaction mixture was extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 149.1 (MH+), 0.24 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112 %

Procedure:
To a stirred solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (20 g, 0.07 mol) in EtOH (300 mL) was added a solution of KOH (20.7 g, 0.37 mol) in water (100 mL) at RT. The reaction mixture was then stirred for additional 1 h at RT and then concentrated in vacuo. The residue was acidified to pH˜2 using 2 N HCl and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)acetic acid (19 g, 98%) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](NCCC)=[CH:18]2.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: CCCNc1cc2cc(F)ccc2[nH]1
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4[nH]ccc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 2-(1H-indol4-yloxy)ethylchloride (0.7 g, 3.6 mmol), 5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (5%-10% methanol-methylene chloride) afforded 0.54 g (43%) of product as a white solid: mp 70-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][C:13](=[O:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere 16.76 g of (3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F2) are dissolved in 300 ml of tetrahydrofurane, the solution is cooled to −78° C., and 75 ml of 1 M solution of potassium tri-sec-butylborohydride in tetrahydrofurane is added dropwise. After stirring for further 1 h, a mixture consisting of 30% hydrogeneperoxide solution and phosphate buffer solution is added. Stirring is continued for further 10 min, the reaction mixture is diluted with 400 ml of ethyl acetate and the aqueous layer is extracted with ethyl acetate, the combined organic phases are concentrated to give a foam, which is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 1/1 to furnish 10.18 g (60% of theory) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NC2CCNCC2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a stirred solution of 4-(5-methanesulfonyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.8 mmol, 1.0 equiv) in ethanol (18 mL) was added 4 M HCl in dioxane (3.52 mL, 14.1 mmol, 5.0 equiv) drop by drop and the reaction mixture stirred at 50° C. for 2 h. It was then cooled down to rt, poured into ice water and the pH adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted six times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure and the crude product was purified by crystallization from heptane to give 0.53 g (74%) of the title compound as colorless solid. MS (ISP): 256.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:20]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:19])#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: C#CCCCCCCCCCCC
Reactant: CCOC(=O)C(Cc1ccccc1Br)C(=O)OCC
Product: CCCCCCCCCCCC#Cc1ccccc1CC(C(=O)OCC)C(=O)OCC
Yield: 30.3 %

Procedure:
Reaction of diethyl(2-bromobenzyl)propan-1,3-dioate (11.87 g, 30 mmol) with 1-tridecyne (11.10 g, 45 mmol) as described in example 3 gave 3.89 g (29%) of the title compound as a pale yellow oil after chromatography. It had νmax (film) 1735, 1755, 2840, 2920 cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.08 (6H, t, J 7 Hz, ester CH3), 1.28 (18H, m, alkylene chain), 2.42 (2H, t, J 6 Hz, C≡C--CH2), 3.31 (2H, d, J 7.5 Hz, ArCH2), 3.90 (1H, t, J 7.5 Hz, methine H), 4.12 (4H, q, J 7.5 Hz, ester CH2), 7.15 (3H, m, aromatics), 7.36 (1H, m, aromatic). M+ 428.2928 (C27H40O4 requires; 428.2926).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7].[NH2:13][CH2:14][CH2:15][C:16](O)=O.[ClH:19]>O>[OH2:1].[ClH:12].[ClH:19].[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=[C:16]1[CH2:15][CH2:14][NH2:13].[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=[C:16]1[CH2:15][CH2:14][NH2:13].[ClH:12].[ClH:12]
Reactant: NCCC(=O)O
Reactant: Nc1ccc(Cl)cc1NCCO
Agent: Cl
Solvent: O
Product: NCCc1nc2ccc(Cl)cc2n1CCO
Reaction time: 24 h

Procedure:
A mixture of 9.7 g. (52 mmole) 2-(2-hydroxyethylamino)-4-chloroaniline, 6.9 g. (78 mmole) β-alanine, 46 ml. concentrated hydrochloric acid and 54 ml. of water is heated at reflux with stirring for 24 hrs. After cooling, the solution is concentrated, and made basic with 10% aqueous sodium hydroxide. Continuous liquid-liquid extraction of the aqueous solution with ethyl acetate affords 9.9 g. of the product, which is converted to it hydrochloride salt. The product has a m.p. of 196°-200° C. after recrystallization from methanol/ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-bromoethyl)-1-nitrobenzene (1 eq) in tetrahydrofuran was added morpholine (3 eq) and stir for 16 h at ambient temperature. Concentrating and passing through a plug of silica gave 4-[2-(4-nitrophenyl)ethylmorpholine. MS: MH+=236.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([O:33]CC)=[O:32])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)c2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
To 107 mg of ethyl 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 100 mg of 3-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoic acid as a colorless foamy substance. ESI+: 565
Reaction SMILES: C[N:2](/[CH:4]=[N:5]\[C:6](=O)[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:15]=[N:16][C:17]3[NH:22][CH2:21][C:20](=[O:23])[N:19]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([O:31][CH3:32])[CH2:27][CH2:26]4)[C:18]=3[N:33]=2)=[CH:9][N:8]=1)C.C(O)(=O)C.[NH2:39]N>O>[CH3:32][O:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:24][N:19]2[C:18]3=[N:33][C:14]([C:10]4[CH:9]=[N:8][C:7]([C:6]5[N:5]=[CH:4][NH:2][N:39]=5)=[CH:12][C:11]=4[CH3:13])=[CH:15][N:16]=[C:17]3[NH:22][CH2:21][C:20]2=[O:23])[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(=O)/N=C\N(C)C)cc4C)nc32)CC1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 0 °C

Procedure:
(Z)—N-((Dimethylamino)methylene)-5-(8-(((trans)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide (0.467 g, 1.00 mmol) was added to acetic acid (6 mL). The reaction was cooled to 0° C. and hydrazine (1.00 mL, 32 mmol) was added dropwise. The reaction was allowed to stir and warm to 25° C. over 10 min. Reaction was concentrated under a stream of nitrogen placed in reaction vessel. Water (5 mL) was added and the product was collected by filtration and purified using reverse-phase semi-preparatory HPLC (20-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.046 g, 0.106 mmol, 11% yield). 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 8.72 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 4.30 (s, 2H), 3.99 (d, J=7.03 Hz, 2H), 3.32 (s, 3H), 3.08-3.17 (m, 1H), 2.71-2.76 (m, 3H), 2.06 (br. s., 2H), 1.80-1.89 (m, 1H), 1.74 (br. s., 2H), 1.09 (d, J=11.32 Hz, 4H); MS (ESI) m/z 435.5 [M+1]+.