Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:14]
Reactant: NCCCCCO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: O=C(NCCCCCO)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-(2-Chloro-4-iodo-phenylamino)-N-(5-hydroxy-pentyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.40 mmol of 5-amino-pentan-1-ol. LC/MS [9.33 min; 461 (M+1)]
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][NH:9][C:10](=[O:26])[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([OH:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10](=[O:26])[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([O:14][Si:38]([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39])[CH3:13])=[O:7])=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 4-bromo-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (4.0 g, 8.6 mmol) in DMF (60 mL) were added imidazole (2.3 g, 33.8 mmol) and TBSCl (2.6 g, 17.2 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature gradually and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to give the title compound (4.68 g, 94%), which was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:47])[C@H:4]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[NH:5][C:6](=[O:38])[C@H:7]([CH:35]([CH3:37])[CH3:36])[NH:8][C:9](=[O:34])[C@H:10]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[N:11]([C:15](=[O:26])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])[N+:12]([O-:14])=[O:13].[OH-].[Li+].Cl>CO>[C:22]([O:21][C:19]([N:17]([CH2:16][C:15]([N:11]([N+:12]([O-:14])=[O:13])[C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:47])=[O:2])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=1)=[O:38])[CH:35]([CH3:36])[CH3:37])=[O:34])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])=[O:26])[CH3:18])=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 3 h

Procedure:
10.0 g of t-butoxycarbonylsarcosylnitroarginylvalyltyrosine methyl ester is dissolved in 30 ml of methanol. To this solution is added 60 ml of 1 N lithium hydroxide. The reaction mixture is stirred for three hours, then neutralized with 1 N hydrochloric acid to pH 7. The solvent is removed by vacuum and the residue is dissolved in N,N-dimethylformamide. The solution is filtered and the solvent removed by vacuum. The residue is dissolved in methanol/2-propanol. The alcohol solution is added to 1 liter of cold rapidly stirring ethyl ether. The white precipitate is filtered and dried in vacuo to afford t-butoxycarbonylsarcosylnitroarginylvalyltyrosine.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][C:14]1[N:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>O.C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2](=[O:10])[NH:13][C:14]2[C:15]([C:16]=1[NH2:17])=[CH:18][CH:19]=[CH:20][N:21]=2)=[O:5])[CH3:8]
Reactant: N#Cc1cccnc1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(N)c2cccnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.14 g. (0.18 g. atom) of sodium in 100 ml. of ethanol was added 28.8 g. (0.18 mole) of diethyl malonate. After stirring at room temperature for 5 minutes, 7.14 g. (0.06 mole) of 2-aminonicotinonitrile was added and the mixture was heated under reflux for 6 hours. The mixture was cooled and was diluted with 100 ml. of water and was acidified with conc. hydrochloric acid. On cooling, a precipitate was formed which was collected and was triturated with 1000 ml. of boiling ethanol. The mixture was filtered and the filtrate was cooled in ice to precipitate 2.9 g. of product, m.p. 264°-267° C. dec.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.O.[CH3:16][C:17]1[CH:33]=[CH:32][C:31]2[C:19](=[CH:20][C:21]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:22]=3[CH:30]=2)[CH:18]=1>C(Cl)(Cl)Cl>[CH:29]1[C:23]2[C:22]3[CH:30]=[C:31]4[C:19](=[CH:20][C:21]=3[S:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)[CH:18]=[C:17]([CH:16]=[O:9])[CH:33]=[CH:32]4
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc2cc3c(cc2c1)sc1ccccc13
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Yield: 22.8 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser and N2 inlet line with bubbler was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Aldrich, 38.6 g, 0.119 mol), H2O (100 mL) and CHCl3 (1500 mL). After refluxing the mixture for 15 min, 8-methylbenzo[b]naphtho-[2,3-d]thiophene (Cambridge Chemicals, Inc., 21.0 g, 89.6 mmol) was added to the flask. After refluxing the mixture for 5 h an additional portion of DDQ (19.3 g, 85 mmol) was added. The mixture was then refluxed overnight, cooled and the deep red solution filtered. The solvent was then removed by rotary evaporation and the residual H2O removed by azeotropic distillation with several portions of PhCH3. The material was then dissolved in PhCH3 (500 mL) and applied to a 40×10 cm column of SiO2 and eluted with additional PhCH3 as the solvent. The appropriate fractions were combined and the solvent removed to give 7.12 g of crude material. This was crystallized (PhCH3), filtered and dried to give 5.35 g (22.7% yield) of benzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde, mp 182°-185°, (C, H, S).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:2][CH2:3]1)=[O:28]
Reactant: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Synthesized from compound 26. To a solution of compound 26 (0.2 g, 0.6 mmol) in 5 mL of CH2Cl2 was added 1 mmol of TEA and 0.8 mmol of 2-trifluoromethyl-benzoyl chloride. The reaction was stirred overnight at room temperature. After the solvents were evaporated, the residue was purified with semi-preparative HPLC to afford a solid (15% yield). MP: 140-142° C.; MS (ES−): 469; 1H NMR (400 MHz, CDCl3): 1.92-2.10 (m, 2H), 2.91-3.10 (m, 4H), 3.36-3.44 (m, 2H), 3.64-3.74 (m, 2H), 3.93 (m, 2H), 7.38 (m, 1H), 7.57 (m, 3H), 7.79 (m, 2H), 7.93 (m, 1H). Anal. Calcd. for C23H21F3N6O2.0.9HCl: C, 54.89; H, 4.39; N, 16.70; Found: C, 54.93; H, 4.43; N, 16.34.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]([OH:15])[CH2:12][C:13]#[N:14])CC1C=CC=CC=1.[H][H].[ClH:18]>C(O)(C)C.[Pd]>[ClH:18].[CH3:1][NH:2][CH2:10][CH:11]([OH:15])[CH2:12][C:13]#[N:14]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)CC(O)CC#N
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CNCC(O)CC#N

Procedure:
4-(N-Methyl-N-benzylamino)-3-hydroxybutyronitrile, 5.1 g (0.02 mole) was dissolved in 40 ml of isopropanol and 0.5 g of 5% palladium on carbon was added to the solution. The mixture was subjected to hydrogen gas under about 55 psi for 18 hr at 60° C. Mass spectrometry of a sample taken from the mixture indicated no reduction had occurred. About 2.1 ml (ca. 0.02 mole) of 37% hydrochloric acid and 0.5 g of 5% palladium on carbon were added and the mixture was subjected to hydrogen gas under 50 psi for 18 hr at room temperature. Approximately 0.02 molar equivalents of hydrogen was absorbed. A sample taken for mass spectroscopy showed product (m/e 115) and a small amount of starting material (m/e 205) unreacted. The mixture was filtered and the filtrate was concentrated to a light yellow liquid weighing 4.73 g. Proton NMR analysis showed mainly 4-methylamino-3-hydroxybutyronitrile and a small amount of starting benzyl compound and solvent was present, NMR analysis is as follows: (D2O, ppm): 4.40 (multiplet, methine proton on carbon 3), 3.20 (multiplet, methylene protons on carbon 4 bearing the protonated amino groups), 2.80 (multiplet, methylene protons on carbon 2 and methyl protons on the amino group).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:39])[N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nnn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn(C)n2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of N-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (100 mg, 0.20 mmol) in dimethylformamide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) and methyl iodide (100 μL, 1.6 mmol) and the mixture was allowed to stir at rt overnight. The mixture was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (51 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.84 (s, 1H), 8.20 (d, 2H), 8.16 (d, 1H), 8.02 (d, 2H), 7.91-7.78 (m, 5H), 7.66-7.64 (m, 3H), 7.47 (d, 1H), 7.42 (ddd, 1H), 4.43 (s, 3H), 2.35 (s, 3H). MS (EI) for C30H24N8O: 513.3 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28](C)[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[CH3:34][O-].[Na+:36]>CO.C(Cl)(Cl)Cl>[CH3:25][C@@:17]12[C@H:12]3[CH2:11][CH:10]=[C:9]4[C@@H:27]5[CH2:28][C:2]([CH3:34])([CH3:1])[CH2:3][CH2:4][C@:5]5([C:31]([O-:33])=[O:32])[CH2:6][CH2:7][C@@:8]4([CH3:30])[C@:13]3([CH3:26])[CH2:14][CH2:15][C@H:16]1[C:21]([CH3:22])([CH3:23])[C@@H:20]([OH:24])[CH2:19][CH2:18]2.[Na+:36]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)CC[C@]2(C(=O)[O-])CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Reaction time: 0.5 h

Procedure:
30 mg of 3-O-(α-L-arabopyranosyl) ursolic acid was dissolved in methanol/chloroform (4 ml, 3/1), added with 5 mg of NaOMe, then stirred at room tempreature for 30 min and filtered to separate out a white solid. The solid was washed with methanol and dried to obtain 3-O-(α-L-arabopyranosyl) ursolic acid sodium salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (4.91 g; 17.1 mmol) is suspended in acetonitrile (25 ml) and N,N-diisopropyl ethyl amin (3.58 ml; 20.5 mmol) is added at 0° C. Bis(2-oxo-3-oxazolidinyl) phosphinic chloride BOP-Cl (5.22 g; 20.5 mmol) is added as a solid and after stirring for 30 min at 0° C. 4-chloroaniline (2.18 g; 17.1 mmol) is added to the reaction mixture. The mixture is stirred for 2 h at 0° C., evaporated to dryness and dissolved in ethyl acetate (ml). The organic phase is washed with 0.1 N HCl (2×ml), with saturated aquous Na2CO3 solution, water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 4.7 g (69.3%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:26].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O-:22])=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:26]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step C (90 mg, 0.26 mmol) in THF (3 mL) and H2O (1 mL) was added 1 N aqueous LiOH (0.31 mL, 0.31 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=325 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([CH3:11])([CH3:10])[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]1N1CCCCC1)[CH:2]=[CH2:3].C([O-])(=[O:22])C.[Na+].C(=O)(O)[O-].[Na+].N>C(O)(=O)C.O>[CH2:1]([CH:4]1[C:5](=[O:22])[CH2:6][C:7]([CH3:13])([CH3:12])[NH:8][C:9]1([CH3:11])[CH3:10])[CH:2]=[CH2:3]
Reactant: CC(=O)[O-]
Reactant: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1C(=O)CC(C)(C)NC1(C)C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
1.46 g of the 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine thus obtained were dissolved in a mixture of 3 ml of acetic acid, 1.5 g of sodium acetate and 3 ml of water, and the solution was allowed to stand overnight. To the solution were then added 6.0 g of sodium bicarbonate and 3 ml of concentrated aqueous ammonia; the mixture was then extracted with hexane. The extract was dried over anhydrous magnesium sulphate and then treated with charcoal. 0.91 g of the title compound was obtained after removal of the hexane. The compound showed a single spot on thin layer chromatography using a 0.25 mm thick layer of alumina and a mixture of benzene/hexane/ethyl acetate/triethylamine (2:2:1:0.5 by volume) as developing solvent; Rf value 0.70.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:22]O>>[CH2:5]([NH:12][C@@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@H]1CC[C@@H](NCc2ccccc2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](NCc2ccccc2)CC1

Procedure:
Thionyl chloride was added to a solution of compound cis-4-(benzylamino)cyclohexanecarboxylic acid (0.5 g, 2.1 mmol) in MeOH (7 ml) at 0° C. and the reaction mixture was heated at reflux for 18 h. Then volatiles were removed in vacuo and the reaction mixture was basified using saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 350 mg of cis-methyl 4-(benzylamino)cyclohexanecarboxylate (66%) as brown color solid.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)([CH3:4])=[O:3]>[Pd].CO>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CP(C)(=O)CN1CCNCC1
Temperature: 25 °C

Procedure:
To a flask was charged with benzyl 4-((dimethylphosphinoyl)methyl)piperazine-1-carboxylate (200 mg) and 10% palladium on carbon in methanol (20 mL). The mixture was stirred at room temperature under H2 atmosphere. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification. LCMS ESI(+) m/z: 177 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[N:15]=CC=N2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC1C(N2N=CC=N2)=[C:19](C=CC=1)[C:20]#[N:21]>>[CH3:1][C:2]1[C:3]([N:11]2[CH:19]=[CH:20][N:21]=[N:15]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1-n1nccn1
Reactant: Cc1cccc(C#N)c1-n1nccn1
Product: Cc1cccc(C(=O)O)c1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 82, substituting 3-methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile for 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile. 1H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.63-7.56 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7](=[N:18][OH:19])[NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[O:4][N:3]=1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[CH3:17])[C:25](=[O:26])[O:19][N:18]=2)[O:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1CNC(=NO)c1cc(N)no1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1Cn1c(-c2cc(N)no2)noc1=O
Temperature: 70 °C
Yield: 57.2 %

Procedure:
3-Amino-N-(5-chloro-2-methylbenzyl)-N′-hydroxyisoxazole-5-carboximidamide (0.320 g, 1.14 mmol) was dissolved in anhydrous THF (6 mL) followed by addition of N,N-carbonyldiimidazole (0.203 g, 1.25 mmol). The solution was heated at 70° C. for 1.5 h. and then concentrated and purified with silica gel chromatography (20% ethyl acetate/hexs) to give the desired product as a colorless oil (200 mg, 57%). LCMS calculated for C13H12ClN4O3(M+H)+: m/z=307.1.
Reaction SMILES: [K].[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][CH2:12][CH:13]=[CH2:14]>CO>[CH2:14]([N:5]1[CH:4]=[C:3]([Br:2])[CH:8]=[N:7][C:6]1=[O:9])[CH2:13][CH:12]=[CH2:11]
Reactant: O=c1ncc(Br)c[nH]1
Reactant: C=CCCBr
Agent: [K]
Solvent: CO
Product: C=CCCn1cc(Br)cnc1=O
Yield: 50 %

Procedure:
A mixture of the potassium salt of 5-bromopyrimid-2-one (0.01 mol) and 4-bromo-1-butene (0.015 mol) was heated in methanol (60 ml) at 70° C. for 40 h. The reaction mixture was then evaporated and the mixture extracted with chloroform. This solution was washed with 1 N NaOH (5 ml). with water (5 ml) and dried (MgSO4) before evaporating; yield 50%, m.p. 127°-128° C. (acetone). (Found: C, 42.06; H, 3.94. Calc. for C8H9BrN2O: C, 41.94; H, 3.96).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].CN([CH:14]=[C:15]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O)C>C(O)C>[CH3:35][S:34][C:30]1[N:29]=[C:28]([C:15]2[CH:14]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a mixture of cyanoacetamide (1.42 gm, 0.0169 mole) in ethanol (20 mL) was added a solution of sodium ethoxide (6.3 mL, 21 wt % solution, 0.0169 mole) in ethanol. The mixture was stirred for 5 minutes and dimethylamino-2-(2-methylsulfanylpyrimidin-4-yl)-1-(3-trifluoromethylphenyl)-prop-2-en-1-one (5.88 gm, 0.0160 mole) in ethanol (40 mL) added. The reaction was stirred for 18 hrs at room temperature and then concentrated to an oil. The oil was dissolved in ethyl acetate (50 mL) and water (50 mL) and the pH adjusted to 5.0 with a 10% solution of sodium hydrogen sulfate. The ethyl acetate layer was removed, dried over sodium sulfate, and concentrated to an oil. The oil was chromatographed on silica eluting with 5% acetone/dichloromethane to give 4.0 gm (68%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14](Cl)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:37])([F:38])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:39])([CH3:40])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(Cl)c1nccs1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1Cc1nccs1
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
(2R,5R)-5-(Chloro-thiazol-2-yl-methyl)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.03 g, 0.05 mmol), Pd/C (0.01 g, 0 mmol), triethylamine (0.01 g, 0.1 mmol) were dissolved in EtOAc (0.2 mL) and hydrogenated at room temperature and 1 bar for 30 minutes, followed by hydrogenation at 40 psi in a Parr hydrogenator for 1 h. The reaction was filtered and solids washed with EtOAc. The filtrate was concentrated and the crude product was purified by column chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60), to give the title compound (0.011 g). MS: [M+H]+=578.