Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:23]1[O:25][CH2:24]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[OH:25][CH2:24][CH2:23][N:11]1[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:20])[CH2:9][C:10]1=[O:19]
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 28.6 gm (0.1 mol) of 5-phenyl-7-chloro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione, 500 ml of methanol, 25 ml of water, 10-15 ml of ethyleneoxide and 1 ml of Triton B (methanolic 35% solution of benzyl trimethylammonium hydroxide) was stirred at room temperature for about eight hours. Thereafter, the clear solution formed thereby was evaporated, the residue was taken up in methylene chloride, and the resulting solution was extracted with water, dried and evaporated. The residue was recrystallized from ethanol, yielding 25.6 gm (78% of theory) of the colorless crystalline compound of the formula ##SPC6##
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: O=C(c1cncc(Cl)n1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C(c1cncc(-c2cnc3[nH]ccc3c2)n1)N1CCCCC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and (6-chloropyrazin-2-yl)(piperidin-1-yl)methanone (75) (41 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(piperidin-1-yl)methanone 138 in 10 mg quantity. The compound 138 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 8.80 (m, J=87.55 1H), 8.60 (d, J=1.82, 1H), 7.42 (m, J=3.17, 1H), 6.64 (m, J=1.58, 1H), 3.87 (s, 2H), 3.59 (m, J=88.29, 1H), 1.75 (s, 4H), 1.69 (m, J=24.99, 2H); MS m/z 307.9 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:39])([F:38])[S:22]([O:25][C:26]1[C:35]([CH2:36]O)=[CH:34][C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)(=[O:24])=[O:23].C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[F:20][C:21]([F:39])([F:38])[S:22]([O:25][C:26]1[C:35]([CH2:36][Br:41])=[CH:34][C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)(=[O:24])=[O:23]
Reactant: BrC(Br)(Br)Br
Reactant: O=S(=O)(Oc1cc2c(cc1CO)CCCC2)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc2c(cc1CBr)CCCC2)C(F)(F)F

Procedure:
Triphenylphosphine (46.8 mg, 0.178 mmol) was added to a stirred solution of 3-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (46.1 mg, 0.149 mmol) and carbon tetrabromide (59.2 mg, 0.178 mmol) in dry CH2Cl2 (1 mL) at 0° C. under N2. The reaction mixture was loaded directly onto a column and purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 3-(bromomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate, as a colorless solid. Rf=0.95 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.21 (s, 1H); 7.01 (s, 1H); 4.48 (s, 2H); 2.81-2.74 (m, 4H); 1.83-1.78 (m, 4H).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>>[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH:20][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)=C(Cc1ccccc1)C2
Agent: Cl
Product: CCCC(=O)NCCC1=C(Cc2ccccc2)Cc2ccc(OC)cc21

Procedure:
Starting with 2-(2-benzyl-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and butyryl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 97%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)[N:5]=1.[CH2:25](I)[CH3:26]>CN(C=O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)[N:5]=1
Reactant: CCI
Reactant: CC(=O)Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 12 h
Yield: 12.9 %

Procedure:
NaH (95%, 0.005 g, 0.21 mmol) was added slowly at RT to a solution of N-[4-(4-Bromo-1-oxo-1H-phthalazin-2-yl)-phenyl]acetamide (0.070 g, 0.20 mmol) in DMF (2 ml). Stirring was continued for 1 h before ethyl iodide (0.046 g, 0.29 mmol) was added. Stirring was continued for 12 h before the solvent was evaporated in vacuum. The resulting raw product was purified by chromatography over silica gel with heptane:EtOAc (3:1 up to 1:1) to give the title compound (0.010 g, 14% yield). MS (ESI+)=388.22 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]1.ClCC[CH2:21][OH:22].[I-].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:21][OH:22])[CH2:13][CH2:14]1
Reactant: OCCCCl
Reactant: COc1ccccc1N1CCN(CCO)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCO)CC1
Yield: 46 %

Procedure:
3-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-propan-1-ol (29A) is prepared as described for 28A from 3-chloro-propan-1-ol with acetone as solvent and under addition of 1.66 g (10 mmol) potassium iodide. The mixture is heated to reflux.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:9]([C:10]1[CH:15]=[C:14]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=1)#[N:16]
Reactant: NCc1ccccc1
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: OCCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(NCc2ccccc2)c1
Yield: 79.2 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 3-iodobenzonitrile (229 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=5/1, Rf=0.5) afforded N-(3-cyanophenyl)benzylamine (165 mg, 80% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])=[N:3][CH:4]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)Nc1ccc(Br)cn1
Reaction time: 12 h

Procedure:
To a solution of 2-amino-5-bromo-pyridine (1.05 eq.) in TBF (0.2M) was added DBU (1.0 eq.) followed by iso-propyl-isocyanate (1.0 eq.). The mixture was stirred for 12 h, diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated. Crystallization from acetone afforded the title compound as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:3][C:2]#[CH:1])=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CCBr
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)CCCCCc1ccccc1

Procedure:
Two milliliters of a dry N,N-dimethylformamide solution of 618 mg of propargyl bromide is added by drops to a mixture of 1 g of 6-phenylhexanoic acid, 862 mg of potassium carbonate and 20 ml of dry N,N-dimethylformamide at room temperature with stirring. After stirring for 24 hours, the resultant solution is poured into an aqueous saturated ammonium chloride solution cooled with ice. The resulting mixture is then extracted twice with diethyl ether. The extracts are combined, washed with water and then with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is subjected to chromatography on silica gel to obtain propargyl 6-phenylhexanoate.
Reaction SMILES: [O:1]([C@H:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[O:1]([C@H:8]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)Oc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of (S)-methyl 4-(1-phenoxyethyl)benzoate (0.7 g, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give (S)-4-(1-phenoxyethyl)benzoic acid (0.5 g, 76%).
Reaction SMILES: Cl.Cl.[CH:3]([N:16]1[C:20]([C:21]([CH2:23]CC)=[S:22])=[CH:19][N:18]=[CH:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH:3]([N:16]1[C:20]([C:21]([CH3:23])=[S:22])=[CH:19][N:18]=[CH:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC(=S)c1cncn1C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(=S)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
by reaction with sodium propyl mercaptide and acidification with HCl: 1-benzhydryl-5-n-propylthiocarbonyl-imidazole-hydrochloride, m.p. 140° C.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1>CO>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C#CC2CC2)c(N)c1
Solvent: CO
Product: CS(=O)(=O)c1ccc(CCC2CC2)c(N)c1
Yield: 34.6 %

Procedure:
The title compound of step 1 (1.2 g) was hydrogenated in MeOH (45 mL) in a manner similar to Example 312, step 2. Preparative HPLC gave the title compound (422 mg, 41%). 1H NMR (CDCl3, 400 MHz): δ 7.19-7.13 (m, 3H), 2.95 (s, 3H), 2.60-2.56 (m, 2H), 1.50-1.44 (m, 2H) 0.68-0.65 (m, 1H), 0.43-0.38 (m, 2H), 0.03-0.01 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[F:9][C:10]1([F:20])[CH2:15][O:14][C:13]([CH3:19])([C:16](O)=[O:17])[CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:20][C:10]1([F:9])[CH2:15][O:14][C:13]([CH3:19])([C:16]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: OCc1ccccn1
Reactant: CC1(C(=O)O)CCC(F)(F)CO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C(=O)OCc2ccccn2)CCC(F)(F)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of pyridin-2-ylmethanol (91 mg, 0.833 mmol), 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (100 mg, 0.555 mmol), HBTU (274 mg, 0.722 mmol) and DIEA (0.2 ml, 1.145 mmol) in DCM (2 mL) was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc and washed with NaHCO3, brine, dried (MgSO4), concentrated and the residue was purified by silica gel chromatography (EtOAc/hexane) to afford pyridin-2-ylmethyl 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylate as racemate. Two enantiomers (elute-1 @ 4.04 min and elute-2 @ 4.61 min) were separated by chiral SFC (Chiralpak AD-H preparative column, 20×250 mm, 5 μm, mobile Phase: 10% 2:1 heptane:EtOH in CO2, 150 bar; temp: 35° C.; flow rate: 45 mL/min, UV: 258 nm).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20].[OH-].[Na+]>C(Cl)Cl.O>[CH2:19]([O:21][C:22](=[O:23])[NH2:9])[CH3:20].[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Agent: NCCc1[nH]c2ccccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(N)=O
Reaction time: 0.17 h

Procedure:
To a solution of 18.9 g 3-phenyl-1H-indol-2-ethanamine in 220 ml methylene chloride are added 15.3 ml of chloroformic ethyl ester followed by 110 ml water. The mixture is stirred for 10 minutes. 6.4 g sodium hydroxide in 100 ml water are added and stirring is continued for further 20 minutes at room temperature. The organic phase is separated, washed once with 2N tartaric acid and water, dried and evaporated under reduced pressure. The oily residue of the heading compound is used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)Cl.[BH4-].[Li+]>C1COCC1>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1nc(-c2ccccc2)nn1-c1ccccn1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccccc2)nn1-c1ccccn1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
A solution of 2-(3-phenyl-1-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)acetonitrile (28 mg, 96.4 μmol) in THF (1.5 mL) was, under argon atmosphere, cooled to 0-5° C. Trimethylchlorosilane (83.8 mg, 98.6 μL, 772 μmol) and lithium borohydride (2M solution in THF, 193 μL, 386 μmol) were consecutively added very slowly. The ice bath was removed after 10 min and the mixture was stirred at 60° C. for 1.5 h. The reaction mixture was cooled to 0-5° C. and MeOH (1 mL) was added slowly (bubbling!). After the temperature adjusted to RT, the mixture was poured into NaOH (1M aqueous solution, 15 mL) and was extracted with dichloromethane (2×25 mL) and ethyl acetate (1×25 mL). The combined organic phase was dried over MgSO4, filtered and evaporated to give the product as yellow waxy solid (18 mg, 67.8 μmol, 70%) which was used without further purification for the next step.
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][N:9]1CCOC[CH2:10]1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].Cl.CNC.C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:8][N:9]([CH3:10])[C:29](=[O:31])[CH2:28][N:25]1[C:26](=[O:27])[N:21]2[CH:20]=[N:19][C:18]([C:15](=[O:17])[NH2:16])=[C:22]2[N:23]=[N:24]1
Reactant: CN1CCOCC1
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Agent: CC(C)OC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. After 1 hour, dimethylamine hydrochloride (0.171 g, 2.100 mmol) and then triethylamine (0.292 mL, 2.100 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 40 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL) then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane) and preparative HPLC to furnish the title compound. Yield: 23 mg, 0.082 mmol, 8%. LCMS (ES+) m/z 266 (M+H)+ at 0.80 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (1H, s), 7.86 (1H, br s), 7.72 (1H, bs), 5.33 (2H, s), 3.10 (3H, s), 2.86 (3H, s).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[CH3:17]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=1[CH3:17]
Reactant: CC[C@H](O)C(=O)OC
Reactant: Cc1cc(O)ccc1Cl
Product: CC[C@@H](Oc1ccc(Cl)c(C)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenol instead of the m-cresol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+].CN(C)C=O.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[N:1]1([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1H-pyrazole (422 mg, 6.21 mmol, 1.50 equiv), sodium hydroxide (248 mg, 6.20 mmol, 1.50 equiv), and N,N-dimethylformamide (20 mL). The mixture was stirred and heated to 80° C. for 30 min, then to this was added 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110° C. in an oil bath. The resulting solution was diluted with 50 mL of H2O. The solids were collected by filtration and dried in an oven. The product was obtained as 0.43 g (62%) of a white solid.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)CCC>[N:10]1([CH2:9][CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(CCN1CCCCC1)c1ccccc1-c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 2.25 g of 3-p-biphenylyl-butylamine, 1.38 g of potassium carbonate, 2.53 g of 1,5-dibromopentane and 15 ml of n-butanol is boiled for 24 hours, while stirring. The mixture is filtered and the filtrate is evaporated and worked up in the customary manner to give 1-piperidino-3-p-biphenylylbutane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCCCCCO)c1ccc(F)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
1.0 g (8.53 mmole) of 6-aminohexanol is dissolved in a mixed solution of 17 mL of methylene chloride and 3.6 mL (26 mmol) of triethylamine. After 1 mL (8.53 mmol) of p-fluorobenzoyl chloride is slowly added at 0° C., ice-bath is ended to raise temperature to a room temperature for reaction for 12 hrs. After the reaction, cold water is added to stop the reaction and 20 mL of methylene chloride is used to extract an organic layer to be dried with MgSO4, filtrated and concentrated. Then, re-crystallization is processed in a mixed solution of dichloromethane/n-hexane for obtaining a product of 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a weight of 1.83 g and a yield of 90%. The reactant is confirmed through NMR to be 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a result as follows:
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]([O:12][CH2:13][C:14]#[CH:15])=[O:11])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)(=O)C.C(N(CC)CC)C>O>[CH3:16][S:17]([O:1][CH:2]([CH2:9][C:10]([O:12][CH2:13][C:14]#[CH:15])=[O:11])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4])(=[O:19])=[O:18]
Reactant: C#CCOC(=O)CC(O)C(=O)OCC#C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOC(=O)CC(OS(C)(=O)=O)C(=O)OCC#C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
6.10 g (0.029 mol) of the obtained di(2-propynyl) 2-hydroxysuccinate and 3.32 g (0.029 mol) of methanesulfonyl chloride were added to 40 g of ethyl acetate, and 2.93 g (0.029 mol) of triethylamine was dropwise added thereto within a range of from 5° C. to 15° C., taking 15 minutes. This was reacted at room temperature for 1 hour, the disappearance of the starting materials was confirmed through gas chromatography, and 20 ml of water was added for liquid-liquid separation. The organic layer was concentrated under reduced pressure. The residue was purified through column chromatography (Wakogel C-200, elution with hexane/ethyl acetate=2/1) to give 4.50 g (yield 54%) of the intended di(2-propynyl) 2-(methanesulfonyloxy)succinate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[NH:4][C:3]([C:2]([F:7])([F:6])[F:1])=[N:5][CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: N=C(N)C(F)(F)F
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1
Temperature: 25 °C

Procedure:
324 mg (purity 85%, 2.5 mmol, 3 eq.) of 2,2,2-trifluoroethaneimidamide were added to a suspension of 200 mg (0.82 mmol) of 2-bromo-1-(4-nitrophenyl)ethanone and 500 mg of sodium sulphate in 10 ml of acetonitrile, and the mixture was treated in an ultrasonic bath for 1 h and then stirred at RT. The sodium sulphate was then filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 104 mg (49% of theory)