Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH:30]([CH3:34])[CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(CC#N)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(CC#N)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 53.1 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.33 g, 45.4 mmol), 3-(4-amino-piperidin-1-yl)-butyronitrile (hydrochloride salt) (50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 25 ml volume. This material was partitioned between water (200 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (11.3 g, 53% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.70 min, m+H=469.3. This material was used in the next step below without additional characterization.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Mg]Br>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH3:11])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1C(O)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 80 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, and then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and additional (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) was added. The mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with DCM. The layers were separated and the aqueous phase extracted twice with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of DCM and purified via silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min) gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellow liquid. 1H NMR (400 MHz, CD3OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H), 7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[I:11]I.CCO>C(O)C>[I:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: II
Reactant: c1csc(-c2cccs2)c1
Solvent: CCO
Product: Ic1ccc(-c2cccs2)s1
Yield: 186.1 %

Procedure:
33.2 g of 2,2'-bithiophene was dissolved in 50 ml of ethanol and I2 /EtOH (20.3 g/220 ml) was added. Then HIO3 /H2O (12 g/20 ml) were added slowly during 2 hours with stirring. The mixture was stirred for further 3 hours and the ethanol was evaporated. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After the solvent was removed, the crude product was vacuum distilled to give 5-iodo-2,2'-bithiophene 36.8 g (105°-110° C./0.1 mm-Hg). The yield is 65-70%. The residue was purified by silica column chromatography and yielded 5.36 g of 5,5'-diiodo-2,2'-bithiophene (6.4%) with melting point of 170° C.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)(=[O:4])=[O:3].[NH3:17]>C(Cl)Cl>[CH3:16][C:7]1[CH:6]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:17])[S:9][C:8]=1[CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14]
Reactant: N
Reactant: CC(=O)OCCc1sc(S(=O)(=O)Cl)cc1C
Solvent: ClCCl
Product: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
To a solution of the above prepared crude acetic acid 2-(5-chlorosulfonyl-3-methyl-thiophen-2-yl)-ethyl ester (53.3 g, ca. 177 mmol) in DCM (180 mL) were added 25% aqueous NH3 (53 mL, ˜700 mmol) and the biphasic reaction mixture was vigorously stirred at rt for 18 h. After the addition of DCM (1200 mL) the reaction mixture was washed with 10% brine (2×400 mL) and the aqueous layers were extracted with DCM (600 mL). The combined organic layers were dried (Na2SO4) and evaporated affording 48.5 g yellow crystalline residue which was crystallized from hot isobutyl acetate (500 mL) affording 34.8 g (74.7%, GC 97.9%) product as a off white powder. ESI-MS (m/z) 286 (M+Na+, 59); 264 (M+H+, 19).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:14](=[O:39])[NH:15][CH:16]([C:32](=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:16]([NH:15][C:14](=[O:39])[CH:9]([NH:7][CH3:6])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:32](=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:19][CH:20]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.25 h

Procedure:
[S-(R*,R*)]-{1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester (4.0 g, 7.24 mmol) was dissolved in CH2Cl2 (24 mL) and treated with trifluoroacetic acid (16 mL). The reaction was stirred for 15 minutes, then concentrated, diluted with EtOAc (300 mL), washed with bicarbonate solution (3×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 2.8 g (85%) of [S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=30:70→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (431 mg) in methanol (10 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (312 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:13]([CH:18]([CH2:21]O)[CH2:19][OH:20])[CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([C@@H:18]1[CH2:19][O:20][C@@H:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][CH2:21]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CO[C@H](c2ccc(C(F)(F)F)cc2)OC1

Procedure:
An equimolar mixture of p-trifluoromethylbenzaldehyde and 2-pentylpropane-1,3-diol in toluene is boiled on a water separator with catalysis by p-toluenesulfonic acid. When the water separation is complete and after conventional work-up, p-(trans-5-n-pentyl-1,3-dioxan-2-yl)-trifluorotoluene, m.p. 44.3°, Δε=+12.9, is obtained.
Reaction SMILES: [C:1]1([PH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:11])OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:23])([F:22])[CH2:20]I>>[F:18][C:19]([F:23])([F:22])[CH2:20][P:7](=[O:11])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCO[PH]([O-])(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)CI
Product: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl diphenylphosphonite (1.98 g; 5.8 mmol) and 2,2,2-trifluoroethyl iodide (6.1 g; 29 mmol) was stirred at room temperature under nitrogen for 24 hrs. The excess reagents were removed under vacuum. The residue was purified on silica gel using a 0-100% hexane-ethyl acetate gradient to give the target as a white powder (800 mg; 49%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (280 mg, 1.71 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (491 mg, 2.56 mmol) and 1-hydroxy-1H-benzotriazole (261 mg, 1.71 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (523 mg, 75%).
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])(O)=[O:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:7]([C:6]1[S:5][CH2:4][C:1](=[O:2])[N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]=12)#[N:8]
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCC(=O)O)=NCC2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)C1=C(C#N)SCC(=O)N1CC2
Reaction time: 48 h

Procedure:
To 3.2 g. of α-(carboxymethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 15 ml. of pyridine and 15 ml. of acetic anhydride are added. The solution is allowed to stand at room temperature for two days. 2.8 g. of 1-Cyano-9,10-dimethoxy-3,4,6,7-tetrahydro-1,4-thiazino[3,4-a]isoquinoline-4-one are obtained in a crystalline form. The product is identical with the product of Example 24.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH:14](OC)[O:15][CH3:16])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:20].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[OH:4][C:5]1[C:13]([CH2:14][O:15][CH3:16])=[CH:12][C:11]([I:19])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:20]
Reactant: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COCc1cc(I)c2c(c1O)CNC2=O
Yield: 85.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (200 mg, 0.379 mmol) was dissolved in nitromethane (10 mL), and the solution was treated with trifluoroacetic acid (0.584 mL, 7.58 mmol) and triethylsilane (0.612 mL, 3.79 mmol), followed y purification by slurry using chloroform to obtain 4-hydroxy-5-methoxymethyl-7-iodoisoindolinone (103 mg, yield-86%).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[CH2:27]([O:30]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:27](=[O:30])[N:10]2[CH2:11][C@H:6]1[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C(C)C)=C[C@H]2C(N)=O

Procedure:
The title compound was prepared from (2S,5R)-5-(allyloxyamino)-4-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (0.0981 g, 0.41 mmol) and N,N-diisopropylethylamine (Intermediate 42, 0.286 mL, 1.64 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a light yellow oil (69 mg, 63%).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:17][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NCc1ccc(C(C)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)Cl)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-(1-hydroxyethyl)phenylmethyl)acetamide (5.26 g) in chloroform (40 ml) was added dropwise a solution of thionyl chloride (2.1 ml) in chloroform (10 ml) at below 5° C. over 20 min. The mixture was stirred at 30° C. for 1 hr. The mixture was poured into a saturated sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (elution solvent; methanol:chloroform=4:96) to give the title compound (4.08 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15](Br)[CH:16]=[CH:17]3)=[CH:12]2)=[CH:6][CH:5]=1.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15]([C:32]#[C:31][CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:17]3)=[CH:12]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cn2cc3nc(Br)ccc3cc2=O)cc1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cc3nc(C#CCc4ccccc4)ccc3cc2=O)cc1

Procedure:
The coupling of 4-(7-bromo-3-oxo-2H-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester (0.35 g, 0.94 mmol) with 3-phenyl-1-propyne (0.29 mL, 2.35 mmol) using triethylamine (0.54 mL, 3.86 mmol), CuI (0.013 g, 0.07 mmol), and Pd(Ph3P)4 (0.043 g, 0.04 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification on a silica gel column eluted with hexane/ethyl acetate 2:1, followed by drying, will afford the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][C:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:1][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:36])(=[O:24])=[O:25]
Reactant: O=Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: C1CCNCC1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2cc(CN3CCCCC3)ccc21

Procedure:
The title compound was prepared from N-(5-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 5, Step F) and piperidine yielding a white solid. MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: [CH2:1](O)[C:2]#[N:3].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([NH:12][CH2:1][C:2]#[N:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCO
Reactant: NCc1ccccc1
Solvent: CO
Product: N#CCNCc1ccccc1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a stirred solution of glycollonitrile (25 g) in methanol was added dropwise over 45 minutes benzylamine (46.9 g) keeping the temperature of the reaction between 15°-20°. Following the addition the reaction mixture was kept overnight at room temperature, and then distilled to give benzylaminoacetonitrile (42.0 g) as a colourless oil, b.p. 120°/15 mm. Reaction of this (3.0 g) with 3,5-dimethylbenzoyl chloride (3.46 g) was described above gave crude N-benzyl-3,5-dimethylbenzoylaminoacetonitrile (5.81 g) as a colourless viscous oil which was used in the next stage without further purification. To this crude amide (2.0 g) in anhydrous methylene chloride (8 ml) was added sulphuryl chloride (0.97 g). Following the cessation of gas evolution (ca. 15 min.), anhydrous methanol (20 ml) and finely powdered anhydrous potassium carbonate (1.95 g) was added to the mixture which was then stirred for 30 minutes. Solids were removed from the solution which was then evaporated and the residual oil chromatographed on a column of silica using methylene chloride as an eluent. Following elution from the column and evaporation of the solvent, the product (1.2 g) was obtained as a very pale-yellow viscous oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Cn1nc(CON)c2c1C1CCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added 3-[(aminooxy)methyl]-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazole 149 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 150 (0.34 g, 83%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([SH:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:14][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)O)c1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: COc1cccc2c(=O)nc(-c3ccccn3)sc12
Temperature: 135 °C
Yield: 27.7 %

Procedure:
A mixture of 3-methoxy-2-mercaptobenzoic acid (1.84 g, 10.0 mmol), 2-cyanopyridine (1.05 g, 10.2 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 18 hrs as described in Example 9. The mixture was concentrated. The obtained crystals were recrystallized from ethanol to give the titled compound (0.75 g, 28%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([NH2:21])=[CH:23][CH:24]=1)#[N:10]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCNC(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.00 g (20.4 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride was dissolved in 50 ml of dimethylformamide. 6.2 ml (43.8 mmol) of triethylamine, 2.00 g (14.6 mmol) of p-aminobenzoic acid, 1.98 g (14.6 mmol) of 1-hydroxybenzotriazole and 2.80 g (14.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the solution at 0° C., and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the product was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Scheme 1, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with benzimidazole (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield methyl 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoate.