Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Cl)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(CCO)C(=N)N
Reactant: CCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.66 mL (150 mmol) of acetyl chloride and 25 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 13.36 mL (50 mmol) of Octanoic acid is added in one portion and the reaction is slowly heated to about 60° C. for about 4 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield pure 2-(1-methylguanidino)ethyl octanoate.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])([C:28]([F:31])([F:30])[F:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([OH:6])=[O:40])([C:28]([F:29])([F:30])[F:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)(C(F)(F)F)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
A solution of sodium chlorite (120 mg; 1.32 mmol; 5 eq.) and sodium dihydrogenphosphate (127 mg; 1.06 mmol; 4 eq.) in water (2 mL) was added dropwise to a mixture of 2-methyl-2-butene (0.25 mL) and 3-(2-formyl-phenoxy)-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg; 0.26 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 3 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with EA (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (100 mg, quantitative) as a colourless oil. HPLC (max plot) 93.5%, Rt 4.22 min. UPLC/MS: (MS−) 374.3 ([M−H]−).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (2.5 g, 8 mmol) in CH2Cl2 (150 mL) was added mCPBA (70%, 2.36 g, 9.6 mmol) slowly at 0° C. The mixture was stirred at rt overnight. The resulting solution was diluted with 150 mL CH2Cl2 and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a white solid (2.6 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.37 (dd, J=1.3, 4.7 Hz, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.99-8.18 (m, 2H), 7.63 (dd, J=1.7, 8.5 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 339 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:21])[C:10]2=[O:28])=[CH:5][CH:4]=1.N[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>ClCCCl.ClCCl.CO>[Cl:27][C:24]1[S:23][C:22]([C:20]([NH:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17](=[O:18])[N:9]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:19][C:15]4[CH:16]=[CH:11][C:12]([C:36]5[CH:37]=[CH:32][CH:33]=[CH:34][N:35]=5)=[CH:13][CH:14]=4)=[CH:30][CH:29]=2)[C:10]3=[O:28])=[O:21])=[CH:26][CH:25]=1
Reactant: Nc1ccncc1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCc1ccc(CBr)cc1)C2=O)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: O=C(Nc1cccc2c1C(=O)N(CCc1ccc(CNc3ccc(-c4ccccn4)cc3)cc1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.1 mmol) of N-{2-[4-(bromomethyl)phenethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide are introduced a little at a time into a solution of 37.4 mg (0.4 mmol) of 4-aminopyridine in 4 ml 1,2-dichloroethane. The mixture is stirred at room temperature overnight and then diluted with dichloromethane/methanol (98:2), washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue is crystallized using dichloromethane/ether and the solid is filtered off with suction and dried under high vacuum. Yield: 25.1 mg (37.2% of theory); MS (ESI): m/z (%)=517 (M+H, 100);); LC-MS (Method 7): rt (%)=3.42 (77).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[NH:37]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][S:47][CH2:48][CH2:49][NH2:50])[N:45]=1)[C:38]([NH2:40])=[NH:39]>>[NH:37]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][S:47][CH2:48][CH2:49][NH:50][C:25]([NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:22])=[O:26])[N:45]=1)[C:38]([NH2:40])=[NH:39]
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: COc1ccc(CN(CCN(C)CCCNC(=O)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 1.00 g (3.0 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=586 ([M+H]+, 4), 121 (100); IR (KBr): 1717 cm-1 (C=O). For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 106°-109° C. (ethanol).
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[F:10][CH:11]([F:20])[O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:1][C:17]1[CH:18]=[C:13]([O:12][CH:11]([F:10])[F:20])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1ncccc1OC(F)F
Solvent: CC#N
Product: Nc1ncc(Br)cc1OC(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
N-Bromosuccinamide (1.00 g, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difluoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20 ml) at 0° C. The reaction mixture was further stirred at 0° C. for 10 min. The mixture was concentrated, and residue was partitioned between EtOAc/sat. Na2CO3/H2O (30 ml/15 ml/15 ml). The organic phase was sequentially washed with sat. aqueous Na2CO3/H2O (15 ml/15 ml) and brine (30 ml), dried (Na2SO4), and concentrated. The resulting residue was extracted with EtOAc/hexanes (6 ml/30 ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80%) of 5-bromo-3-(difluoromethoxy)pyridine-2-amine. LCMS (m/z, MH+): 238.9, tR=0.52 min; 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J=2.0 Hz, 1H), 7.41 (m, 1H), 6.50 (t, J=72.8 Hz, 1H), 4.75 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52](=[O:60])[CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][NH:55]1>CN(C=O)C.O>[CH3:50][O:51][C:52](=[O:60])[CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][N:55]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: COC(=O)CC1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1CCCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A stirring solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.00 g, 12.5 mmol) in DMF (50 ml), under argon was treated sequentially with N,N-diisopropylethylamine (6.8 ml), HATU (4.77 g, 12.5 mmol) then after stirring for 0.25 h, piperidin-2-yl-acetic acid methyl ester (Beckett et al, J. Med. Chem., 563, 1969) (1.83 g, 12.5 mmol) was added. The mixture was stirred for 16 h at room temperature and was then diluted with water. The product was extracted into diethyl ether. The organic phase was washed with water (3×) and brine, was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a yellow gum (4.00 g, 85%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.CS(C)=[O:32].N([O-])=O.[Na+].Cl>O.C(O)(=O)C>[OH:32][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Reactant: CS(C)=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CO)c3c2)c1=O
Yield: 38.3 %

Procedure:
To a mixture of 3-[3-[3-(bromomethyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.840 g, 1.67 mmol), dimethylsulfoxide and sodium nitrite is added glacial acetic acid. The resultant mixture is stirred overnight at 50° C., cooled and acidified with 10% aqueous hydrochloric acid. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic layers are washed with saturated sodium carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound as an off-white solid (0.290 g, 38.3%, mp 168-169° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][C:3]=1[O:12][CH3:13].Cl.C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1cccc(OC)c1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(O)c1I
Yield: 74.8 %

Procedure:
To a solution of 2-iodo-1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene (Intermediate 46, 16.2 g, 55.1 mmol) in dichloromethane (100 ml, SCRC) was bubbled HCl (g) for 30 mins. TLC showed that the reaction was completed. The reaction mixture was poured into an aqueous saturated solution of NaHCO3 (200 ml,) and extracted with dichloromethane (3×200 ml, SCRC). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel (EtOAc:PE=1:50) to afford the title compound as a yellow liquid (10.3 g).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=388.12.
Reaction SMILES: F[B-](F)(F)F.C(N(C(C)C)[CH:10]=[N+:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])(C)C.CC(C)([O-])C.[K+].[C:27]([O:31][C:32]([N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C@H:35]1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(=O)C>C1COCC1>[C:27]([O:31][C:32]([N:34]1[C@H:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:46]=2)[CH2:36]/[C:37](=[CH:10]\[N:11]([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])/[C:38]1=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(C=[N+](C(C)C)C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate (2.13 g, prepared according to Example 11) is added to a 1 M solution of potassium-tert-butoxide in THF (5.69 ml). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at 60° C. for 1 h. The mixture is then cooled to room temperature and diluted by addition of 10 ml isopropyl acetate. The mixture is then filtered through silica and concentrated in vacuo to afford (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Spectroscopic data as for Example 19, Method 1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][S:7](=[O:15])(=[O:14])[NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[O:5].C(N(CC)CC)C>CC(C)=O>[C:9]([NH:8][S:7](=[O:14])(=[O:15])[NH:6][C:4](=[O:5])[CH:3]=[CH2:2])(=[O:13])[CH:10]=[CH2:11]
Reactant: O=C(CCCl)NS(=O)(=O)NC(=O)CCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)NS(=O)(=O)NC(=O)C=C
Temperature: 25 °C

Procedure:
60 g (0.208 mol) of N,N'-bis-(3-chloropropionyl)-sulphuric acid diamide are dissolved in 1 l of absolute acetone. 100 g (0.99 mol) of absolutle triethylamine are added over the course of 15 minutes from a dropping funnel. The mixture is stirred at room temperature until no further precipitate forms and is filtered. The filtrate is concentrated until crystallisation commences. It is then allowed to complete crystallisation at 10°C and after filtration, washing with absolute ether and drying N,N'-bis-acryloyl-(sulphuric acid diamide) mono-triethylamminium salt of melting pont 104°C is obtained. This can be purified further by recrystallisation or can be obtained as free N,N'-bis-acryloyl-sulphuric acid diamide by dissolving in water and acidifying with hydrochloric acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16](Cl)[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C1COCC1.CCCCCC>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16]([C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Clc1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)c1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
The product from step (g) (109 mg, 0.35 mmol) in anhydrous THF (5 ml) was cooled to −78° C. under a nitrogen atmosphere and treated with 1.6 M n-butyl lithium in hexane (0.25 ml). The reaction mixture was stirred at −78° C. for 5 minutes followed by the addition of trimethyl acetyl chloride (0.22 ml, 1.75 mmol). After 10 additional minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and solvent evaporated in vacuo to give the subtitled compound as an orange oil which was used in the next step without further purification. MS: ESI (positive): 362, 364 (M+H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[C:16]([C:18]1([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)#N.C[OH:34].Cl>CN(C=O)C.O>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]2[C:18]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16](=[O:34])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:2]2=[S:3])=[CH:25][C:26]=1[F:32])#[N:29]
Reactant: CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: N#Cc1ccc(NC2(C#N)CCCC2)cc1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCC3)cc1F
Temperature: 60 °C
Yield: 7 %

Procedure:
A mixture of 4-isothiocyanato-2-trifluoromethylbenzonitrile (1a) (0.171 g, 0.75 mmol) and 4-(1-cyanocyclopentylamino)-2-fluorobenzonitrile (54b) (0.115 g, 0.5 mmol) in dry DMF (1 ml) was heated under microwave irradiation at 60° C. for 48 hours. To this mixture were added methanol (3 ml) and aq 2M HCl (2 ml). The second mixture was refluxed for 1 hour. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (15 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 98:2) to yield 4-[1-(4-cyano-3-fluorophenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]non-3-yl]-2-trifluoromethylbenzonitrile (54c) [RD168] (0.017 g, 0.037 mmol, 7%), of which the structure is illustrated in Formula 30, as an off-white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:27])[C:12]([C:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:17])[CH3:16])=[N:13][N:14]=1.CI.[C:30](=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:27])[C:12]([C:15]([N:18]([CH3:30])[C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH3:17])[CH3:16])=[N:13][N:14]=1
Reactant: O=C([O-])O
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 16 mg) was added to a DMF (10 ml) solution of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}benzamide (130 mg), followed by stirring at room temperature for 30 minutes. Then, methyl iodide (0.027 ml) was added thereto and the whole was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution and then the organic layer was separated. Furthermore, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=100:3) to obtain 104 mg of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}-N-methylbenzamide (colorless solid).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chlorosulfonic acid (4.3 mL, 64.6 mmol) in dichloromethane (20 mL) is added dropwise to a solution of diphenyl ether (10 g, 58.8 mmol) in dichloromethane (20 mL) at 0° C. under nitrogen atmosphere. The reaction mixture is slowly warmed up to RT and stirred for 2 h. To the mixture are added oxalyl chloride (6.5 ml, 76.4 mmol) and then DMF (1.5 mL) at RT. After being heated at 40° C. for 1 h, the reaction mixture is stirred at RT for 15 h. The mixture is poured to ice-water and extracted with ether. The organic layer is dried over MgSO4 and evaporated in vacuo to give the title compound quantitatively: NMR (CDCl3) 7.10 (t, 4H, J=8.6 Hz), 7.22-7.30 (m, 1 H), 7.46 (t, 2H, J=8.6 Hz), 7.98 (d, 2H, J=9.1 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[CH2:11]1[O:18]C(=O)C[O:14][C:12]1=[O:13].[C:19]1(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>>[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9].[C:12]([OH:14])(=[O:13])[CH2:11][OH:18].[C:19]1(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1COC(=O)CO1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: O=C1CCCCCO1
Agent: [Sn+2]
Product: CC(O)C(=O)O
Product: O=C(O)CO

Procedure:
L-Lactide (220 g), 35 g of glycolide and 45 g of ε-caprolactone were subjected to a polymerization reaction in the presence of 0.01 g of stannous octoate in vacuo (10−3 mmHg) at 150° C. for 24 hours. After the reaction, the product was purified by dissolving in chloroform followed by separating in methanol to give 185g of copolymer of lactic acid, glycolic acid and ε-caprolactone.