Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])=[O:5])#[N:2].C([O-])(=O)C.[Na+].[Cl:20][C:21]([Cl:25])([Cl:24])[C:22]#[N:23]>C(O)C>[NH2:23][C:22]([C:21]([Cl:25])([Cl:24])[Cl:20])=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])=[O:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COc1ccncc1NC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccncc1NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
2-Cyano-N-(4-methoxy-3-pyridyl)acetamide 8 (26.4 g, 138.1 mmol) was slurried in ethanol (300 mL). Sodium acetate (23.56 g, 287.2 mmol) was added followed by trichloroacetonitrile (23.92 g, 16.85 mL, 165.7 mmol). The mixture was stirred at room temperature overnight. The suspension was filtered and the solids washed with ethanol. The solids (46.5 g) were slurried for 90 minutes in 10% aqueous ethanol, filtered and dried to afford 3-amino-4,4,4-trichloro-2-cyano-N-(4-methoxy-3-pyridyl)but-2-enamide (37.2 g, 80%). LC-MS (M+H)+ 336.9; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, 1H), 7.43-7.47 (m, 1H), 6.35-6.39 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21]CC3C=CC=CC=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:29]CC2C=CC=CC=2)[CH:12]=[C:11]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C(OCC)(=O)C>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=2[OH:29])[CH:12]=[C:11]([CH:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[C:3]=1[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(OCc3ccccc3)cccc2OCc2ccccc2)nc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2O)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A suspension of tert-butyl 2-amino-6-[2,6-bis(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinate (1.00 g, 1.052 mmol) and 10% Paradium-carbon (0.500 g) in 20 mL of ethyl acetate was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. After paradium carbon was removed by filtration on Celite®, the filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]-6-(2,6-dihydroxyphenyl)-nicotinate as a brown oil. (0.710 g, yield; 97%)
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3C(OCC)=O)[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:29](N(CC)CC)C.C(OC(=O)C)(=O)C.O>Cl.O1CCCC1>[CH3:28][C:21]1[CH:22]=[C:16]2[C:15]3[C@H:11]([CH2:10][CH2:9][NH:8][C:6](=[O:5])[CH3:29])[CH2:12][CH2:13][C:14]=3[CH:19]=[CH:18][N:17]2[N:20]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@H](CCNC(=O)OC(C)(C)C)CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCC[C@@H]1CCc2ccn3nc(C)cc3c21
Temperature: 100 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of ethyl (9S)-9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (140 mg, 0.361 mmol) in 12M hydrochloric acid (4 mL) was stirred at 100° C. for 3 days, and concentrated under reduced pressure. To a mixture of the residue and triethylamine (503 μL, 3.61 mmol) in tetrahydrofuran (3.6 mL) was added acetic anhydride (102 μL, 1.08 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (69.7 mg, yield 75%, >99.9% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[C:6]([CH3:9])=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(N)c1O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(C(O)[C@H](C)NC(=O)OCc3ccccc3)oc12
Yield: 57 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 57% yield from the above cyanohydrin (609 mg, 2.60 mmol) and 6-amino-o-cresol (330 mg, 2.60 mmol) using the procedure described above for compound 16. An analytical sample (1.2:1 mixture of isomers) was obtained by flash chromatography (30% EtOAc in hexanes). oil; IR (neat) υ 1705 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.35-7.10 (m, 7H), 5.50 and 5.38 (2×d, J=8.9 and 8.3 Hz, 1H), 5.15-4.90 (m, 3H), 4.41 (s, 1H), 2.36 (5, 3H), 1.35 and 1.14 (2×d, J=6.7 and 7.0 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 165.41, 164.85, 156.29, 156.12, 150.14, 139.67, 136.28, 128.50, 128.39, 128.13, 127.97, 127.84, 126.36, 126.31, 124.59, 124.51, 121.54, 117.28, 117.12, 70.99, 70.56, 66.96, 66.71, 50.42, 50.25, 17.41, 15.26, 15.08; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H20N2O4) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 1.9 g of 2,4-dichloroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 2.6 g (80%) of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 206-208° C.; mass spectrum (m/e): M+H 332.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:26]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:32](Cl)=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:32](=[O:33])[N:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1

Procedure:
A partial solution of 1.32 g (5.74 mmole) of (S)-1-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid in 25 ml of dried DMF was treated dropwise over 5 min with 1.48 g (11.47 mmole of diisopropylethyl amine at 25° under nitrogen with stirring. The clear solution which resulted was treated dropwise over 15 min with a solution of 1.26 g (5.74 mmole) of dipentylcarbamoyl chloride in 5 ml of DMF and the mixture was stirred under nitrogen at 25° for 16 hr. The solution was concentrated in vacuo and the residue was dissolved in 100 ml of dichloromethane which was extracted with 2×100 ml of 0.5M citric acid and 2×25 ml of water. Without drying, the solution was concentrated in vacuo to 1.85g (78%) of medium yellow oil which was homogeneous by the (silica gel, 1:1:1:1 ethylacetate: n-butanol: acetic acid: water, Rf =0.50).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>C(O)=O.CO>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[N:12]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cccc(C)c1N
Solvent: O=CO
Solvent: CO
Product: Cc1cccc(C)c1N=Cc1ccccn1
Reaction time: 5 h

Procedure:
A mixture of 2-pyridine-carboxaldehyde (10 ml, 0.1 mole), 2,6-dimethylaniline (12.9 ml, 0.1 mole), 3 drops of formic acid and 30 ml methanol was stirred for five hours. The methanol was removed under vacuum. An oil-like residue was recrystallized from n-hexane. 2-(N-(2,6-dimethylphenyl)-iminomethyl)-pyridine was isolated as yellow crystals. Yield: 13.6 g (62%). 1H NMR (200 MHz; CDCl3; δ, ppm; J, Hz): 2.17 s (6H, CH3), 6.94-7.12 m (3H, C6H3), 7.39 d,d,d (1H, H(5) 3J4,5=7.5, 3J5,6=4.9, 4J3,5=1.3); 7.83 t,d,d (1H, H(4) 3J=7.7, 4J4,6=1.8, 5J=0.6); 8.28 d,t (1H, H(3) 3J3,4=7.9, J=1.1); 8.35 s (1H, HC═N); 8.71 d,d,d (1H, H(6) 3J5,6=4.9, 4J4,6=1.6, 5J3,6=1.0). 13C NMR, DEPT (50 MHz; CDCl3; δ, ppm): 18.3 (CH3), 121.2 (C(3)H), 124.0 (C(4′)H), 125.3 (C(5)H), 126.8 (C(2′,6′)), 128.1 (C(3′,5′)H), 136.7 (C(4)H), 149.6 (C(6)H), 150.3 (C(1′)), 154.4 (C(2)), 163.4 (HC═N).
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Br[CH2:15][C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[C:22]([C:17]1[C:16]([CH2:15][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:23]
Reactant: N#Cc1ncccc1CBr
Reactant: Oc1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#Cc1ncccc1COc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of sodium ethoxide, prepared from 13.8 g of sodium metal and 240 ml of absolute ethanol, 56.9 ml of 3-fluorophenol was added and the mixture was stirred at room temperature for 30 minutes. Crude 3-bromomethyl-2-cyanopyridine (103 g) was added to the mixture at 5° C., and the mixture was reflexed for 2 hours. After being concentrated, the reaction mixture was diluted with ether, and the resultant insoluble materials were removed by filtration. The filtrate was washed with 10% aqueous sodium hydroxide solution and with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was crystallized by trituration with a mixture of ether and n-hexane to yield 58.0 g of pale brown crystals, which were recrystallized from isopropyl ether to give pale yellow needles, mp 52°-53° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].CN(C)CCN(C)C.C([Li])CCC.[Si:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][C:46](=[O:49])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>O1CCCC1>[Si:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:48][CH2:47][C:46]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=3[O:12][CH2:13][O:14][CH3:15])([OH:49])[CH2:45][CH2:44]2)=[CH:41][CH:42]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.3 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 1-bromo-2,4-bis(methoxymethoxy)benzene (277 mg, 1.00 mmol) and anhydrous tetrahydrofuran (5 ml). The stirred solution was cooled to −78° C. and N,N,N′,N′-tetramethylethylene diamine (0.32 ml, 2.10 mmol) was added followed by dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol, 2.40M solution in cyclohexanes). The resulting solution was stirred for 40 min at −78° C., then 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (304 mg, 1.00 mmol) was added via syringe as a solution in anhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30 min at −78° C., then allowed to warm to room temperature over 3 hr. The reaction was quenched with aqueous hydrochloric acid (5 ml, 0.10M), then poured into a separating funnel containing ethyl acetate (50 ml) and water (10 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 3:7, v/v) furnishing the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (6H, s), 1.63 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 2.56 (2H, m), 2.70 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s), 5.24 (2H, s), 6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H, d), 7.05 (2H, d), 7.33 (1H, d).
Reaction SMILES: [Na].[OH:2][NH:3][C:4]([NH2:6])=[NH:5].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1)(O)=O>C(O)C>[NH2:5][C:4]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[O:2][N:3]=1
Reactant: CC(N)c1ccc(C(=O)O)cc1
Reactant: N=C(N)NO
Agent: [Na]
Solvent: CCO
Product: CC(N)c1ccc(-c2nc(N)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.8 g of sodium is dissolved in 60 ml of absolute ethanol, and 12 g of molecular sieve (4Å) and 2.63 g of N-hydroxyguanidine are added. The batch is stirred for 1 hour at room temperature and then 1.14 g of 1-(4-carboxyphenyl)ethylamine are added. The resulting turbid yellowish solution is heated under reflux for 2 hours after which time it can be established by thin layer chromatography that the reaction is complete. The batch is filtered and the solvent is removed under reduced pressure. The residue is digested in water and cooled in an ice bath, and then the precipitate is isolated by filtration, washed with a small amount of water and dried under reduced pressure to give 1-[4-(3-amino-1,2,4-oxadiazol-5-yl)phenyl]ethylamine having a melting point of 150°-151°.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:32]N1C(=O)CCC1=O.CCOC(C)=O>ClCCl>[Br:32][C:8]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][C:7]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2sccc2c1Br
Temperature: 23 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.06 g, 0.31 mmol) in dichloromethane (1 mL) was added TBAF (1M THF, 0.46 mL) followed by N-bromosuccinimide (NBS) (0.07 g, 0.4 mmol). The resulting mixture was allowed to stir at 23° C. for 16 h at which time the entire reaction mixture was placed on a silica gel column. Flash column chromatography (20% EtOAc in hexanes) affords one major peak containing a mixture of 4-bromo and 2,4-dibromo products. Separation of the desired product from the byproduct by RP-HPLC (10-100% gradient 0.1% formic acid in H2O to CH3CN over 10 min) afforded ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.03 g, 35% yield).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([OH:11])[CH2:10][CH2:9]CCC1.S(=O)(=O)(O)O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.NC(N)=[S:26]>O>[CH:1]1([NH:4][C:5](=[O:11])[CH2:10][CH2:9][SH:26])[CH2:23][CH2:18][CH2:19][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CC#N
Reactant: OC1CCCCC1
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(CCS)NC1CCCCC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A pre-mix of acrylonitrile/cyclohexanol (13.3 g/25.1 g) and concentrated sulfuric acid (51.1 g) were added through two addition funnels into a flask containing chlorobenzene (60 g) at 45°-55° C. The mixture was then heated to 60°-70° C. for 3-5 hours and cooled to 20° C. when water (150 g) was added slowly. After 30 minutes stirring, thiourea (19 g) was added and the mixture brought to 60° C. for 1 hour. On cooling to 20° C., caustic (50%, 80 g) was added between 20b 60° C. C under nitrogen and held at 60° C. for 1 hour. The organic layer was separated and washed with warm water to yield 33.9 of N-cyclohexyl-3-mercaptopropionamide in chlorobenzene (72.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (82.9 mg, 70%)
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[C:10]1(=[C:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[O:6])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCCCCC
Reactant: O=C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCC1=C1CCCC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 52 %

Procedure:
To a stirring solution of cyclopentanone (336.5 g, 4.0 moles) in absolute ethanol (500 mL) at room temperature was added KOH (5.6 g, 0.1 mole) in one portion. The reaction was stirred at room temperature for 65 hours. The reaction was determined to be completed by TLC and GC analyses. Hexane was added to the reaction mixture and the layers were separated. The organic layer was washed successively with 10% HCl (aqueous), saturated NaHCO3 (aqueous) and brine. The resulting organic layer was dried with MgSO4, filtered, and concentrated. The brown oil was distilled under vacuum to give 2-cyclopentylidenecyclopentan-1-one (155 g, 52% yield). The structural formula of 2-cyclopentylidenecyclopentan-1-one is shown in FIG. 1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[C:16](O)([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.Cl>C(Cl)Cl>[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([O:12][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11]
Reactant: CC(C)(C)O
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Oxalyl chloride (87.3 g, 0.68 mol) was added to a solution of TFMAA (15.0 g, 0.11 mol) in methylene chloride (90 mL) in a dropwise manner at room temperature under an nitrogen atmosphere. The solution was heated to reflux for 5 hours, and the solvent and excess reagent were removed on a rotary evaporator. The resulting acid chloride was added to a stirred solution consisting of t-butanol (44 g, 0.59 mmol) and pyridine (33.6 g, 0.42 mol) in dichloromethane at 0° C. over a 10 min period. After stirring overnight at room temperature, the solution was neutralized with diluted aqueous HCl and washed with saturated aqueous sodium bicarbonate. The organic phase was removed, and the aqueous phase was extracted with pentane. The combined organic solvents were reduced to a small volume by distillation and then the residue was chromatographed on a column of silica gel. The product was re-purified by distillation to give 14.0 g of TBTFMA as a colorless liquid (70%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].O>C(Cl)Cl.CN(C=O)C>[CH3:20][NH:21][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: CN
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1oc2ccccc2c1C
Temperature: 2 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methylbenzofuran-2-carboxylic acid (1.0 kg, 5.676 mol) in methylene chloride (5.8 L) and DMF (5 mL) was chilled to ˜2° C. A solution of oxalyl chloride (864 g, 6.81 mol) was added to the reaction mixture keeping the temperature below 10° C., over a period of 2 hrs. A vigorous evolution of a gas was observed. The reaction mixture was stirred overnight under nitrogen at room temperature and then refluxed for 3 hrs. All of the solids were dissolved to give a brown color solution. HPLC analysis of an aliquot indicated that the reaction was complete. The mixture was concentrated on a rotary evaporator and the residual oxalyl chloride was chased with DCM (2 L). The solid product was re-dissolved in DCM (6 L) in a round bottom flask (10 L) and chilled to ˜−5° C. A solution of methyl amine (40% in water, 1.7 L, 3.5 eq, 19.86 mol) was carefully added to the acid chloride solution while keeping the temperature below 8° C. then stirred overnight at room temperature. Analysis of an aliquot indicated that the reaction was complete. Water (8.0 L) was added to the reaction mixture, the layers were separated, the aqueous layer was back extracted with DCM (2×3 L), the combined organic layer was washed with water (4 L) and dried over Na2SO4. The organic layer was filtered, the filtrate was concentrated and traces of DCM were co evaporated with heptanes (2 L). The heptanes slurry was filtered and the cake was washed with heptanes (2×2 L). All the brown color was removed in the heptane filtrate. The solid product was dried under high vacuum overnight to a constant weight. Yield of the title compound was 1.015 kg (94.5%. 1H NMR {CDCl3}: δ (ppm) 8.45 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2 H), 7.30 (m, 1 H), 3.03 (d, 2 H), 2.63 (s, 3 H). HPLC: 99.0 area % (RT=7.91 min)