Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH:30]=[CH:29][C:28]2=[O:33])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:33]=[C:28]1[CH:29]=[CH:30][C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:36]([O:38][CH3:39])=[O:37])[NH2:8])=[CH:12][CH:13]=1)=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of #251 (800 mg, 1.47 mmol, 1 eq.) in dichloromethane (16 mL) was added TFA (4.8 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and filtered. The filtrate was lyophilized to afford #252 (800 mg, 97.5%) as a white solid. HPLC (Protocol Q3) [M+H+] 1445.4, retention time=0.90 min.
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].N[CH2:20][CH2:21][SH:22]>>[S:22]1[CH2:21][CH2:20][N:2]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCS
Product: c1ccc2c(c1)C1CC(C3=NCCS3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g) and 2-aminoethanethiol (2.0 g) is stirred at 130° C. for 4 hours. The reaction mixture is recrystallized from ethanol to give 11-(2-thiazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.5 g) as crystals melting at 160 to 161° C. IR (KBr), 1619 cm-1 (S--C=N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=[O:15])[CH2:13][CH3:14].Cl.[NH2:21]O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:21][O:15][C:12]=1[CH2:13][CH3:14]
Reactant: NO
Reactant: CCC(=O)C(Cc1ccc(OC)cc1Cl)C(=O)CC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1Cc1ccc(OC)cc1Cl

Procedure:
4-[(2-Chloro-4-methoxyphenyl)methyl]-3,5-diethylisoxazole [I; Ar is 2-Cl-4-CH3OC6H3, Y is CH2, R is C2H5 ] was prepared from 30.9 g. of 4-[(2-chloro-4-methoxyphenyl)methyl]-3,5-heptanedione and 7.96 g. of hydroxylamine hydrochloride in 65 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a pale yellow oil, b.p. 144°-147° C. (0.08 mm.); yield 21.6 g.; MIC=12 μg/ml (herpes 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]1[O:6][CH2:5]1.[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([OH:6])[CH2:5][S:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)[C@@H]1CO1
Product: COC(=O)[C@@H](O)CSCc1ccccc1
Yield: 92 %

Procedure:
This reaction was performed as previously described by Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 497, using (S)-Methylglycidate 110a and Benzyl mercaptan. (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid methyl ester 110b (7.41 g, 31.41 mmol, 92%) was isolated as a viscous oil: MS calcd. for C11H14O3S (M+H+) 227.1, found 227.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[NH:27][C:26](=[O:28])[C:25]([Cl:29])=[CH:24][CH:23]=2)=[CH:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)=[CH:10][CH:9]=1.O.[Cl-].[NH4+]>C(#N)C>[Cl:29][C:25]1[C:26](=[O:28])[NH:27][C:22](/[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[CH:15]/[C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17]2)=[CH:23][CH:24]=1
Reactant: C1CCNC1
Reactant: O=C1CC[C@H](C=C(c2ccc(CBr)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@H](/C=C(\c2ccc(CN3CCCC3)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Separately, pyrrolidine (0.424 mL) was added to a solution of 6-{1-[4-(bromomethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-one (E:Z=1:2 mixture) (206 mg) in acetonitrile (8.24 mL) at room temperature, and the mixture was stirred at room temperature for one hour. Water and a saturated ammonium chloride solution were sequentially added to the reaction solutions at room temperature, and the mixtures were combined, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=5:1) to give the title compound as a white solid (70 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
(31) (Canadian Journal of Chemistry. 1968 46, 1952-6). To a solution of 2,6-dichlorobenzaldehyde (1.75 g, 10.0 mmol) and acetophenone (1.20 g, 10.0 mmol) in 30.0 ml of methanol was added 4.4 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 1.68 g (60.6%) of yellow needles: mp 84.5-85.3° C. (lit. mp 83° C. Kuck and Grutzmacher, Org. Mass. Spect. 1978, 13, 90-102). 1H NMR (250 MHz) δ 8.05-8.01 (m, 2 H), 7.90-7.84 (d, 1 H), 7.70-7.64 (d, 1 H), 7.62-7.48 (m, 3 H), 7.41-7.37 (d, 2 H), 7.24-7.18 (dd, 1 H); 13C NMR (62.7 MHz) 190.3, 139.0, 135.3, 133.3 132.8, 130.7, 130.0, 129.0, 128.9 ppm.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[C:38]([CH:3]=[O:4])[C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-n2nc(C)c(C=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 1 h

Procedure:
At room temperature, a mixture of N,N-dimethylformamide 20 ml and phosphorus oxychloride 0.85 ml was stirred for one hour. To the above-mentioned mixture was added 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 3) 2.0 g and was stirred at 100° C. for three hours. At room temperature, to the resulting mixture was added water 10 ml. The mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-4-formyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 51”) 1.7 g.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([C@@H:8]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H]4CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H]4CCN[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (2S,4R)-tert-butyl 2-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.190 g, 0.387 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo and EtOAc (2 mL) was added to the residue. The precipitate was collected by filtration and washed with EtOAc (1 mL) and petroleum ether (2 mL) to give (R)-9-((2S,4R)-2-benzylpiperidin-4-yl)-1-methyl-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #109-2, Enantiomer 2, SFC (Table 1, Method 21) Rt=4.521 min, 0.190 g, 97%) as a solid. LC/MS (Table 1, Method 4) Rt=1.617 min; MS m/z: 391 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C(CO)c1ncn2ccsc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
7-Hydroxyacetylimidazo[5,1-b]thiazole (1.42 g) was dissolved in 10 ml of DMF. Imidazole (847 mg) and 1.77 g of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere. The mixture was stirred at room temperature for 24 hr. Brine was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic layers were combined together, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.19 g of 7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(N(C)CCN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.13 g, 0.44 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.053 g, 1.3 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then 4-(2-chloro-ethyl)-morpholine (0.12 g, 0.66 mmol) was added in one portion as a solution in DMF (I ml) and the reaction mixture was heated to 70° C. for 24 hours. After this time, the reaction mixture was cooled to RT and water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 95% EtOAc, 5% MeOH) gave the title compound (0.051 g, 30% yield) as a white solid. 1H-NMR: (400 MHz, CDCl3), 7.72 (1H, d), 7.49 (1H, s), 7.16 (1 H, d), 5.42-5.29 (1H, m), 3.73-3.67 (4H, m), 3.66-3.59 (2H, t), 3.15 (3H, s), 2.61-2.54 (2H, m), 2.53-2.46 (4H, m), 1.41 (6H, d).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.P(O)([O-])([O-])=O.[Na+].[Na+].[O:21]=[CH:22][C@@H:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24].[OH:33][CH2:34][C:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43]O)[OH:42])[OH:40])[OH:38])=[O:36]>>[CH2:31]([OH:32])[C@H:29]1[O:30][C@H:22]([O:21][CH2:43][C@H:41]2[O:42][C:35]([OH:36])([CH2:34][OH:33])[C@@H:37]([OH:38])[C@@H:39]2[OH:40])[C@H:23]([OH:24])[C@@H:25]([OH:26])[C@@H:27]1[OH:28]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
8400 units of β-amylase of barley origin were added to 5 ml of a reaction mixture of a citric acid-disodium phosphate buffer (pH 4.8) containing 10% glucose and 30% fructose, and the reaction was carried out at 25° C. overnight. The yield of the isomaltulose formed during the reaction was 15%, in relation to glucose added. Note, the isomaltulose was determined according to the same procedures as described in Example 1.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1cccc(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)[CH:3]=O.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([OH:25])[N:19]=1>>[NH2:17][C:18]1[NH:23][C:22]2[NH:24][CH:3]=[C:2]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)[C:21]=2[C:20](=[O:25])[N:19]=1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Reactant: Nc1cc(O)nc(N)n1
Product: COC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1

Procedure:
reacting 2-bromo-4-(4-carbomethoxyphenyl)butanal with 2,4-diamino-6-hydroxypyrimidine to give methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate;
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:14](Br)[C:15]#[CH:16].C(NC(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([C:11]([O:13][CH2:16][C:15]#[CH:14])=[O:12])=[C:5]([C:7]([F:8])([F:10])[F:9])[N:6]=1
Reactant: O=C(O)c1sc(Cl)nc1C(F)(F)F
Reactant: C#CCBr
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C#CCOC(=O)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 4.63 g (0.02 mole) of 2-chloro-4-trifluoromethyl-5-thiazolecarboxylic acid, 2.42 g (0.02 mole) of propargyl bromide, 2.59 g (0.02 mole) of diisopropylamine, and 50 ml. of methylene chloride was stirred for 16 hours. The methylene chloride solution was washed successively with diluted hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give propargyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate as a colorless liquid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].Cl[C:5]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:18])(=[O:17])[N:6]=1>ClCCl>[CH2:1]([O:3][C:5]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:17])(=[O:18])[N:6]=1)[CH3:2]
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc2c1C(Cl)=NS2(=O)=O
Solvent: ClCCl
Product: CCOC1=NS(=O)(=O)c2cccc([N+](=O)[O-])c21
Reaction time: 8 h

Procedure:
Ethanol (100 ml) was added to a solution of 3-chloro-4-nitro-benzoisothiazole-1,1-dioxide (0.86 g) in dichloromethane (110 ml). The resulting solution was allowed to stand overnight at room temperature. Removal of the solvent in vacuo gave an amorphous brown solid, which was triturated under ether (100 ml) to give the title compound as a white solid (0.82 g), mpt 190°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[O:24][N:23]=[C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30]([C:28]3[N:29]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:34])([F:18])[F:33])[O:24][N:23]=4)[O:26][CH:27]=3)=[O:31])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1coc(-c2noc(C(F)(F)F)n2)n1
Product: CC(C)(CNC(=O)c1coc(-c2noc(C(F)(F)F)n2)n1)c1coc(-c2ccc(F)cc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxylic acid as described in example 8 step 6 (6 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.88-8.86 (m, 1H), 8.49 (s, 1H), 8.25-8.21 (m, 2H), 7.46 (s, 1H), 7.23-7.19 (t, J=8.8 Hz, 2H), 3.62-3.60 (d, J=6.0 Hz, 2H), 1.39 (s, 6H). MS (ESI) m/z: Calculated for C20H15F4N6O4: 465.11. found: 466.1 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([S-:6])=[CH:4][N:3]=[N:2]1.[Na+].Cl[CH2:9][C:10]#[N:11]>ClCCl.CN(C)C=O>[S:1]1[C:5]([S:6][CH2:9][C:10]#[N:11])=[CH:4][N:3]=[N:2]1
Reactant: N#CCCl
Reactant: [S-]c1cnns1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCSc1cnns1
Reaction time: 8 h

Procedure:
To a stirred solution of sodium 1,2,3-thiadiazol-5-thiolate (15 g) in dichloromethane (150 ml) and dimethylformamide (20 ml) was added chloroacetonitrile (4.76 ml) at room temperature. After stirring overnight, the precipitate was filtered off and the filtrate was poured into the mixture of water (30 ml) and dichloromethane (300 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (450 ml) eluting with ethyl acetate to give (1,2,3-thiadiazol-5-yl)thioacetonitrile (10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]>C(N(CC)C1C=CC=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[O:15][CH2:16][CH:17]=[CH:18][C:10]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: C#CCOc1cc(C(=O)OC)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cc(OC)c(OC)c2c1C=CCO2
Yield: 99.9 %

Procedure:
Methyl 3,4-dimethoxy-5-(2-propynyloxy)benzoate (390 g, 1.56 mol) in N,N-diethylaniline (0.4 L) was refluxed for 40 min. The solution was cooled and diluted with methylene chloride (2 L). The organic solution was extracted with 1N hydrochloric acid (5×1 L), dried (MgSO4) and concentrated to give title compound (390 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(N[C@H]5CCCNC5)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A mixture of (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (78.0 mg, 0.169 mmol) and TFA (0.30 mL, 3.894 mmol) in DCM (1.5 mL) was stirred at 25° C. for 1 h. The mixture was concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide (S)-2-(2-(piperidin-3-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (41.1 mg, 0.086 mmol, 51% yield) as a yellow-orange solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 8.16 (1H, br. s.), 7.84 (1H, dd, J=7.5, 1.1 Hz), 7.69 (1H, d, J=7.6 Hz), 7.35-7.46 (1H, m), 7.25-7.34 (1H, m), 6.97-7.09 (1H, m), 4.33-4.45 (1H, m), 3.74 (1H, dd, J=12.3, 3.3 Hz), 3.64 (2H, t, J=7.1 Hz), 3.41 (1H, dt, J=12.7, 3.8 Hz), 3.04-3.16 (2H, m), 3.01 (2H, t, J=7.0 Hz), 2.26-2.35 (1H, m), 2.08-2.19 (1H, m), 1.90-2.04 (1H, m), 1.70-1.84 (1H, m). 19F NMR (377 MHz, MeOH-d4) δ ppm −77.49 (3F, s). m/z (ESI, +ve) 362.3 (M+H)+.
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:36]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:41][CH2:42][C:43]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:14]2[CH:34]=[CH:35][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2, chloroform/MeOH 99:1) as a colorless oil (70%). M+ (ESI): 604.0. HPLC, Rt: 6.2 min purity: 100%). 1H NMR (CDCl3) δ: 7.61 (m, 1H), 7.41-7.05 (m, 5H), 6.85 (m, 1H), 4.75 (s, 1H), 4.72 (s, 1H), 4.56 (m, 2H), 4.42 (m, 2H), 3.92 (s, 1.5H), 3.90 (s, 1.5H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 2.41 (m, 4H), 1.74-1.09 (m, 23H), 0.90 (t, J=6.6 Hz, 3H).