Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2C=CC=CC=2C(=[O:10])S1.OO.C(Cl)(Cl)Cl.[S:17]1(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1>FC(F)(F)C(O)=O>[S:17]1(=[O:10])(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[S:18]1
Reactant: O=c1ssc2ccccc12
Reactant: O=C1SS(=O)c2ccccc21
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1SS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3H-1,2-Benzodithiol-3-one (39.2 g, 0.23 mole) in trifluoroacetic acid (250 mL) was added 40 mL of a 30% aqueous solution of hydrogen peroxide. Cooling was necessary to maintain the internal reaction temperature between 40°-45° C. After 30 minutes, an additional 40 mL of 30% H2O2 was added and the reaction mixture was heated to ensure an internal reaction temperature of 40°-45° C. 30 minutes later, the last portion of 30% H2O2 (40 mL) was added under the same temperature conditions and the rate of the reaction was monitored by TLC (CHCl3) until the disappearance of the slow moving sulfoxide byproduct, i.e., 3H-1,2-benzodithiol-3-one 1-oxide (90 minutes). The reaction mixture was then filtered and the filtrate was added onto 3.5 L of crushed ice. The white precipitate was filtered through a 600 mL fritted glass funnel of coarse porosity and thoroughly washed with water until the filtrate was neutral and free of peroxides. The solid material was then transferred into a 500 mL separatory funnel to which was added dichloromethane (200 mL) and a 1% solution of sodium bisulfite (100 mL). After vigorous shaking, the organic phase was decanted and washed with water (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the amorphous solid was dried under vacuum. The crude compound (20.8 g) was dissolved in boiling dichloromethane (ca. 70 mL). Hexanes (ca. 50 mL) was added, and the boiling solution was allowed to cool to ambient temperature and then kept in the refrigerator at 10° C. The crystalline material was collected by filtration, washed with cold hexanes and dried under vacuum.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][NH:33][C:34]([C:36]1[C:41]([NH2:42])=[N:40][C:39]([NH2:43])=[C:38]([Cl:44])[N:37]=1)=[O:35])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(C)(C)C>O1CCOCC1.Cl>[ClH:44].[NH2:7][C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:22]=1)[CH2:32][NH:33][C:34]([C:36]1[C:41]([NH2:42])=[N:40][C:39]([NH2:43])=[C:38]([Cl:44])[N:37]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)NC[C@@H](N)CCCCNC(=O)CCc2ccc(OCc3ccccc3)cc2)nc1Cl

Procedure:
A solution of ((S)-5-[3-(4-benzyloxy-phenyl)-propionylamino]-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (0.29 g, 0.45 mmol) in 1,4-dioxane (3 mL) and HCl (5 mL of a 4 M solution in 1,4-dioxane, 20 mmol) is stirred at RT for 2 h. The solvent is removed in vacuo and the resulting residue is triturated with diethyl ether and then the diethyl ether is decanted. The remaining solid is dissolved in a minimal amount of MeOH then diethyl ether is added to cause precipitation. The supernatant solvents are decanted and the remaining solid is washed with diethyl ether then dried under vacuum to afford the title compound as yellow solid. [M+H]+ 540.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][N:3]=1.[BH4-].[Na+]>C1COCC1.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: C=C(c1ccc(SC)cc1)c1ccc(F)nc1
Agent: Cl[Ru](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)vinyl)pyridine (992 mg, 4.04 mmol) was dissolved in THF (12 mL) and water (4 mL) and the flask was cooled in an ice water bath under nitrogen. Then, ruthenium trichloride hydrate (212.4 mg, 0.9422 mmol) was added, and then sodium borohydride (393 mg, 10.4 mmol) was added portionwise over about 5 min. More THF (2 mL) was added, and the reaction was warmed to room temperature and stirred. After 2 hours and 15 minutes, more RuCl3*H2O (214 mg, 0.951 mmol) was added and the flask was again cooled in an ice water bath. Then, more sodium borohydride (384 mg, 10.2 mmol) was added, and the reaction was warmed to room temperature. The stirring was continued. Gas evolution was observed. After 50 min, more sodium borohydride (139 mg, 3.67 mmol) was added, and stirring was continued for 1 h. The reaction was diluted with water (20 mL) and DCM (30 mL). The suspension was filtered through a Celite® (diatomaceous earth) pad, which was washed repeatedly with DCM. The biphasic mixture was treated with saturated sodium bicarbonate (50 mL), and the layers were separated. The aqueous phase was extracted with DCM, and all the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM) to give 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (875 mg). 1H NMR (CDCl3, 400 MHz) δ 8.10 (d, J=1.96 Hz, 1H), 7.56 (td, J=8.07 Hz, 2.64 Hz, 1H), 7.24-7.19 (m, 2H), 7.15-7.09 (m, 2H), 6.84 (dd, J=8.41 Hz, 2.93 Hz, 1H), 4.15 (q, J=7.24 Hz, 1H), 2.47 (s, 3H), 1.64 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 248 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:1][C:2]1[S:22][C:5]2[N:6]([CH:25]([CH3:27])[CH3:26])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: CC(C)Br
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(s1)N(C(C)C)c1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (3.12 g) in dry dimethylformamide (50 ml) was added sodium hydride (0.63 g, 50% dispersion). The reaction mixture was stirred for 30 minutes at room temperature, then 30 minutes at 60-70° C. The reaction was cooled to 40° C., isopropyl bromide (1.13 ml) added and left for one hour. Water was added and the reaction extracted with ethyl acetate, washed with water, dried and evaporated under reduced pressure. Chromatography using 2% methanol/dichloromethane and flash silica gave the title compound, m.p. 120-121° C. Similarly prepared from the same starting material were:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:34][CH2:35]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.58 h
Yield: 50.7 %

Procedure:
3-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 250 mg, 0.76 mmol) in THF (5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 138 mg, 3.45 mmol) in anhydrous THF (5 mL) at 0° C. and stirred under nitrogen for 35 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 501 mg, 1.38 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. and the solvents removed in vacuo. The residue was suspended between aq Na2CO3 (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with aq Na2CO3 (20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 34%).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH3:14])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C([O-])([O-])=O.[Na+].[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1.O.CCOC(C)=O>[CH2:23]([O:22][C:21]([NH:2][C:3]12[CH2:4][CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])([CH2:9][CH2:10]1)[CH2:7][CH2:8]2)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)C12CCC(N)(CC1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (1.16 g, 5.29 mmol, Prime Organics) in 1,4-dioxane (15 mL) was added a solution of Na2CO3 (0.90 g, 8.49 mmol) in water (15 mL). The reaction mixture was stirred for about 5 min at ambient temperature. Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.32 g, 5.29 mmol) was added and the reaction mixture was stirred at ambient temperature for about 72 h. The reaction mixture was diluted with EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give methyl 4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (1.68 g, 95%): LC/MS (Table 1, Method a) Rt=2.44 min; MS m/z: 318 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([C:29](Cl)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([C:29]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:30])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCOCCOCCN1
Product: O=C(N1CCOCCOCCOCCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([OH:16])=O.[N:17]1([C:23]([S:25][CH3:26])=[S:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([S:25][CH3:26])=[S:24])[CH2:18][CH2:19]1)=[O:16]
Reactant: COc1ccc(CC(=O)O)c(OC)c1OC
Reactant: CSC(=S)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCN(C(=S)SC)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In 6.2 ml of methylene chloride were dissolved 310 mg (1.37 mmol.) of 2,3,4-trimethoxyphenylacetic acid and 289 mg (1.64 mmol.) of methyl 1-piperazinecarbodithioate. To the solution was added 395 mg (1.92 mmol.) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 1 hour. A precipitated solid was removed by filtration, and to the filtrate were added methylene chloride and 1-N hydrochloric acid. The organic solvent potitoh was taken out, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column. The obtained oil was crystallized from a mixture of ethanol and hexane, yielding 257 mg of the desired compound as a white crystalline product, m.p. 119°-120° C., yield 48.8%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(C3CCOCC3)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3CCOCC3)cc2F)n1
Yield: 59 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 equiv.) at 100° C. for 20 min in microwave to give methyl 6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate in 59% yield. LC/MS=352.2 (MH+), Rt=0.92 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CO>C1COCC1.CCOC(C)=O.O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: O=Cc1ccc2occc2c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc2occc2c1)c1ccccn1
Temperature: 4 °C
Reaction time: 0.17 h

Procedure:
Under argon at −78° C., a mixture of 2-bromopyridine (1.11 g, 7.05 mmol) in THF (30 mL) was dropwise treated with n-BuLi (1.05 equiv. 2.7 mL of 2.5M BuLi in hexanes) over a period of 10 min, and stirred for 10 min. The resulting brown solution was treated dropwise with a solution of benzofuran-5-carbaldehyde (0.937 g, 6.41 mmol) in THF (10 mL) and continued to stir for 15 min at −78° C. The mixture was treated with MeOH (3 mL), followed by H2O (20 mL) and warmed to 4° C. The mixture was treated with EtOAc, the layers separated, and the aqueous layer extracted 1× with EtOAc. The combined organic layers were dried over MgSO4 and evaporated, which resulted in a dark yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>ClCCl.CN(C1C=CN=CC=1)C>[C:3]([O:2][CH3:1])(=[O:4])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:13])=[O:8]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(C)CC1
Yield: 12.6 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.60 g, 3.18 mmol) in 10 mL of dichloromethane (DCM) at ca. 0° C. N-Methyl piperazine (0.353 mL, 0.31 g, 3.18 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by mass-guided preparative HPLC afforded 0.09 g (13% yield) of the title compound (25) as a white solid after lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.93-6.78 (m, 2H), 4.77 (s, 2H), 3.73 (s, 3H), 3.56-3.54 (m, 2H), 3.35-3.25 (m, 2H), 2.37-2.33 (m, 4H), 2.31 (s, 3H). MS (ESI): m/z 271.13 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:11]([C:10]1[C:5]2[C:4]([NH:23][CH:24]3[CH2:25][CH2:26]3)=[N:3][C:2]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=3)=[N:7][C:6]=2[NH:8][CH:9]=1)#[N:12]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc(C(N)=O)cc3)nc(NC3CC3)c12
Temperature: 135 °C
Reaction time: 20 h
Yield: 28.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (175 mg, 0.451 mmol), 4-aminobenzamide (122 mg, 0.897 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 334.3 (M+H); UV 204.6, 230.2, 308.1 nm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[C:21]([F:23])([F:22])[F:20])=[N:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl) carbonyl]cyclohexane-carboxylate (608 mg, 1.756 mmol) in THF (15 ml) was added trifluoromethyl trimethylsilane (0.520 ml, 3.51 mmol). Then, tetrabutylammonium fluoride (7.0 ml, 7.00 mmol) was added to the mixture slowly. After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexane) to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for C14H17BrF3NO3S [M+H]+ 416, 418. found 416, 418. 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 4.11 (q, J=7.1, 2H), 2.47-2.32 (m, 1H), 2.28-1.92 (m, 4H), 1.55-1.16 (m, 5H), 0.90 (t, J=7.3, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6].Cl.ClCCl.C[O:30]C(C)(C)C>>[CH:16]1[CH:17]=[C:18]2[C:10]([CH2:9][C@@H:8]([NH:7][C:5]([CH2:4][CH2:3][C@@H:2]([NH2:1])[C:22]([OH:24])=[O:30])=[O:6])[C:19]([OH:21])=[O:20])=[CH:11][NH:12][C:13]2=[CH:14][CH:15]=1.[NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6]
Reactant: COC(C)(C)C
Agent: Cl
Agent: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: ClCCl
Product: N[C@H](CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
A solution of the base addition salt of D-isoglutamyl-D-tryptophan is prepared by the acid deprotection of the dipeptide Boc-D-Glu-(γ-D-Trp-OR2)-α-OR1, wherein each of R1 and R2 is independently selected from the group consisting of benzyl and C1-C4 alkyl. For example, HCl deprotection of Boc-D-Glu-(γ-D-Trp-OR2)-α-OR1 in an inert solvent such as dichloromethane, affords the HCl salt of H-D-Glu-(γ-D-Trp-OR2)-α-OR1. For the combination where R1 is benzyl and R2 is methyl, the product HCl.H-D-Glu-(γ-D-Trp-OR2)-α-OR1 precipitates out of dichloromethane and can be removed by filtration. Treatment of the acid addition salt with a metal hydroxide in an inert solvent such as methanol for one phase homogeneous hydrolysis or with tert-butyl methyl ether for two phase hydrolysis affords H-D-iGlu-D-Trp-OH base addition salt in solution. Upon extraction of the reaction mixture with a water immiscible solvent such as ethyl acetate or tert-butyl methyl ether, the aqueous phase is neutralized to pH of about 6 to about 7 and the solution is evaporated to reduced the volume to an estimated ratio of less than about 1 part solute:8 parts water. The solute, as predicted by the speciation calculations as shown in FIG. 8, is the base addition salt (in mono carboxylate form) of H-D-iGlu-D-Trp-OH. If sodium hydroxide is used as the metal hydroxide, the solute will be the mono sodium form of the H-D-iGlu-D-Trp-OH in water. Adjustment of this solution to pH of about 2.5 to about 3.0 will result in the precipitation of solid thymodepressin, H-D-iGlu-D-Trp-OH.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:8]=2[O:9][C:10]=1[CH3:11])=O.CO.[OH-].[Na+]>O1CCCC1>[C:16]([C:14]1[CH:13]=[CH:12][C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=3[Cl:1])[C:7]=2[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.57 g, 1.6 mmol), methanol (6 ml), tetrahydrofuran (6 ml) and a 2M aqueous sodium hydroxide solution (8.5 ml) was refluxed under heating for 40 min. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 3N hydrochloric acid and the precipitated solid was extracted with hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (0.54 g, quantitative) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1([O:22][CH3:23])[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1([O:22][CH3:23])[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3F)(OC)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1(Cc2ccccc2F)CCN(c2ccc(C(=O)O)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 1D (20.54 g, 55.4 mmol) in dioxane (100 mL) was treated with 1N NaOH (100 mL, 100 mmol), stirred overnight, acidified with 1N HCl, extracted with ethyl acetate (3×), dried (MgSO4), and filtered. Concentration of the filtrate gave a residue that was purified by silica gel chromatography eluting with to provide the desired product (xx g, xx %). MS (ESI) m/e 344 (M+H)+.
Reaction SMILES: [NH3:1].[CH:2]([CH2:15][C:16](Cl)=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C(Cl)Cl>[CH:2]([CH2:15][C:16]([NH2:1])=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: S=C(Cl)CC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na2SO4, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallised. 16.8 g of product (yield=86%) are obtained.