Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C([NH2:18])=O.C(O)=O.Cl>C(NC(C1(C2C=CC(Cl)=C(Cl)C=2)CCC1)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH2:18])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: NC=O
Agent: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O=CO
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 180 °C

Procedure:
The 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (9,1 g) prepared above, formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180° C. for 16 hours to result in N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine. Concentrated hydrochloric acid (20 ml) was added, and the mixture was refluxed for 3 hours. The solution was then cooled and washed with ether, and sodium hydroxide solution was added. The product was extracted with ether, and the ether extract was washed with water, dried and evaporated. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was isolated by distillation (boiling point: 112 to 118° C. under 0.27 mbar). The amine was dissolved in 2-propanol and concentrated hydrochloric acid, and the solution was evaporated to dryness to result in 1-[1-(3,4-dichlorophenyl)cyclobutyl]-ethylamine.hydrochloride (melting point: 185 to 195° C.). (Formula III: n=0; R1 =methyl; R2, R3 and R4 =H; R5 =4-Cl; R6 =3-Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OB(O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 78 %

Procedure:
A mixture of 3,4,5-trichlorophenylboronic acid (4.5 g, 20 mmol), 2-bromo-3,3,3-trifluoro-prop-1-ene (4.9 g, 28 mmol), Cs2CO3 (20 mL, 2 M, 40 mmol) and Pd(PPh3)2Cl2 (421 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.3 g; yield 80%). 1H NMR (500 MHz, CDCl3): δ 7.40 (s, 2H), 5.99 (s, 1H), 5.76 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][Br:17])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ncsc2C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ncsc2CBr)c1
Yield: 104.6 %

Procedure:
A mixture of 3-(5-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.40 g), N-bromosuccinimid (2.01 g) and α,α′-bis(isobutyronitrile) (0.02 g) in CCl4 (40 mL) was heated at reflux for 30 min. The cooled mixture was filtered and the solvent was evaporated to give crude 3-(5-bromomethyl-thiazol-4-yl)-benzoic acid methyl ester (3.36 g) as an oil.
Reaction SMILES: C(OC([NH:8][C@@:9]([CH3:26])([C:17]([NH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:26][C@:9]([C:17]([NH:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8]
Reactant: CCOC(=O)CNC(=O)[C@@](C)(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)[C@](C)(N)Cc1ccccc1
Reaction time: 1.5 h

Procedure:
[N-(tert-butyloxycarbonyl)-α-methyl-(R)-phenylalanyl]glycine, ethyl ester was stirred at ambient temperature in 4N HCl in dioxane (30 ml). After 1.5 h, the solvent was removed in vacuo. The residue was transferred to a separatory funnel with EtOAc. Extraction with EtOAc (2×) and washing of the combined organic layers brine and drying with MgSO4 afforded 0.63 g of crude product after evaporation of the solvent. This was used in the next step without further purification. MS (ESI) 265 (M+H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCN(C)C.CC(C)C[Li].[O:27]=[C:28]1[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:29]1>C(OCC)C>[OH:27][C:28]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)CCN(C)C
Agent: [Li]CC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 1,1-dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added N,N,N′,N′-tetramethylethane-1,2-diamine (0.41 mL, 2.7 mmol), and the solution was cooled to −78° C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-1-carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than −60° C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H), 4.00 (d, 1H), 3.84 (d, 2H), 3.80 (broad s, 1H), 3.55 (broad s, 1H), 3.10 (broad s, 1H), 1.92 (m, 1H), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI) for C21H30N2O5: 335 (M-tBu), 315 (M-OtBu).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C#N)=[CH:6][C:5]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([O-:3])=[O:2].C(=O)([O-])[O-:28].[K+].[K+]>CN(C)C(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:28])=[CH:6][C:5]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture of 26.2 parts of intermediate 55, namely 4-nitro-α-phenyl-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneacetonitrile, 10.2 parts of potassium carbonate and 376 parts of N,N-dimethylacetamide was stirred at room temperature while air was bubbled through. The reaction mixture was poured into water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated, yielding 25 parts (98.6%) of [4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone (interm. 56).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O:33]CC)=[O:32].[OH-].[Na+].Cl.CCOC(C)=O>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
Ethyl 6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (128.8 g, 250.4 mmol) was dissolved in EtOH (250 mL) and THF (500 mL). NaOH (6N) (62.60 ml, 375.6 mmol) was added and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was transferred to a 2 L separatory funnel and 1N HCl (500.8 ml, 500.8 mmol) was added to the mixture. Additional EtOAc (250 ml) was added and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude solid was recrystallized from THF and hexanes to provide 122.0 g of the title compound as a faint pink solid (yield 95.0%). 1H NMR analysis showed that the solid contained THF. The THF content was 27 mol % (5.2% weight) and the desired product content by weight was 94.8%. MS (apci) m/z=486.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([OH:22])([CH3:21])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:24][C:2]([F:1])([F:23])[C:3]([OH:22])([CH3:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(/C=C/c1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of 4,4,4-trifluoro-3-hydroxy-3-methyl-1-[4-(pyrid-4-ylsulfonyl)phenyl]but-1-yne (0.32 g, 0.90 mmol) in dry tetrahydrofuran (5 mL) was added lithium aluminum hydride (44.4 mg, 1.17 mmol) portionwise over 1 minute and the suspension was stirred for 1 hour. The crude reaction mixture was treated sequentially with water (0.4 mL), 2N sodium hydroxide (0.4 mL), and water (1 mL). This mixture was stirred for 10 minutes, filtered through diatomaceous earth with ethyl acetate. The combined washings and filtrate were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were dried and evaporated. The crude oil was purified by chromatography with ethyl acetate:dichloromethane as the eluent (1:5) to yield the title compound as a white solid (60 mg, 18%); mp 168°-171° C.; NMR (CDCl3): 1.59 (s,3, CH3), 2.43 (s,1, OH), 6.41 (d,1, J=15.9, vinylic), 6.93 (d,1, J=15.9, vinylic), 7.56 (d,2, J=5.9, Ar), 7.76 (d,2, J=5.9, Ar), 7.93 (d,2, J=8.3, Ar), 8.82 (d,2, J=5.9, Ar); MS (EI): m/z=357(M+). Analysis for C16H14F3NO3S: Calculated: C, 53.77; H, 3.95; N, 3.92; Found: C, 53.41; H, 4.05; N, 3.84.
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1I.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[F:27])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Reactant: Fc1ccc(F)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc2ncc(C#Cc3cc(F)ccc3F)cn2n1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
2-tert-Butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) (100 mg, 0.37 mmol) was dissolved in DMF (1 ml). 1,4-Difluoro-2-iodobenzene (176 mg, 0.73 mmol, 2 equiv.), Et3N (150 μl, 1.1 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium (II) dichloride (13 mg, 0.02 mmol, 0.05 equiv.), triphenylphosphine (3 mg, 0.011 mmol, 0.03 equiv.) and copper (I) iodide (2 mg, 0.011, 0.03 equiv.) were added under nitrogen and the mixture was heated to 80° C. TBAF 1M in THF (440 μl, 0.44 mmol, 1.2 equiv.) was added dropwise in 20 minutes at 80° C. The reaction mixture was stirred for 5 minutes at 80° C. The reaction mixture was evaporated and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->50:50. The desired 2-tert-butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine (73 mg, 64% yield) was obtained as a light yellow solid, MS: m/e=313.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([S:12](=[O:16])(=[O:15])[NH:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:11][C:10]1[CH:9]=[C:8]([S:12]([NH:13][CH3:14])(=[O:16])=[O:15])[CH:7]=[C:3]([C:4]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[O:6])[C:2]=1[F:1]
Reactant: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared in analogy to Example BO by reaction of 2,3-Difluoro-5-methylsulfamoyl-benzoic acid and 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7]) to yield the title compound as a light yellow amorpous solid. (m/e): 462.1 (M−H, 100%).
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Al+3].[Cl-].[Cl-].[Cl-].[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([C:11]([OH:13])=[O:12])([CH2:8]3)[CH2:2]1)[CH2:4]2
Reactant: BrBr
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Temperature: 5 °C
Reaction time: 48 h
Yield: 75.6 %

Procedure:
More specifically, adamantane-1-carboxylic acid (1) (45 g, 0.25 mol) was added to mixture of AlCl3 (45 g, 0.34 mol) and Br2 (450 g) at 0° C. and stirred at 0-10° C. for 48 hrs, kept 5 hrs at about 20° C., poured on to 500 g crushed ice, diluted with 300 ml CHCl3 and decolorized with solid Na2S2O5. The aqueous phase was extracted with Et2O (50 ml×2). The combined organic solution was washed with H2O and extracted with 10% NaOH. The alkaline extraction was acidified with 2N H2SO4 and provided 49 g (yield=75.7%) of 3-bromo-adamantane-1-carboxylic acid (2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCOCC2)CCOC1
Reaction time: 5 h

Procedure:
650 mg of tetrahydro-4H-pyran-4-one together with 950 mg of morpholine were dissolved in 10 ml of toluene and the mixture was heated under reflux in a light water separator for 5 hours. Subsequently, the mixture was concentrated under reduced pressure, and residue (1.3 g) was used further without further workup.
Reaction SMILES: [OH:1][C@@:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH2:20])=[O:8])=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[OH:1][C@@:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH:20][S:39]([CH3:38])(=[O:41])=[O:40])=[O:8])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCNS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-((2R)-2-hydroxy-2-phenylpropanoyl)-N-(2-(2-aminoethyl)-5-chlorobenzyl)-L-prolinamide (90 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added triethylamine (50 microliters, 0.35 mmol) and methanesulfonyl chloride (16 microliters, 0.21 mmol). The mixture was stirred at ambient temperature for 30 min. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid (TLC Rf=0.2 (98:2 CH2Cl2:MeOH); HPLC RT=3.05 min, method A; LC-MS m/z=508).
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([O:8][CH:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[C:12]=3[C@H:11]([CH3:31])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([O:8][C@H:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]4)[C:12]=3[C@H:11]([CH3:31])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CC(OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 37.3 %

Procedure:
(R)-tert-Butyl 4-(7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.832 g, 1.608 mmol) was subjected to chromatography on SiO2 eluting with 2:1 hexanes:ethyl acetate to give tert-butyl 4-((5R,7R)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.31 g, 37%); then switching to 1:1 hexane:ethyl acetate to give tert-butyl 4-((5R,7S)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (415.3 mg, 49%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:11]1([CH2:17][C:18]2[N:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1c[nH]c(CN2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-n1ccnc1CN1CCOCC1

Procedure:
Combine 10 g of 2-fluoronitrobenzene, 13 g of 2-((4-morpholinyl)methyl)-imidazole, 18 mL of N,N-diisopropyl ethylamine, and 150 mL of acetonitrile, and heat at reflux for 48 hr. Remove the solvent under vacuum, and dissolve the residue in 500 mL of 2N H2SO4. Wash the aqueous portion with 400 mL of ether, basify with K2CO3, and extract with two 400 mL portions of CH2Cl2. Combine extracts, dry over MgSO4, charcoal treat and remove the solvent under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:32]1[C:36]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.CN>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O.C(N(CC)CC)C>[CH3:36][NH:32][C:27](=[O:29])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.4 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), methylamine hydrochloride (47 mg), and triethylamine (100 μL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) and crystallized from acetonitrile to give the title compound (64 mg, yield 41%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 0.418 g of 2-chlorobenzene-sulfonyl chloride in 5 ml of dichloromethane, cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-amino-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.346 μl of triethylamine. The mixture is stirred at room temperature overnight and diluted with 50 ml of dichloromethane. The mixture is washed with 20 ml each of H2O, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates (4) with the solvent ethyl acetate-hexane (1:1) to give a solid. Crystallization from ethyl acetate gives 0.165 g of white crystals, m.p. 206°-210° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CCN(CC)CC.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C(Cl)Cl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH:6]=[O:7])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccnc2C=O)cc1
Yield: 58.2 %

Procedure:
To a suspension of 2-imidazolecarboxaldehyde (1.01 g, 10.51 mmol) in CH2Cl2 (25 mL) was added Et3N (2.9 mL, 21.02 mmol) and tosyl chloride (3.01 g, 15.77 mmol) and the reaction mixture was heated to reflux overnight. Then the mixture was cooled and washed with saturated NH4Cl (4×30 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded 1-(toluene-4-sulfonyl)-1H-imidazole-2-carbaldehyde as a yellow oil (1.53 g, 58%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 7.31 (s, 1H), 7.49 (d, 2H, J=6.0 Hz), 7.83 (s, 1H), 8.00 (d, 2H, J=7.5 hz), 9.78 (s, 1H).