Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](C=O)[CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].C(O)C>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[NH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)/C=C/CN(C=O)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)/C=C/CN

Procedure:
A solution of ethyl (2E)-4-(diformylamino)but-2-enoate (XV) (0.89 mg, 4.8 mmol) in a mixture trifluoroacetic acid-ethanol (absolute) (2:1, 10 mL) was stirred under reflux overnight (the reaction was followed by LC-MS and stopped when complete conversion was achieved). The solvent was evaporated under vacuum to obtain compound ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) as brown oil (undetermined yield), which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:22][N:36]=[C:25]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(Cl)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) (157 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a light yellow solid (60 mg, 24%). MS (EI) 492.1 [(M)+]; mp 260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCN(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a mixture of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (55 mg, 0.175 mmol) produced in Example (70b), propionaldehyde (20 mg, 0.350 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (75 mg, 0.350 mmol), followed by stirring for 1 hour and 15 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 56 mg of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine as a colorless solid.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][O:5][N:6]=[C:7]([C@H:11]1[C:16](=[O:17])[CH2:15][C@H:14]([CH2:18][CH:19]([S:21][CH2:22][CH3:23])[CH3:20])[CH2:13][C:12]1=[O:24])[CH2:8][CH2:9][CH3:10].[OH:25]O>CC(C)=O>[Cl:1][CH:2]=[CH:3][CH2:4][O:5][N:6]=[C:7]([C@H:11]1[C:12](=[O:24])[CH2:13][C@H:14]([CH2:18][CH:19]([S:21]([CH2:22][CH3:23])=[O:25])[CH3:20])[CH2:15][C:16]1=[O:17])[CH2:8][CH2:9][CH3:10]
Reactant: OO
Reactant: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)SCC)CC1=O
Solvent: CC(C)=O
Product: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)S(=O)CC)CC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In this example, a mixture containing 2.2 g of trans-2-[1-(3-chloroallyloxyimino)butyl]-5-(2-ethylthiopropyl) cyclohexane 1,3-dione and 1 ml of aqueous 30% hydrogen peroxide in 10 ml of acetone was stirred at room temperature for about 21/2 days and then concentrated by evaporation. The residue was mixed with 50 ml of ethyl ether, washed with 30 ml of saturated aqueous sodium bicarbonate solution, then washed with 30 ml of water, dried over magnesium sulfate and evaporated to dryness affording 1.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Temperature: 55 °C
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.18 g, 0.61 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (0.56 g, 2.44 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.116 g, 75%). LCMS m/z (%)=267 M+H+, (35Cl, 100), 269 (37Cl, 28.5)), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][O:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:12])[NH:7][O:8][CH2:9][CH2:10][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NOCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NOCCN1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 45.6 %

Procedure:
To a solution of (2-bromo-ethoxy)-carbamic acid tert-butyl ester (252 mg, 1.05 mmol) in DMF (2 mL) at room temperature is added morpholine (0.14 mL, 1.6 mmol). The reaction mixture is stirred for 7 hours at 50° C. The reaction mixture is diluted with EtOAc, and washed with water. The organic layer is dried over MgSO4, filtered, concentrated, and purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product (118 mg, 46%): MS APCI (+) m/z 247 detected.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[N:7][N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:4][CH:3]=1.Cl[Si](C)(C)C.[C:19](Cl)([Cl:21])=[O:20]>C(N(CC)CC)C>[Cl:21][C:19]([N:10]1[CH2:11][CH2:12][N:8]([N:7]=[C:5]2[CH2:4][CH:3]=[C:2]([CH3:1])[O:6]2)[C:9]1=[O:13])=[O:20]
Reactant: CC1=CCC(=NN2CCNC2=O)O1
Reactant: O=C(Cl)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC1=CCC(=NN2CCN(C(=O)Cl)C2=O)O1

Procedure:
50.0 pts. by wt. of 1-(5-methylfurylideneamino)-2-oxo-imidazolidine, 84.3 pts. by wt. of triethylamine, 84.0 pts. by wt. of chlorotrimethylsilane and 51.4 pts. by wt. of phosgene are reacted as in Example 1.2. After recrystallisation from acetonitrile, 50.7 pts. by wt. of 1-chlorocarbonyl-2-oxo-3-(5-methylfurylideneamino)-imidazolidine of dec. pt. 180°-186° C. are obtained.
Reaction SMILES: [CH:1]([P:4]([CH2:9][CH2:10][N:11](CC1C=CC(OC)=CC=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[CH:1]([P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])([CH:6]([CH3:7])[CH3:8])=[O:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(CCP(=O)(C(C)C)C(C)C)C(=O)OC(C)(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(C)P(=O)(CCNC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl [2-(diisopropylphosphoryl)ethyl](4-methoxybenzyl)carbamate (1.06 g, 2.68 mmol) in MeCN (20 mL) was cooled to 0° C. CAN (4.40 g, 8.03 mmol) in water (10 mL) was added dropwise via addition funnel over 15 minutes, and the reaction was subsequently stirred at 0° C. for an additional 1 h. The solution was then diluted with water and extracted with EtOAc (4×). The combined organic layers were washed with 10% Na2SO3 (2×). The sodium sulfite layers were then back-extracted with additional EtOAc (2×). All of the organic extracts were combined, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded tert-butyl [2-(diisopropylphosphoryl)ethyl]carbamate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 5.59 (bs, 1H), 3.50-3.42 (dt, J=13.0, 6.5 Hz, 2H), 2.01-1.92 (m, 2H), 1.88-1.83 (m, 2H), 1.39 (s, 9H), 1.18 (dd, J=14.9, 7.2 Hz, 6H), 1.14 (dd, J=15.3, 7.2 Hz, 6H). MS: cal'd 278 (MH+), exp 278 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CO[C:21](OC)([CH3:24])[C:22]#[N:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: COC(C)(C#N)OC
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c2ncc(C#N)c(-c3ccccc3Cl)c2c1
Yield: 91.8 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (20.0 g), 2,2-dimethoxypropionitrile (11.5 g), p-toluenesulfonic acid hydrate (1.46 g) and toluene (200 ml) was refluxed for 3 hrs., with removal of water by a Dean-Stark apparatus. The mixture was washed with sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resultant precipitate was collected by filtration and washed with hexane to give 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarbonitrile (20.7 g, 92.0%), which was recrystallized from ethanol to give pale yellow plates. m.p. 153°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:7]1[C:6]([CH3:13])([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: CC1(C)CC(=O)c2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(F)ccc2C1(C)C
Yield: 26 %

Procedure:
A solution of 10.0 g of 6-fluoro-3,3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxypropane was boiled under reflux for 96 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 8:1). In addition to 11.9 g of educt, there were obtained 3.38 g (26%) of (RS)-2-(2-buten-1-yl)-6-fluoro-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of ethyl 4-bromo-2-chlorobenzoate (1.00 g, 3.79 mmol), tributyl(vinyl)tin (2.41 g, 7.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (439 mg, 0.38 mmol) in DMF (15 mL) was stirred at 100° C. for 1 hr. After cooling, the mixture was diluted with water (150 mL), and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=20:1) to give the title compound (820 mg, 100%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:12][CH2:10][CH3:11])[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCN
Product: CCNc1cc(Cl)nc(N)n1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In a 50 mL flask under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and ethylamine (2.0 M in CH3OH) (15.24 mL, 30.5 mmol) and the reaction mixture was stirred at 50° C. for 3 hours. The mixture was cooled to room temperature and concentrated. The resulting yellow solid was dissolved in EtOAc and the solution was washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound (368 mg, 69%) as a yellow solid. LC-MS (ES) m/z=173 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[N:30][NH:31][N:32]=2)[CH:25]=[CH:26][CH:27]=1.[Cl:35][C:36]([Cl:52])=[CH:37][CH2:38][O:39][C:40]1[CH:49]=[C:48]([Cl:50])[C:43]([O:44][CH2:45][CH2:46]O)=[C:42]([Cl:51])[CH:41]=1>>[Cl:52][C:36]([Cl:35])=[CH:37][CH2:38][O:39][C:40]1[CH:49]=[C:48]([Cl:50])[C:43]([O:44][CH2:45][CH2:46][N:30]2[N:31]=[N:32][C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:33])[F:34])[CH:23]=3)=[N:29]2)=[C:42]([Cl:51])[CH:41]=1
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: FC(F)(F)c1cccc(-c2nn[nH]n2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cccc(-c2nnn(CCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)n2)c1
Reaction time: 1 h
Yield: 112.7 %

Procedure:
Diisopropyl azodicarboxalate (0.056 gram, 0.00028 mole) was added to a stirred, cold (0° C.) mixture of 0.072 gram (0.00028 mole) of triphenylphosphine, 0.045 gram (0.00021 mole) of 5-(3-trifluoromethylphenyl)-2H-1,2,3,4-tetrazole and 0.075 gram (0.00023 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)ethan-1-ol. The cold reaction mixture stirred for one hour at which time the mixture was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, eluting with hexanes:ethyl (80:20). The appropriate fractions were combined and concentrated under reduced pressure to yield 0.125 gram of an oil. This oil was combined with similarly obtained oils from three reactions preformed in a similar manner. The combined oil was further purified by column chromatography on silica gel, eluting with mixtures of hexanes, methylene chloride and ethyl acetate to yield 0.267 gram of the subject compound as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F-].[K+].[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23]Br)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH3:9]>>[NH:7]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:8]([C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([CH2:23][O:3][C:1]([CH3:2])=[O:4])=[O:22])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Agent: [F-]
Agent: [K+]
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
Acetic acid (230 μl, 4.02 mmol), KF (0.234 g, 4.02 mmol), 5 (1.00 g, 2.01 mmol)
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][N:24]=3)[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: c1cnc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (26, 162 mg, 0.47 mmol) in 1 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 67 mg, 0.56 mmol) and potassium hydroxide (79 mg, 1.4 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (27, 150 mg, 69%). MS (ESI) [M+H+]+=465.4.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1>>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
The title compound was prepared from tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4b) and (2-amino-1,3-thiazol-4-yl)acetic acid according to the procedure of Example 1, step A. The crude product was purified by preparative TLC plate eluting with 5% MeOH in dichloromethane to afforded the product (7.5 mg, 83%). m/z (ES) 637 (MH)+, 659 (MNa)+.
Reaction SMILES: ClCCl.[CH3:4][C:5]1[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:38][N:39]=[C:40]=[O:41]>C(OCC)(=O)C>[CH3:38][NH:39][C:40]([N:21]1[CH2:22][CH2:23][N:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=3[CH3:4])=[CH:14][CH:13]=2)(=[O:16])=[O:17])[CH:19]([C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)[CH:20]1[CH3:24])=[O:41]
Reactant: Cc1ccccc1COc1ccc(S(=O)(=O)N2CCNC(C)C2C23OCC(C)(CO2)CO3)cc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a dichloromethane (5 ml) solution of 1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-3-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine (compound of formula XLV, 1.78 g, 3.64 mmol) at about 0° C. was added methyl isocyanate (0.24 ml, 4.0 mmol). The reaction was allowed to stir for about 0.5 hour at about 23° C., was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate and then was concentrated to give 1.927 g of a compound of formula XLIV.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=2)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: COc1ccc(N)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(OC)c(OCc3ccccc3)c2)ccc1OCc1ccccc1
Reaction time: 12 h
Yield: 71 %

Procedure:
N,N-1,3-Diisopropyl carbodiimide (0.40 g, 3.36 mmol) was added to a solution of 1-benzyloxy-2-methoxy-5-aminobenzene (0.771 g, 3.36 mmol), 4-benzyloxy-3-methoxy benzoic acid (0.87 g, 3.36 mmol) and 1-hydroxybenzotriazole (0.454 g, 3.36 mmol) in N,N-dimethylformamide (15 ml) and stirred for 12 hrs. The product was precipitated by diluting with a mixture of ethyl acetate/hexane (1:1) (120 ml). Filtration of the reaction mixture provided 1.12 g of 4-Benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide. Yield 69%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.FC(F)(F)C(O)=O.[CH2:35]([C:37]1([OH:41])[CH2:40][NH:39][CH2:38]1)[CH3:36]>>[CH2:35]([C:37]1([OH:41])[CH2:40][N:39]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH:11]3[CH2:14][N:13]([C:15]([C:17]4[O:18][C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[N:20][N:21]=4)=[O:16])[CH2:12]3)=[C:2]([CH3:1])[CH:3]=2)[CH2:38]1)[CH3:36]
Reactant: CCC1(O)CNC1
Reactant: Cc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(C)c2)C1
Yield: 11 %

Procedure:
Using a similar protocol as described in Example 70 employing 74A and 70A as starting materials afforded 35 mg (11%) of 74 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.78 (q, 2H), 2.24 (s, 3H), 3.01 (d, 2H), 3.31 (d, 2H), 3.57 (s, 2H), 4.35 (m, 1H), 4.68 (m, 1H), 4.75 (m, 1H), 5.07 (m, 1H), 5.12 (m, 1H), 6.45 (d, 1H), 7.06 (d, 1H), 7.11 (s, 1H), 7.52 (t, 2H), 7.60 (t, 1H), 8.16 (d, 1H), MS (APCI+) m/z 449 [M+H]+, LC purity: 97%.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].O=[C:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19](OC)=[O:20].C([O-])(=O)C.[NH4+]>O>[OH:20][C:19]1[N:3]2[C:2](=[N:1][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=32)[C:10]([C:11]#[N:12])=[C:14]2[CH2:18][CH2:17][CH2:16][C:15]=12
Reactant: N#CCc1nc2c([nH]1)CCCC2
Reactant: COC(=O)C1CCCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1c2c(c(O)n3c4c(nc13)CCCC4)CCC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
A mixture of 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl acetonitrile (8.5 g), methyl 2-oxocyclopentanecarboxylate (7.5 g) and ammonium acetate (20.3 g) was stirred at 140° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with chloroform. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and concentrated reduced pressure. The residue was solidified using hexane/EtOAc to obtain 11-hydroxy-2,3,6,7,8,9-hexahydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carbonitrile (2.56 g).