Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].Br[Mg][CH2:25][CH3:26]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:12]([N:8]2[CH2:7][C@H:6]([C:4](=[O:5])[CH2:25][CH3:26])[CH2:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: -10 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of N-methoxy-1-[(1R)-1-(4-methoxyphenyl)ethyl]-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (20 g, 65.28 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), followed by the addition of bromo(ethyl)magnesium in THF (1 M) (44 mL) dropwise with stirring at −10° C. The resulting solution was stirred at −10° C. for 2 h, quenched by the addition of 200 mL of water/ice and extracted with 3×500 mL of ethyl acetate. The organic layers were combined, washed with 2×500 mL of hydrogen chloride (1 M) and 3×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate: petroleum ether (1:5-1:1) to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-propionylpyrrolidin-2-one 1.22.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])=[CH:9][C:8]=1[CH3:32])C.[OH-].[Na+]>CO>[CH3:32][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)COc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O

Procedure:
A solution of example 4 (0.105 g) in methanol (15 mL) was treated with 2N NaOH (0.5 mL) and the mixture heated to reflux for 20 minutes. The cooled reaction was concentrated and the residue diluted with water (20 mL) 2N hydrochloric acid was added and the resulting suspension extracted with dichloromethane (20 mL). The organic extract was dried over MgSO4 and concentrated to give the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:12][S:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)n1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (2.90 g, 20.0 mmol) in methylene chloride (40 mL) was added with methanesulfonyl chloride (1.86 mL, 24.0 mmol) and diisopropylethylamine (3.10 g, 24.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the objective 1-(methanesulfonyl)-1H-indole-3-carboxaldehyde (4.06 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].FC(F)(F)S(O[CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)(=O)=O.O>CS(C)=O>[C:19]12([CH2:18][O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[CH:5]=[O:6])[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2
Reactant: O=S(=O)(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (0.54 g, 4.42 mmol) in dimethyl sulfoxide (5 mL) was added sodium hydride (60%, 0.186 g) in portions. The mixture was stirred for 10 minutes and then was added a solution of Intermediate 34 (1.32 g, 4.42 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at 70° C. for 48 hours and the mixture was poured into water and extracted with ether. The organic layer was washed with a solution of sodium hydroxide 2N, water and brine. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting by hexane/ethyl acetate (10:1) to give the title compound as an oil (0.493 g, 41%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](I)[CH:9]=2)[CH2:5][O:4][C:3]1=[O:16].C([Si](CC)(CC)[CH:20]([OH:31])[CH2:21][C:22]#[C:23][Si](CC)(CC)CC)C>CS(C)=O>[CH3:1][N:2]1[C@@H:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][CH:13]=2)[NH:14][CH:23]=[C:22]3[CH2:21][CH2:20][OH:31])[CH2:5][O:4][C:3]1=[O:16]
Reactant: CC[Si](C#CCC(O)[Si](CC)(CC)CC)(CC)CC
Reactant: CN1C(=O)OC[C@@H]1Cc1ccc(N)c(I)c1
Solvent: CS(C)=O
Product: CN1C(=O)OC[C@@H]1Cc1ccc2[nH]cc(CCO)c2c1

Procedure:
Prepared from (S)-3-methyl-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-one and 1,4-bis-triethylsilyl-3-butyn-1-ol as described for Intermediate 2, δ (360 MHz, D6 -DMSO) 2.72-2.84 (6H, m, CH of CH2, CH2 and N--Me), 3.13 (1H, dd, J=3.8 and 13.5Hz, CH of CH2), 3.61-3.67 (2H, m, CH2), 3.94-4.02 (2H, m, CH2), 4.11-4.17 (1H, m, CH), 4.58 (1H, t, J=5.3Hz, OH), 6.93 (1H, dd, J=1.5 and 8.3Hz, Ar--H), 7.10 (1H, d. J=1.5Hz, Ar--H), 7.26 (1H, d, J=8.3Hz, Ar--H), 7.38 (1H, s, Ar--H), 10.72 (1H, s, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)[C:3]=1[OH:22].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)[C:3]=1[OH:22])=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
74 mg (0.178 mmol, 70% pure) of the compound from Example 71A and 44 mg (0.160 mmol) of the compound of Example 23A were dissolved in 1 ml anhydrous DMF, and 81 mg (0.213 mmol) of HATU and 37 μl (0.213 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 30 min and then stirred into about 10 ml of water. The resulting precipitate was filtered off with suction, dissolved in about 3 ml of methanol and separated into its components by preparative HPLC (Method 33). The product fractions were combined and freed from the solvent. The residue obtained was triturated with a little dichloromethane at RT. Filtration with suction and drying of the solid under high vacuum gave 36 mg (37% of theory) of the title compound.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:26][C:25]1([F:28])[F:27])=[O:23])=[O:19])C1C=CC=CC=1>CO.[Pd]>[F:28][C:25]1([F:27])[CH2:26][CH:24]1[C:22]([NH:21][NH:20][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])=[O:23]
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CC1(F)F
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CC1(F)F
Reaction time: 8 h
Yield: 135.1 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-[(2,2-difluorocyclopropyl)carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 268 (0.36 g, 0.90 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature overnight. The mixture was filtered through Celite pad and concentrated to provide 269 (0.37 g, quant. yield) as a white foam.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH3:9])=[C:6]([CH3:10])[N:5]=1
Reactant: Cc1cc(C#N)c(O)nc1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cc(C#N)c(Cl)nc1C
Yield: 53.6 %

Procedure:
An intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxypyridine (42 g) and phosphorus pentachloride (81 g) was heated at 140°-160° for 2 hours. Phosphoryl chloride was removed by distillation under reduced pressure and icewater (500 g) was added to the residue. The mixture was adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallised from ether/petroleum ether (b.p. 60°-80°) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g) m.p. 83°-87°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1c(C=O)cccc1OCc1c(C)cccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(CO)cccc1OCc1c(C)cccc1C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,6-Dimethylbenzyloxy)-2-methoxybenzaldehyde (Step B, 10.6 g, 32.7 mmol) in dry THF (40 ml) was added drop wise LiAlH4 (1M in THF, 0.95 g, 23.7 mmol) at 0° C. under argon. The reaction mixture was stirred for 1 hours or until all the starting material is consumed, then quenched by adding water slowly, followed by addition of 1N HCl (5 ml), water (10 ml), and EtOAc (20 ml) was added to the reaction mixture. The reaction mixture was concentrated, and passed through a short silica gel column using ethyl acetate to give the title compound as an off white solid.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:18])=O)C.[H-].[Na+].[C:21]1(=[O:25])[O:24]C[CH2:22]1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[O:18]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:6]1[CH2:4][CH2:22][C:21]([OH:25])=[O:24]
Reactant: O=C1CCO1
Reactant: CCOC(=O)C1CCCCCCCCCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CCC1CCCCCCCCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Cyclododecanone and diethyl carbonate were allowed to react in the presence of a base to give 2-ethoxycarbonylcyclododecanone in 93% yield. Ten grams of the 2-ethoxycarbonylcyclododecanone was dissolved in 40 ml of toluene and the resulting solution was added dropwise into a solution of 2.4 g of sodium hydride (purity 60%) suspended in toluene and kept at 80° C. After the completion of the dropping, the solution thus obtained was stirred for 30 minutes and then the reaction temperature was cooled to room temperature. Thereafter, into the solution was dropped 5.7 g of β-propiolactone and further 25 ml of aqueous sodium hydroxide solution was added, and was refluxed for 4 hour. After the reaction was complete, the aqueous layer of the solution was drawn off and acidified with hydrochloric acid to give 8.5 g of β-(2-oxocyclododecyl)propionic acid as white crystals. The product melts at 101° to 102° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.CCOC(C)=O>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:13]=[CH2:14]
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2c1ccc(Br)c2Br
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1ccc2c(c1Br)COC2=O

Procedure:
4,5-Dibromo-2-benzofuran-1(3H)-one (3.00 g, 10.3 mmol), potassium vinyltrifluoroborate (12.7 g, 20.6 mmol) and Pd (dppf)Cl2 (839 mg, 1.03 mmol) in TEA (2.7 mL) and EtOH (15 mL) were heated at 60° C. for 2 h. Analysis by TLC showed clean and complete reaction. The reaction mixture was diluted with EtOAc (500 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to purification over silica gel to give 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][F:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][CH2:32][CH2:31][CH2:30][O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCCCF)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCCCF)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-{7-[2-(3-fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3),: 7.58 (d, J=6.7 Hz, 1H, Ar—H), 7.56 (d, J=6.2 Hz, 1H, Ar—H), 7.29 (t, J=7.6 Hz, 1H, Ar—H), 7.28 (d, J=2.2 Hz, 1H, Ar—H), 7.17 (d, J=2.1 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.59 (s, 1H, C═C—H), 4.25 (dt, J=47.1 Hz, J=6.1 Hz, 2H, O—CH2—CH2—CH2F), 3.46 (t, J=5.9 Hz, 2H, O—CH2—CH2—CH2F), 3.38 (m, 1H, CH3—CH—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.56 (s, 3H, C═C—CH3), 1.70 (m, 2H, O—CH2—CH2—CH2F), 1.32 (d, J=5.7 Hz, 6H, CH3—CH—CH3), 1.30 (d, J=6.6 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:17][S:18][CH:19]=[C:3]12
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate (2.0 g., 0.0072 mol) and N-chlorosuccinimide (0.97 g., 0.0072 mol) in pyridine (20 ml) is heated on a steam bath for 18 minutes. The reaction mixture is cooled and poured into a large volume of ice water. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol gives the product (1.1 g.), mp 175°-176° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.Cl.[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH:34]5[CH2:37][N:30]([CH2:36][CH2:35]5)[CH2:31][CH2:32]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1CN2CCC(C2)N1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCN3CCC2C3)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 1,4-diazabicyclo[3.2.1]octane dihydrochloride (102 mg, 552 μmol), propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) and N,N-diisopropylethylamine (469 μl, 2.76 mmol) in tetrahydrofuran (4.5 ml) was stirred overnight at 25° C. The mixture was applied on basic silica gel and purified by column chromatography using dichloromethane/methanol 19:1 as eluent to give 4-(1,4-diaza-bicyclo[3.2.1]octane-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (45 mg, 35.7%) as a white solid. mp: 110.1, MS: m/z=457.2 (M+H+).
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[N+]=[N-].C(N(CC)CC)C.[I:32][C:33]1[CH:40]=[CH:39][C:36](CBr)=[CH:35][CH:34]=1>Cl.CO.C(Cl)Cl>[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([C@H:4]([NH2:1])[C:5](=[O:11])[N:6]3[CH2:10][CH2:9][S:8][CH2:7]3)[CH2:17][CH2:16]2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N=[N+]=[N-])C(=O)N2CCSC2)CC1
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@H](C(=O)N1CCSC1)C1CCN(Cc2ccc(I)cc2)CC1
Reaction time: 4 h

Procedure:
tert-Butyl 4-[(1S)-1-azido-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]piperidine-1-carboxylate (Example 96, step B, 215 mg, 0.6 mmol) was dissolved in a freshly prepared HCl in methanol (1 mL acetyl chloride in 9 mL of methanol) and stirred for 4 h and concentrated to remove the Boc group. A portion of this material (29 mg, 0.1 mmol) was dissolved in methylene chloride (1 mL) and triethylamine (0.041 mL, 0.3 mmol) and 4-iodobenzylbromide (44 mg, 0.15 mmol) was added. The reaction mixture was stirred for 8 h, concentrated and purified by flash chromatography (silica gel, eluent: 20% acetone in CH2Cl2) to give the 4-iodobenzylamine. This material was dissolved in wet THF (10% water) and triphenyl phosphine (26 mg, 0.1 mmol) was added. The reaction mixture was heated in an oil bath at 60° C. for 3 h, concentrated and subjected to preparative TLC on silica gel (eluent: 10% MeOH in CH2Cl2) to afford 32 mg of the title compound. 1H NMR (500 MHz, CD3OD) δ 7.85 (d, 2H, J=6 Hz), 7.34 (d, 2H, J=6 Hz), 4.75–4.46 (m, 2H), 4.38–4.28 (m, 1H), 4.47 (s, 2H), 3.92–3.64 (m, 2H), 4.53 (bs, 2H), 3.16–3.02 (m, 4H), 2.19 (m, 1H), 1.98 (m, 2H), 1.83 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C@@H:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C@H:7]([C:18]([O:20]C)=O)[CH2:6]1.[CH2-:23][CH2:24][CH2:25][CH2:26][CH2-:27].[Mg+2].[Mg+2].[Br-].[Br-].[Cl-].[NH4+]>C1COCC1>[OH:20][C:18]1([C@@H:7]2[CH2:6][C@H:5]([NH:4][CH2:3][CH:2]([CH3:1])[CH3:22])[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: [CH2-]CCC[CH2-]
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)CN[C@H]1C[C@@H](C2(O)CCCCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (3.0 g) was dissolved in THF (30 ml), a solution (15.2 ml) of 3 M pentamethylenebis(magnesium bromide) in THF was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hr. 2 N Aqueous ammonium chloride solution (50 ml) was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10→10:0) was concentrated under reduced pressure to give the object compound (1.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO3 and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. 1H NMR (300 MHz, CDCl3) δ 8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). 19F NMR (282 MHz, CDCl3) δ −129.8. High resolution mass spec: calculated for C11H14NOClF(M+H)+: 230.0748, found: 230.0760.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH3:86])[C:52]([C:54]2[CH:55]=[C:56]([S:60]([C:63]3[CH:64]=[C:65]4[C:70](=[C:71]([CH3:73])[CH:72]=3)[N:69]=[CH:68][C:67]([C:74]([NH2:76])=[O:75])=[C:66]4[NH:77][C:78]3[CH:83]=[CH:82][CH:81]=[C:80]([O:84][CH3:85])[CH:79]=3)(=[O:62])=[O:61])[CH:57]=[CH:58][CH:59]=2)=[O:53])=[CH:47][CH:46]=1)(C(C)(C)C)(C)C>>[OH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH3:86])[C:52]([C:54]2[CH:55]=[C:56]([S:60]([C:63]3[CH:64]=[C:65]4[C:70](=[C:71]([CH3:73])[CH:72]=3)[N:69]=[CH:68][C:67]([C:74]([NH2:76])=[O:75])=[C:66]4[NH:77][C:78]3[CH:83]=[CH:82][CH:81]=[C:80]([O:84][CH3:85])[CH:79]=3)(=[O:61])=[O:62])[CH:57]=[CH:58][CH:59]=2)=[O:53])=[CH:47][CH:46]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCO[Si](C)(C)C(C)(C)C)cc5)c4)cc23)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5, using Intermediate 78 as a substrate. ES/MS calcd. for C42H49N4O7S+ 753.3. Found m/z=753.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[N:24]#[C:25][NH2:26]>C(O)C>[NH2:26][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[CH:22][CH:23]=1)=[NH:24]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: N#CN
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(NC(=N)N)cc1)C(=O)OC(C)(C)C

Procedure:
10 mmol of di-(tert-butyl) 4-aminobenzylimidodicarbonate and 100 mmol of cyanamide are heated at reflux for 2 days in 80 ml of anhydrous ethanol. Removal of the ethanol by evaporation, and purification by chromatography on silica, yield the expected product.