Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:26])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][N:18]=3)[CH:16]=2)=[CH:4][CH:3]=1.[N:27]#[C:28][NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([NH:29][C:23]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:15]2[CH:16]=[C:12]([CH2:11][CH2:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:26])[CH:13]=[N:14]2)[CH:22]=1)=[O:25])#[N:27]
Reactant: CN(CCc1cnn(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Reactant: N#CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCc1cnn(-c2cc(C(=O)NC#N)ccn2)c1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A mixture of 2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylic acid (70 mg, 0.2 mmol), cyanamide (17 mg, 0.4 mmol), HATU (113 mg, 0.3 mmol) and DIEA (59 mg, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and purified by prep-HPLC to give the compound (15 mg, 20%). 1H NMR (400 MHz, DMSO-d6): 2.67-2.74 (3H, m), 2.94-2.98 (2H, m), 3.28 (1H, m), 3.43-3.45 (1H, m), 4.26-4.30 (1H, m), 4.44-4.48 (1H, m), 7.31-7.36 (2H, m), 7.59-7.61 (2H, m), 7.70-7.71 (1H, m), 7.76 (1H, s), 8.31 (1H, s), 8.42 (1H, d, J=5.2 Hz), 8.58 (1H, s), 9.56 (1H, br). [M+H] Calc'd for C20H19FN6O, 379. Found, 379.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.O>CCOCC>[OH:1][CH2:2][CH2:3][N:4]([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH3:16])[CH:19]=1)[CH2:8][CH2:7][OH:6]
Reactant: OCCN1CCOC1c1ccccc1
Reactant: COc1cccc(CCl)c1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1cccc(CC(c2ccccc2)N(CCO)CCO)c1
Yield: 70.7 %

Procedure:
A solution of 3-(2-hydroxyethyl)-2-phenyloxazolidine (11.0 g) in anhydrous ether (30 ml) is added dropwise with stirring to Grignard reagent which is prepared from magnesium turnings (3.3 g) and m-methoxybenzyl chloride (20.7 g) in anhydrous ether (150 ml), and the mixture is refluxed for 3 hours. After the reaction, the reaction mixture is decomposed by adding water thereto. The ether layer is separated and extracted with 10% hydrochloric acid (100 ml). The hydrochloric acid layer is made alkaline with ammonia and extracted with ether. The ether layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give crude dl-N,N-bis(2-hydroxyethyl)-2-(3-methoxyphenyl)-1-phenylethylamine (12.7 g) as an oily substance. When this substance is recrystallized from ethanol, it shows a melting point of 67°-69° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]2=[CH:5][N:4]=1.[Br:21]N1C(=O)CCC1=O.O>O1CCCC1>[Br:21][C:5]1[N:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:11][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCn2c(cnc2C(F)(F)F)C1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11a (370 mg, 1.27 mmol) was dissolved in 30 mL of tetrahydrofuran, followed by addition of N-bromosuccinimide (453 mg, 2.54 mmol) under −78° C. After stirring for 1 hour, the reaction mixture was heated to room temperature and reacted for 12 hours. The reaction mixture was added with 50 mL of H2O, extracted with ethyl acetate (60 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (510 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][O:10][CH:11]=[CH2:12].[OH-].[Na+]>Cl.C1(C)C=CC=CC=1>[CH3:9][O:10][CH:11]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:12]
Reactant: Oc1ccccc1O
Reactant: C=COC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(C)Oc1ccccc1O
Temperature: 0 °C

Procedure:
110 parts by weight of pyrocatechol is suspended in 100 parts by weight of toluene. At +5° C. 64 parts by weight of vinyl methyl ether which has a temperature of -40° C. is poured in all at once and then 1 drop of concentrated hydrochloric acid is added. The whole is heated to about +20° C. while stirring, whereupon the reaction commences and the temperature of the contents of the flask rises to about 65° C. External cooling with ice-water may be applied if necessary. The whole is kept for half an hour at 65° C. and then 5 parts by weight of 2-normal caustic soda solution is added. The whole is cooled, and dried by means of sodium sulfate, and the solvent is evaporated in a rotary evaporator. The product is distilled in vacuo. The yield is 155 parts by weight. The boiling point is 85° to 90° C. at 0.5 mm.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][NH:8][CH2:9][CH2:10][OH:11]>>[CH3:7][N:8]([CH2:9][CH2:10][OH:11])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: CNCCO
Reactant: Brc1nccs1
Product: CN(CCO)c1nccs1

Procedure:
The title compound was prepared as an oil from 2-bromothiazole (15 g) and 2-methylaminoethanol (45 ml) by an analogous procedure to that described in Preparation 7
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4].[OH-:21].[Na+].O.Cl>O1CCOCC1>[O:18]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([OH:4])=[O:21]
Reactant: [OH-]
Reactant: O=C(Cn1cccc1C(=O)C(Cl)(Cl)Cl)c1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Cn1cccc1C(=O)O)c1ccccn1
Temperature: 25 °C

Procedure:
To a solution of 2,2,2-trichloro-1-{1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrol-2-yl}ethanone (600 mg, 1.8 mmol) in 1,4-dioxane (20 ml) was added a solution of a aqueous solution of sodium hydroxide (1 M) (3.6 mL, 3.6 mmol) at 0° C. The mixture was allowed to warm to room temperature. After completion (30 minutes; reaction monitored by LCMS) water was added (40 mL). The mixture was then acidified with aqueous HCl (1 M) and extracted with EtOAc (3×40 mL). The organic layers were dried (Na2SO4), filtrated and concentrated in vacuo to give 1-[2-oxo-2-(pyridin-2-yl)ethyl]-1H-pyrrole-2-carboxylic acid as a pale brown solid that was used such as in the next step without purification (500 mg). ESI-MI m/z [M+H]+ 245.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]1([N:20]2[C:24]3([CH2:25][CH2:26][N:27]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:28][CH2:29]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1-c1nccs1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccccc1-c1nccs1)CC2

Procedure:
To a mixture of 2-(2-thiazolyl)benzaldehyde (200 mg, 1.06 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.232 mg, 1.00 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (376 mg, 1.79 mmol). The resultant mixture was stirred at room temperature for 18 h, quenched with aqueous NaHCO3 (50 mL) and extracted with CHCl3 (2×50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in 1:1 CHCl3:CH3OH (30 mL) and treated with 2 mL of 1 N HCl in Et2O. The HCl salt was precipitated by addition of Et2O, collected by filtration and dried in the vacuum oven at 60° C. for 18 h to yield the product as an amorphous solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([CH3:13])([CH3:12])[CH2:6]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:4][CH:5]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]2[CH:9]([CH2:26][N:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:28]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC(C)(C)C=CC1=O
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CC(C)(C)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 23.2 g of 6-acetoxy-4,4-dimethylcyclohex-2-enone and 0.8 cm3 of trifluoroacetic acid in 770 cm3 of dichloromethane are added, at room temperature, 43 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is stirred at room temperature for 15 hours then 5 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8 cm, height 53 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 250 cm3 fractions. Fractions 18 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.6 g of (3aRS,5RS,7aRS)-5 -acetoxy-2-benzyl-7,7-dimethyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([C@@H:27]([N:29]3[CH2:34][CH2:33][C@:32]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:31][C:30]3=[O:46])[CH3:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[OH:45][C:42]([CH3:43])([CH3:44])[CH2:41][C@@:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C:30](=[O:46])[N:29]([C@H:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:22][CH:23]=2)[CH3:28])[CH2:34][CH2:33]1
Reactant: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.40 mL) was added to a solution of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.29 g) in dichloromethane (10 mL). The resulting solution was stirred at room temperature overnight. Then, more dichloromethane was added and the solution was neutralized using aqueous saturated NaHCO3 solution. The organic phase was separated, washed with water, and dried (MgSO4). The solvent was removed under reduced pressure to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH2:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][NH:36][CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A2) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:27][N:28]=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[F:22][C:23]([F:38])([F:39])[C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:27][N:28]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[N:30]=[N:29]1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Yield: 88 %

Procedure:
Heat a mixture of tri-n-butyl-phenylethynyl-stannane (11.0 g, 30.0 mmol) and 3,5-bis-trifluoromethyl-benzyl azide (9.68 g, 36.0 mmol) in toluene (40 mL) at reflux until reaction is complete. Concentrate to remove the solvent in vacuo and purify the residue by flash chromatography on silica gel (elution with 17% ether in hexanes) to give the title compound (17.5 g, 26.4 mmol, 88%). MS (ES) 660.1, 662.1 (M+1); LC Rf=0.1 (17% ether in hexanes).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32]C2C=CC(C#N)=CC=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:43].[K+].Cl>C(O)CC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:31][CH2:32][C:5]2[CH:42]=[CH:41][C:8]([C:9]([OH:10])=[O:43])=[CH:7][CH:6]=2)=[CH:41][CH:42]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CCCO
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 135.1 %

Procedure:
A solution of 430 mg (0.77 mmol) of methyl 4-{(3E)4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate in 20 ml of 1-propanol is mixed with 1.73 g (30.84 mmol) of potassium hydroxide and stirred at 110° C. for 5 hours. The mixture is adjusted to pH 2 with 1 M hydrochloric acid and evaporated. The resulting residue is purified directly by preparative HPLC. 290 mg (0.52 mmol, 53% yield) of the title compound are obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH:12]12[CH2:20][CH:16]([CH2:17][NH:18][CH2:19]1)[CH2:15][N:14]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13]2>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH:2]([OH:1])[CH2:3][N:18]2[CH2:19][CH:12]3[CH2:20][CH:16]([CH2:15][N:14]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13]3)[CH2:17]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(C2CO2)cc1
Product: CC(C)OC(=O)N1CC2CC(CN(CC(O)c3ccc(C#N)cc3)C2)C1

Procedure:
The crude reaction mixture from step (a) above was condensed with iso-propyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (5.2 g; see Example H above) according to the method described in Example 7 above to give the title compound in a 73% overall yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(O[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CS(=O)(=O)OCCCOCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccn(CCCOCCOC3CCCCO3)c12
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved in N,N-dimethylformamide (4 mL), cesium carbonate (1.30 g) was added, and the mixture was stirred at 40° C. for 4.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (380.2 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][O:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH2:28][O:29][CH3:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1
Reactant: COCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COCC[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
In a round bottom flask under argon was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methoxy-butyramide (26 mg, 0.051 mmol) dissolved in methanol (3 mL). This mixture was treated with p-toluenesulfonic acid monohydrate (1.5 mg, 0.008 mmol) and stirred at 25° C. for 16 h. After this time period, the mixture was concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (4 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4-methoxy-butyramide (22 mg, 92%) as a light yellow foam: HR-ES-MS m/z calculated for C21H25N4O6Cl [M+H]+ 465.1536, observed 465.1536; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06 (br. s., 2H), 3.20 (s, 3H), 3.22-3.31 (m, 4H), 3.67-3.78 (m, 1H), 3.78-3.90 (m, 1H), 4.07 (dd, J=13.6, 3.9 Hz, 1H), 4.27 (d, J=18.4 Hz, 1H), 4.50 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.4 Hz, 1H), 4.78 (s, 1H), 4.79-4.88 (m, 1H), 4.92 (d, J=5.4 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.30-7.40 (m, 1H), 7.41-7.55 (m, 3H), 7.64 (d, J=7.2 Hz, 1H), 10.64 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][CH2:8]1
Reactant: O=C1CCOc2c1ccc(Cl)c2Cl
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)c(Cl)c2OCC1Br
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg. (0.46 mmol) 7,8-dichlorochroman-4-one was dissolved in anhydrous ethanol (5 ml) and Chloroform (5 ml). To this solution was added pyridinium tribromide (0.442 g, 1.38 mmol, 3 equiv). The reddish brown mixture was heated with stirring at 50 C for 30 min. The reaction mixture was then cooled and the solvent was evaporated. Then water (20 ml) was added to the residue and it was then extracted with 20 ml of dichloromethane. The dichloromethane layer was then washed with 5% sodium bicarbonate solution followed by water (20 ml). The organic layer was then dried and the solvent was evaporated in vacuum to yield the crude product which was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[O:7][C:6](=[S:32])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
The product was prepared, from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile and Lawesson's reagent using the procedure of Example 9, as a yellow solid: 248-249° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.15 (bs, 1H), 8.02 (d, 1H, J=10.48 Hz), 7.85-7.78 (m, 3H), 7.13 (d, 1H, J=8.92 Hz), 1.71 (s, 6H); MS (APCI) m/z 313 ([M+H]+, 100%); Anal. Calcd. For C17H13FN2OS: C, 65.37; H, 4.19; N, 8.97. Found: C, 65.26; H, 4.31; N, 8.61.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CO>[NH:17]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:18]([C:31]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 97.4 %

Procedure:
8.8 Grams (20 mM) of H-Gly-Arg-CHA.2HCl was dissolved in 21.5 ml of DMF, to this solution was added 5.1 ml (40 mM) of NEM. To the mixture was further added with 9.6 g (20 mM) of Z-D-Lys(BOC)-OSu and reacted at room temperature for 18 hours. After the reaction was completed, the DMF was removed by evaporation under a reduced pressure and the residue obtained was dissolved in MeOH and reprecipitated in 1 liter of AcOEt. The crystals precipitated were collected by filtration and dried to obtain 14.9 g (97.4%) of Z-D-Lys(BOC)-Gly-Arg-CHA.HCl. Rf1 =0.50. Melting point: 207.5° C. (decomposed). [α]D20 -8.0 (C=0.5, MeOH)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:13]C)[C:5]([CH:10]([CH3:12])[CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:12])[CH3:11])=[C:4]([OH:13])[CH:3]=1
Reactant: COc1cc(I)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(I)cc(O)c1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To a solution of 5-Iodo-2-isopropyl-1,3-dimethoxy-benzene (805 mg, 2.63 mmol) in anhydrous dichloromethane (26 mL) at 0° C. was added boron tribromide (2.63 mL, 2.63 mmol) 1M in dichloromethane), maintaining the temperature of the reaction at 0° C. during the addition. After stirring at room temperature for 18 hours, water (10 mL) was slowly added to the reaction. After stirring 30 minutes, the dichloromethane layer was collected, dried using anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with 90/10 hexane/ethyl acetate yielded 5-Iodo-2-isopropyl-3-methoxy-phenol (612 mg, 80%) as an oil, MS (M+H)=293.