Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[N:2]1[C:6](=[O:7])CCC1=O.[CH2:9]([N:16]1[CH2:23][CH:22]2[O:24][CH:18]([CH2:19][N:20]([CH2:25][CH2:26]C(N)=O)[CH2:21]2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH2:30]>CC(C)([O-])C.[K+].C(O)(C)(C)C>[C:10]([O:30][C:6](=[O:7])[NH:2][CH2:26][CH2:25][N:20]1[CH2:19][CH:18]2[O:24][CH:22]([CH2:23][N:16]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[CH2:21]1)([CH3:15])([CH3:11])[CH3:9]
Reactant: NC(=O)CCN1CC2CN(Cc3ccccc3)CC(C1)O2
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Yield: 100 %

Procedure:
N-Bromosuccinimide (6.0 g, 33 mmol) was added in portions over 1 minute to a solution of 3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propionamide (see step (i) above; 5 g, 12 mmol) in potassium tert-butoxide in tert-butanol (1 M, 81 mL) and tert-butanol (20 mL). The mixture was then heated at 60–65° C. for 30 minutes. The reaction was allowed to come to room temperature and then water (100 mL) was added. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered (washing the filter cake with ethyl acetate (50 mL)) and then the filtrate concentrated under reduced pressure to give the title compound as a brown oil (6.5 g, >100%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[Cl:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:20])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reactant: Cc1cc(B(O)O)ccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2c[nH]c3cc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)ccc23)ccn1
Temperature: 130 °C

Procedure:
To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.095 g of crude (2-methyl-4-pyridinyl)-boronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to 0.071 g of crude product. Purification via flash chromatography on silica gel (95:5:0.5 methylene chloride/methanol/ammonium hydroxide) afforded 2-chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide as a tan powder. MS (m/z): 424 (M−1); Rf 0.06 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: [OH:1][C@H:2]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][NH:4][C@H:5]([CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[OH-].[K+].CO>O>[OH:1][C@H:2]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][NH:4][C@H:5]([CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: COC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A solution of methyl 3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-yl-ethylamino)propyl]-1H-indole-7-carboxylate (440 mg, 1.24 mmol) and potassium hydroxide (1.14 g, 20 mmol) in water (2 mL)/methanol (10 mL) is stirred at room temperature for 19 hours. After concentrated, the resultant is purified by reversed phase column chromatography (octadecylsilyl, trifluoroacetic acid/water/methanol) to give the desired 3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indole-7-carboxylic acid.2 trifluoroacetate (560 mg, yield: 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([OH:37])[CH2:11][CH:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[CH2:11][C@@H:10]([OH:37])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 107D (0.5 g, 0.840 mmol) in a mixture of methanol (4 mL) and ethyl acetate (4 mL) was treated with Pd(OH)2 on carbon (0.175 g, 20% Pd by wt.) and HCl solution (0.40 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 2 hours, filtered through a bed of celite®, rinsed with methanol, and concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH3:4].[CH3:17][O-:18].[Na+]>C(OC)=O>[CH:17]([CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:13]([O:15][CH3:16])=[O:14])=[O:18]
Reactant: C[O-]
Reactant: CCCCOc1ccccc1CC(=O)OC
Agent: [Na+]
Solvent: COC=O
Product: CCCCOc1ccccc1C(C=O)C(=O)OC
Temperature: 25 °C
Yield: 82 %

Procedure:
11.1 g of the product obtained by Method D are dissolved in 50 ml of methyl formate, and the solution is slowly added at 0° C. to 3.5 g of sodium methylate. The mixture is warmed to room temperature, and the bulk of the methyl formate is removed under reduced pressure. The remainder is poured onto cold 2N NaOH, and the mixture is extracted with 30 ml of methyl t-butyl ether. The aqueous phase is acidified, and the methyl α-formyl(2-butoxyphenyl)acetate is extracted with dichloromethane. Drying the organic phase over Na2SO4 gives 10.2 g (82%) of pure product.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][O:18][CH3:19])[C@H:12]([CH2:20][OH:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25].CO>C1COCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][O:18][CH3:19])[C@H:12]([CH2:20][O:21][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: COCO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a stirred solution of (±)-cis-4-methoxymethoxy-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (1.98 mmol, 0.5 g) in ether (5 mL) at 0° C. was added LAH powder (50 mg) in one lot and continued stirring at 0° C. for additional 20 min followed 10 min at room temperature. TLC analysis of an aliquot of the reaction mixture showed complete consumption of starting material. The reaction mixture was diluted with ether (5 mL), cooled to 0° C., added ethyl acetate drop-wise followed by saturated sodium sulfate. The organic layer was separated, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes to provide (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.506 g, 93%) as an oil. To a stirred suspension of sodium hydride (4.16 mmol, 0.1 g) in THF (8 mL) at room temperature was added (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.84 mmol, 0.506 g) followed 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 1.74 mmol, 0.6 g). The resultant reaction mixture was kept stirring at 50-60° C. for 2 h. The reaction mixture was cooled to room temperature and excess NaH was decomposed by addition of methanol drop-wise. This was diluted with ethyl acetate (20 mL), washed with water (5 mL), separated the organic layer, dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography by eluting with 40% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.93 g, 82% yield) as a light yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21]Br)=[CH:20][C:14]=2[CH:13]=1)=[O:11]>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][C:4]3[NH:3][CH:7]=[CH:6][N:5]=3)=[CH:20][C:14]=2[CH:13]=1)=[O:11]
Reactant: COC(=O)c1cc2cc(CBr)ccc2s1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.34 g.:50% dispersion in oil) was added portion-wise to a stirred solution of imidazole (0.48 g.) in dry dimethylformamide (DMF) (20 ml.). After 1/2 hour a solution of 5-bromomethylbenzo[b]thiophene-2-carboxylic acid methyl ester (2.0 g.) in DMF (15 ml.) was added dropwise. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and H2O (100 ml.) added to the residue. The aqueous solution was then extracted with EtOAc (3×50 ml.) and the combined organic extracts were washed (H2O), dried (MgSO4), filtered and evaporated to give a solid which was recrystallized from MeOH/H2O to give 5-(1-imidazolylmethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, 0.7 g., m.p. 168°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:26])=O>C(Cl)Cl>[ClH:26].[Cl:26][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCO)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.3 %

Procedure:
In an atmosphere of dry air, 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piperidine (1.96 g, 7.8 mmol) was dissolved in methylene chloride (10 ml) to which, with cooling in an ice bath, were subsequently added dropwise DMF (0.1 ml) and thionyl chloride (2.5 ml, 34.2 mmol). After 7 hours of stirring at room temperature, the solvent was removed by evaporation, and the resulting residue was subjected to azeotropic distillation using benzene (15 ml×2). Thereafter, the thus obtained residue was washed with an ether-methylene chloride (4:1) mixture solution (30 ml) to obtain 2.3 g (96.3%) of the title compound in the form of light beige powder.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:14][CH2:13][NH:12][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Yield: 75.9 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with 1-(2-aminoethyl)pyrrolidine (2.73 mL, 21.5 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (3.71 g, 76%).
Reaction SMILES: [ClH:1].C([NH:21][C@@H:22]([C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][C:35]([OH:43])([CH2:36]3)[CH2:34]1)[CH2:40]2)[C:23]([N:25]1[C@H:30]([C:31]#[N:32])[CH2:29][C@H:28]2[C@@H:26]1[CH2:27]2)=[O:24])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[CH2:29]1[C@@H:30]([C:31]#[N:32])[N:25]([C:23]([C@@H:22]([NH2:21])[C:33]23[CH2:34][C:35]4([OH:43])[CH2:41][CH:39]([CH2:38][CH:37]([CH2:36]4)[CH2:42]2)[CH2:40]3)=[O:24])[C@@H:26]2[C@H:28]1[CH2:27]2.[ClH:1]
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of aqueous hydrochloric acid (34.5% w/w) (2.3 g) and methanol (20 ml) was added to a mixture of (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (10.0 g) in methanol (80 ml), and the mass was stirred at 25° C. for 3 hours. Completion of the reaction was verified by HPLC. Solvent was distilled from the reaction mixture to give a residue. Ethyl acetate (100 ml) was mixed with the residue for 30 minutes at ambient temperature. The solid was filtered and washed with ethyl acetate (2×5 ml). The solid was dried under vacuum at 50-60° C. for 8 hours to give the title product (6.0 g). (Yield=90%; HPLC purity=99.5%)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.[N:11]1([CH2:17][C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[O:21][CH2:22][CH2:23][CH2:24][CH:25]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH4-].[Na+].[CH2:32](O)C>>[N:11]1([CH2:17][C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]2[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:32])=[O:8])[N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1n[nH]c(N)n1
Reactant: CCO
Reactant: O=CCCCOc1cccc(CN2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (0.568 g) and 4-[3-(1-piperidinylmethyl)phenoxy]butanal in ethanol (40 ml) were heated at reflux for 2 h. The cooled reaction mixture was treated with sodium borohydride (0.4 g) and stirred at room temperature for 15 h. The solvent was evaporated and the residue was dissolved in 2N hydrochloric acid which was washed with ethyl acetate, basified with sodium carbonate and extracted with ethyl acetate. The combined organic extracts were evaporated to yield the title compound as a white solid which was recrystallised from a mixture of ethyl acetate and ethanol (1:1) (0.5 g) m.p. 170°-1° dec.; tlc System B, Rf 0.8.
Reaction SMILES: [NH2:1][N:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]1=[NH2+:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH-].[Na+].[Cl:26][CH2:27][C:28](OC)=O>CCO>[Cl:26][CH2:27][C:28]1[N:10]=[C:3]2[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([CH3:8])[N:2]2[N:1]=1
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C)n2nc(CCl)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A mixture of 1-amino-3,6-dimethylpyrazin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (2.0 g, 5.9 mmol) and NaOH (480 mg, 12 mmol) in EtOH (20 mL) was stirred at 60° C. for 1 h. Methyl 2-chloroacetate (1.34 g, 12.4 mmol) was then added slowly. The reaction mixture was refluxed for 4 h, then the solvent was removed. The product was purified by silica gel column chromatography to give 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine as a yellow solid (420 mg, yield 36.3%). ESI MS: m/z 197 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[C:4](=O)[CH2:5][CH2:6][C:7]=1[CH3:8].[CH:10]1([Li])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O.[CH3:21]CCCCC>O1CCCC1.C1(C)C=CC=CC=1>[CH:10]1([CH2:2][C:3]2[C:4]([CH3:21])=[CH:5][CH2:6][C:7]=2[CH3:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CCCCCC
Reactant: CC1=C(CO)C(=O)CC1
Reactant: [Li]C1C=Cc2ccccc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC1=CCC(C)=C1CC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
2-(hydroxymethyl)-3-methyl-2-cyclopenten-1-one (2.98 g, 14.3 mmol) prepared in Example 15 was dissolved in 2 mL of tetrahydrofuran. This solution was added to a solution prepared by stirring indenyllithium (4.36 g, 35.8 mmol) dissolved in 30 mL of tetrahydrofuran at −30° C. The solution was stirred at room temperature for 12 hours. After adding 40 mL of water, the solution was extracted twice with 40 mL of diethyl ether using a separatory funnel. After taking the organic layer, moisture was removed with magnesium sulfate, and the solvent was removed using a rotary evaporator. A pure target compound (2.29 g, yield: 72%) was obtained by column chromatography (hexane:toluene=10:1) using silica.
Reaction SMILES: [CH2:1]([N:13]1[C:17](=[O:18])[C:16]2([CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[NH:15][C:14]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:29]1[CH2:40][CH:30]1[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH:37]1[O:39][CH2:38]1>C(O)CCCCCCC.C(OCC)(=O)C>[CH2:1]([N:13]1[C:17](=[O:18])[C:16]2([CH2:19][C:20]([CH3:27])([CH3:26])[N:21]([CH2:38][CH:37]([OH:39])[CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH:30]([OH:29])[CH2:40][N:21]3[C:22]([CH3:25])([CH3:24])[CH2:23][C:16]4([NH:15][C:14](=[O:28])[N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:17]4=[O:18])[CH2:19][C:20]3([CH3:26])[CH3:27])[C:22]([CH3:25])([CH3:24])[CH2:23]2)[NH:15][C:14]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: CCCCCCCCCCCCN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O
Solvent: CCOC(C)=O
Solvent: CCCCCCCCO
Product: CCCCCCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COCCOCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCCCCCC)C4=O)C(C)(C)C2)C1=O
Temperature: 180 °C

Procedure:
A mixture of 8.6 g of 3-dodecyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.7 g of ethylene glycol bis(2,3-epoxypropyl)ether in 3 ml of octanol was heated to 180° C. for 30 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and subjected to column chromatography through alumina eluted successively first with diethyl ether, second with a 10:1 by volume mixture of ethyl acetate and triethylamine, and lastly with methanol. The eluate eluted with the last solvent was separated and the solvent was removed therefrom by evaporation under reduced pressure, giving the desired Compound No. 355 in the form of white crystals melting at 74°-76° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>COCCOC>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 28.2 g (0.2 mol) of 1-fluoro-4-nitrobenzene, 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml of triethylamine in 30 ml of 1,2-dimethoxyethane was heated for half an hour with stirring. The mixture was poured into 1.5 liters of ice-cold water and the crystalline precipitate was filtered off, reimpasted in water and then in isopropyl alcohol and dried under vacuum at 40° C. over phosphorus pentoxide. Yellow crystals (36.6 g) which, after purification by recrystallization from refluxing 96° ethanol, melted at 124° C., were obtained, the elemental analysis of which, calculated for C12H14N4O2, was:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][Cl:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl-:15].[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc(Oc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 44.1 %

Procedure:
A stirred solution of 5.0 grams (0.0228 mole) of 3-phenoxyphenylmethyl chloride and 5.6 grams (0.0217 mole) of triphenyl phosphine in 50 mL of dry toluene was heated at reflux for 8 hours. The reaction mixture was cooled and filtered to collect a solid. The solid was washed with pentane and dried, yielding 4.6 grams of 3-phenoxyphenylmethyltriphenylphosphonium chloride. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2SC=C[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])N=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2nccs2)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 26, 150 mg, 0.43 mmol) in dichloromethane (10 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (230 mg, 0.52 mmol) and N,N-diisopropylethylamine (170 mg, 1.30 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (47 mg, 22%) as a white solid: LR-ES-MS m/z calculated for C26H34N4O5 [M]+ 482, observed [M+H]+ 483; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.94 (m, 11H) 1.04 (br. s., 3H) 1.06 (br. s., 3H) 3.81 (s, 3H) 3.89 (s, 2H) 4.13 (d, J=18.4 Hz, 1H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.70 (s, 1H) 4.81 (dd, J=10.4, 4.7 Hz, 1H) 6.44 (d, J=2.2 Hz, 1H) 6.95-7.05 (m, 1H) 7.18-7.24 (m, 1H) 7.25-7.36 (m, 2H) 7.53 (d, J=2.2 Hz, 1H) 10.79 (s, 1H).