Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH:47]([CH3:49])[CH3:48])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH:47]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1)([CH3:49])[CH3:48]
Reactant: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 114.2 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-isopropyl-1H-indol-3-yl)propanoic acid (609 mg) synthesized in Referential Example 1(e) were used, whereby the title compound (1.12 g) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)C(=O)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Isobutyryl chloride (0.03 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 72 (14 mg, 15% yield) as a white fluffy solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([C:31](=[O:34])[CH2:32][CH3:33])[CH:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C.C(OCC)(=O)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([C:31](=[O:34])[CH2:32][CH3:33])[CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:14]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCC(=O)N1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCS
Product: CCC(=O)N1C(=S)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
1,6-Dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-(1-oxopropyl)-5-pyrimidinecarboxylic acid, methyl ester (1.6 g., 3.3 mmole) in 20 ml of dichloromethane under argon at room temperature is treated with trifluoroacetic acid (0.75 ml., 1.1 g., 9.7 mmole) and ethanethiol (0.4 ml, 0.33 g, 5.4 mmole). After 3 hours, volatiles are evaporated in vacuo and the residue (solidified) is triturated with isopropyl ether to give 0.95 g. of product, m.p. 167°-171°. TLC(silica gel; ethyl acetate:hexanes, 1:1) Rf =0.50.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][OH:36]>CN(C)C=O>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:34][CH2:35][OH:36])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCBr
Reactant: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a 5 ml N,N-dimethylformamide solution of 150 mg (0.423 mmol) of the compound obtained in Example 36, 87.7 mg (0.635 mmol) of potassium carbonate and 33 μl (0.466 mmol) of 2-bromoethanol were added. The mixture was stirred at 100° C. for 1 hour and at 120° C. for 2 hours. Further, 16 μl (0.233 mmol) of 2-bromoethanol was added, and the mixture was stirred at 120° C. for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and further recrystallized (toluene) to obtain 60 mg (36%) of the captioned compound.
Reaction SMILES: [Cl:1][CH:2]([F:10])[CH:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]>[Zn]>[Cl:1][C:2]([F:10])=[C:3]([Cl:9])[O:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(Cl)C(Cl)OC(F)(F)F
Agent: [Zn]
Product: FC(Cl)=C(Cl)OC(F)(F)F
Temperature: -75 °C
Yield: 83 %

Procedure:
In a 1 l three necked flask, equipped with magnetic stirrer, thermometer, dropping funnel, and connected through a Vigreux column and a condenser to a trap maintained at -75° C., 80.0 g of zinc powder, activated by washing with HCl 3N, 550 ml of DMF and 50 mg of KI were charged under nitrogen atmosphere. The internal temperature was brought to 80° C. and 102.0 g of 1,1,2,2-tetrachloro-1-fluoro-2-trifluoromethoxyethane (377m moles), were added dropwise. During the addition, the temperature increased up to 90° C. When the addition was over, the reaction mixture was stirred for 1 additional hour at 90° C. In the cold trap 62.8 g (315 mmoles) of 1,2-dichloro-1-fluoro-2-trifluoromethoxyethane (cis/trans 50%/50%) condensed. The 1,2-dichloro-1-fluoro-2-trifluoromethoxyethene (trans+cis) yield was 83%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]1[CH2:27][O:26]1)([CH3:20])([CH3:19])[CH3:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]([OH:26])[CH2:27][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2)([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CC1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CC1CC1

Procedure:
5-Amino-1-cyclopropylmethyl-7-fluoro-1,3-dihydro-indol-2-one (1.00 g, 4.55 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.79 g, 4.55 mmol) and lithium trifluoromethanesulfonate (0.618 g, 4.55 mmol) in acetonitrile (20 ml) are heated at 90° C. for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% ethyl acetate/hexane) gives the title compound as a white solid. HPLC r.t. 4.35 min; MS for C20H28FN3O4 m/z 394.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].COC(OC)OC.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][CH:20]([C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)[O:4][CH2:3]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 101.3 %

Procedure:
After successive addition of 37.5 g of 2,2-dimethyl-propane-1,3-diol, 18,75 ml of ortho-formic acid trimethylester and 20 mg of p-toluene sulfonic acid, a solution of 25 g of 4-bromobenzaldehyde in 250 ml of dichloromethane is stirred for 24 hours at room temperature. To finish the compound it is poured into saturated, aqueous NaHCO3 solution and extracted with diethylether. Crystallization of the crude product from hexane yields 37.1 g of 4-(5,5-dimethyl-1-,3-dioxan-2-yl)-bromobenzene with a melting point of 62°-64° C.
Reaction SMILES: BrC1N=C(NC2C=CC(C3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)C(=O)N(C)C=1.[CH3:30][CH:31]1[CH2:34][N:33]([C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:32]1.Br[C:43]1[C:44](=[O:51])[N:45]([CH3:50])[CH:46]=[C:47]([Br:49])[CH:48]=1>>[Br:49][C:47]1[CH:48]=[C:43]([NH:41][C:38]2[CH:37]=[CH:36][C:35]([N:33]3[CH2:34][CH:31]([CH3:30])[CH2:32]3)=[CH:40][N:39]=2)[C:44](=[O:51])[N:45]([CH3:50])[CH:46]=1
Reactant: CC1CN(c2ccc(N)nc2)C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Product: CC1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Yield: 43.8 %

Procedure:
Using the same procedure as described for the preparation of 121a, a reaction of 236b (1.04 g, 6.40 mmol) with 3,5-dibromo-1-methylpyridin-2(1H)-one (1.90 g, 7.12 mmol) afforded a 44% yield (980 mg) of 236c as a brown solid: mp 135-136° C.; 1H NMR (500 MHz, DMSO-d6) d 8.49 (d, 1H, J=5.5 Hz), 8.42 (s, 1H), 7.50 (d, 1H, J=4.5 Hz), 7.41 (d, 1H, J=7.0 Hz), 7.20 (d, 1H, J=14.5 Hz), 6.85 (dd, 1H, J=14.5, 5.0 Hz), 3.91 (m, 2H), 3.49 (s, 3H), 3.34 (m, 2H), 2.75 (m, 1H), 1.21 (d, 3H, J=11.5 Hz; MS (ESI+) m/z 350.2 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.CC1(S(N)(=O)=O)CC1>>[CH2:12]([C:9]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:10][CH2:11]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)NS(=O)(=O)C1(Cc2ccccc2)CC1
Agent: CC1(S(N)(=O)=O)CC1
Product: NS(=O)(=O)C1(Cc2ccccc2)CC1
Yield: 66 %

Procedure:
This compound, Example 7,1-Benzylcyclopropylsulfonamide, was obtained in 66% yield from N-tert-butyl(1-benzyl)cyclopropylsul-fonamide using the procedure described for the synthesis of 1-Methylcyclopropylsulfonamide, followed by recrystallization from the minimum amount of 10% EtOAc in hexane: 1H NMR (CDCl3) δ 0.90 (m, 2H), 1.42 (m, 2H), 3.25 (s, 2H), 4.05 (s, 2H), 7.29 (m, 3H), 7.34 (m, 2H); 13C NMR (CDCl3) δ 11.1, 36.8, 41.9, 127.4, 128.8, 129.9, 136.5.
Reaction SMILES: [CH:1]1([CH:4]([O:12][CH2:13][CH:14]=[N:15][OH:16])[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.C1([C@@H]2OCC3=NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:12][CH2:13][C:14]3=[N:15][O:16][C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)/C=C/CC(OCC=NO)C1CC1
Agent: C1O[C@@H](C2CC2)C[C@H]2CON=C12
Product: COC(=O)[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21

Procedure:
Methyl (2E)-5-cyclopropyl-5-{[2-(hydroxyimino)ethyl]oxy}pent-2-enoate (C35) was converted to the product using the method described for synthesis of rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) in Example 2. The product was obtained as a solid; the indicated relative stereochemistry was assigned by analogy with C27 in Example 3. Yield: 3.30 g, 14.7 mmol, 95%. 1H NMR (400 MHz, CDCl3) δ 4.70 (br d, J=13.3 Hz, 1H), 4.61 (d, J=10.2 Hz, 1H), 4.13 (dd, J=13.3, 1.2 Hz, 1H), 3.83 (s, 3H), 3.55-3.64 (m, 1H), 2.84 (ddd, J=11.0, 7.9, 1.9 Hz, 1H), 2.39 (ddd, J=12.9, 6.6, 1.7 Hz, 1H), 1.75 (ddd, J=12.9, 11.5, 11.3 Hz, 1H), 0.89-0.98 (m, 1H), 0.51-0.64 (m, 2H), 0.38-0.45 (m, 1H), 0.22-0.29 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][N:20](C)C)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]#[N:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: O
Product: N#CCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 45.8 %

Procedure:
18.7 g of N-[2-(3-benzyloxy-4-nitrophenyl)ethenyl]-N,N-dimethylamine and 21.3 g of hydroxylamineorthosulfonic acid in 420 ml of water are stirred for 3 days at room temperature. The thus-separated solid product is chromatographed on silica gel with cyclohexane/acetic acid (1:1), thus obtaining 7.7 g of (3-benzyloxy-4-nitrophenyl)acetonitrile, mp 73°-85° C.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[CH:24][N:23]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[CH:24][N:23]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ncno2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ncno3)N1C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
BCl3 (1M in DCM, 1.2 mL, 1.2 mmol) was added to (2S,5R)-6-(benzyloxy)-2-(1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (50 mg, 0.167 mmol) in DCM (10 mL) at −78° C. The mixture was warmed to 0° C. and stirred for 2 hrs. The reaction was then quenched by the addition of MeOH (1 mL) and the resulting solution was concentrated under vacuum to give (2S,5R)-6-hydroxy-2-(1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (34 mg, 98%) as a white solid, which was used directly in the next step. ESI-MS (EI+, 211, m/z): [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (466 mg, 1.5 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (467 mg, 1.5 mmol) according to the general procedure M. Obtained as an orange oil (360 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 39.4 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.040 ml) and ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 31) (0.10 g) as colorless crystals.
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:34])[N:14]([CH3:33])[C:15]([CH:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>O1CCCC1>[C:29]([O:28][CH:24]([C:15]1[N:14]([CH3:33])[C:13](=[O:34])[C:12]2[NH:8][CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[C:25]([OH:27])=[O:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
An ice cold mixture of 2-(1-benzyl-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (200 mg, 0.423 mmol) in Tetrahydrofuran (THF) (2.0 mL) was treated with dropwise addition of LDA, 2M solution in heptane/THF/ethylbenzene (0.423 mL, 0.846 mmol) and then allowed to stir at 0° C. for 20 minutes. Additional LDA (0.212 mL, 0.423 mmol) was added and then stirred an additional 20 minutes. The mixture was quenched by adding 1N HCl, acidified to pH 2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude debenzylation product which was used crude in the next step. LC/MS (m/z) ES+=369 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)[C:6]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][CH:8]=1)#[CH:2].C[Si]([N:32]=[N+:33]=[N-:34])(C)C>>[CH2:10]([O:9][C:6]1[C:5]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:4][C:3]([C:1]2[NH:34][N:33]=[N:32][CH:2]=2)=[CH:8][N:7]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: C#Cc1cnc(OCC(C)C)c(-c2nc3c(CCC)n(C)nc3c(=O)[nH]2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CCCc1c2nc(-c3cc(-c4cnn[nH]4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 49.4 %

Procedure:
5-(5-Ethynyl-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-a]pyrimidin-7-one (Example 27) (200 mg, 0.54 mmol) and trimethylsilylazide (630 mg, 5.4 mmol) were stirred at 170° C. in a sealed pressure vessel for 14 h. The reaction mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The brown precipitate was filtered off and the 2 phases separated. The organic phase was washed with more sodium bicarbonate solution and brine, dried with (MgSO4) and concentrated. This residue was combined with the original precipitate and purified by flash column chromatography (gradient elution from dichloromethane to 5% methanol:dichloromethane) to give 109 mg of a white solid (49%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:64])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][N:39]([NH:64][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:40][C@H:41]([OH:63])[C@@H:42]([NH:50][C:51](=[O:62])[C@H:52]([C@H:58]([CH2:60][CH3:61])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:36][CH:37]=2)=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2 ml of DMF and 418 μl of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane in 5 ml of DMF to form the title compound: m.p: 202°-204° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O)(C)C.[CH:8]1([C:14](=O)[CH:15]([CH3:24])[C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([C:14]2[C:15]([CH3:24])=[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:2]([CH3:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CNN
Reactant: CC(C(=O)C1CCCCC1)C(=O)C1CCCCC1
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C2CCCCC2)nn(C)c1C1CCCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
Methylhydrazine (1.0 g, 0.022 mole) is added at 60° C-70° C with stirring to an isopropanol (200 ml) solution of 1,3-dicyclohexyl-2-methyl-1,3-propanedione (5.0 g, 0.02 mole) having a m.p. =36°--37° C and prepared by the procedure of Example 3 above. The reaction is heated at reflux for 4 hours, then cooled, water (300 ml) added and the resulting solid filtered off. The solid is dissolved in anhydrous toluene, methyl hydrazine (1.0 g, 0.022 mole) added and the reaction mixture heated at 90° C for 4 hours. Then additional methyl hydrazine (1.0 g, 0.022 mole) is added and heating continued for 3 hours. The reaction mixture is cooled. The solvent removed on a rotary evaporator and the resulting solid crystallized from hexane/benzene to give 1.7 g (32%) of the desired product, m.p. 120° C to 122° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: C1CCNC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(CN3CCCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
A suspension of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.18 g, 17.44 mmol), potassium carbonate (2.89 g, 20.93 mmol) and N,N-dimethylformamide (75 mL) was treated with pyrrolidine (1.875 mL, 22.67 mmol), and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to ambient temperature, diluted with ether (115 mL), and filtered. The filtrate was concentrated to dryness to provide the title compound. MS ESI(+) m/z 288.2 [M+H]+.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccccc1Cl
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2Cl)C1=O
Yield: 71.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-chloroaniline (0.464 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.253 g (72%) was obtained as a yellow solid.