Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[OH:19])[CH:3]=1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[O:19][CH2:21][CH2:22][OH:23])[CH:3]=1
Reactant: OCCBr
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCO
Reaction time: 22 h
Yield: 82.2 %

Procedure:
A solution of 4-chloro-2-(3-formyl-2-hydroxyphenoxy)benzonitrile (0.30 g, 1.11 mmol), 2-bromoethanol (0.10 mL, 0.18 g, 1.4 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were heated with stirring in dry DMF (3 mL) at 50° C. After 22 h, 2-bromoethanol (0.19 mL, 0.33 g, 2.7 mmol) was added, and stirring continued for an additional 24 h at 50° C. The reaction mixture was cooled, poured into-water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-[3-formyl-2-(2-hydroxyethoxy)phenoxy]benzonitrile (0.29 g, 83%) as a tan oil, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][OH:19])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4].I[CH3:44].O>CN(C)C=O>[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][O:19][CH3:44])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2cc(COC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (4.2 mg, 60% dispersion in mineral oil, 0.10 mmol) in N,N-dimethylformamide (2.5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic add ethyl ester (Example 85) (50 mg, 0.087 mmol). After the reaction was stirred at room temperature for 30 min, iodomethane (60 μL, 0.96 mmol) was added, and the reaction was stirred for 18 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 15-25% ethyl acetate/hexanes as eluent afforded the title product (30 mg, 59%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 3.4 (s, 3H), 3.75 (s, 3H), 3.8 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.75 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].CON(C)[C:22]([C@@H:24]1[CH2:28][S:27][C:26]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34](S(C2C=CC=CC=2)(=O)=O)[CH:33]=[CH:32]3)=[N:25]1)=[O:23]>C1COCC1.[OH-].[Na+].C(O)C>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([C:26]3[S:27][CH:28]=[C:24]([C:22]([C:10]4[CH:9]=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:23])[N:25]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CON(C)C(=O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)c2csc(-c3ccc4[nH]ccc4c3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solution of 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C. The mixture was allowed to stir for 2 h and a solution of Weinreb amide 65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed to increase at RT and stirred overnight. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was refluxed in 1 N NaOH in 5 mL ethanol solution to obtain the deprotected compound 31 and purified by column chromatography to obtain pure compound as a light yellow solid (36.3%). 1H NMR (300 MHz, CDCl3) δ 8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8, 2.7 Hz), 7.46 (d, 1H,) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz), 6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)+, 392.9 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[C:15]([O:16]CC2C=CC=CC=2)=[CH:14][C:13]([O:24]CC2C=CC=CC=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([OH:24])=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Reaction time: 22 h
Yield: 94 %

Procedure:
A solution of 2-[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-2-methylpropionic acid methyl ester, 17, (0.58 g, 1.34 mmol) in MeOH (100 mL) containing 10% Pd/C (0.116 g) is stirred under an atmosphere of H2 for 22 hours. The reaction solution is filtered through Celite™ and the collected solids are washed with hot MeOH. The combined filtrate and washings are concentrated under reduced pressure to afford 0.321 g (94% yield) of the desired compound as a grey solid. 1H NMR (250 MHz, MeOD) δ ppm 7.67 (1H, d, J=2.4 Hz), 6.58 (1H, d, J=2.4 Hz), 3.69 (3H, s), 1.56 (6 H, s). HPLC-MS: m/z 255 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.C(N(C(C)C)C=O)(C)C.[C:30]12([NH2:40])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.C(N(CC)CC)C>O>[C:30]12([NH:40][C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[N:10]=[C:9]([Cl:18])[N:8]=3)[CH2:37][CH:36]3[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]3)[CH2:31]1)[CH2:39]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)N(C=O)C(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(NC34CC5CC(CC(C5)C3)C4)c2c1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 183 mg (1.21 mmol) of 1-adamantylamine and 0.84 ml (6.05 mmol) of triethylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 90 mg (20.7%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].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.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC(CO)CO
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: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 24.67 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.4 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (26 mg, 0.052 mmol, 24.67% yield) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=CCCOCc1ccccc1
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 15.6 mL of oxalyl chloride in 420 mL of dichloromethane at −78° C. was added 24.0 mL of dimethyl sufoxide and stirred for 10 min, followed by addition of 19.95 g (0.12 mol) of 3-benzyloxy-1-propanol and stirred for 45 min. After adding 58.5 mL of triethylamine, the mixture was stirred in an ice bath for 20 min. 42 mL of water was added and the mixture was extracted with 660 mL of benzene/d iethyl ether (1/1). The organic layer was washed with 5% hydrochloric acid (42 mL), water (42 mL) and brine (42 mL), dried over anhydrous sodium sulfate and concentrated. Distillation at 68-70° C./3 mmHg gave 17.0 g of a liquid in 86.3% yield. 1H NMR (CDCl3): δ 9.79 (t, J=1.8 Hz, 1H, CHO), 7.35-7.31 (m, 5H, ArH), 4.53 (s, 2H, ArCH2O), 3.81 (t, J=6.0 Hz, 2H, CH2O), 2.69 (td, J=6.0, 1.8 Hz, 2H, CH2C═O). 13C NMR (CDCl3): δ 201.08, 137.72, 128.35, 127.69, 127.62, 73.18, 63.75, 43.81. EIMS m/z 164 (M+), 107, 91, 79.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1nc2cc(C#N)ccc2n1CC(=O)NC1CCCCC1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-phenylaminomethyl]-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (247 mg) in dimethylformamide (2.5 ml) were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mire was stirred at room temperature for 24 hours. Thereto were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mixture was stirred at room temperature for 24 hours. Further, ethyl bromoacetate (0.07 ml) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (124 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
In a mixed solvent (16 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2R)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 77; 400 mg, 1.62 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 402 mg, 1.62 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 288 mg (36%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [O:1]([C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](#N)C.[C:30]1([CH3:41])[CH:35]=[CH:34][C:33]([S:36]([O:39]C)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CCOCC>[C:30]1([CH3:41])[CH:31]=[CH:32][C:33]([S:36]([O-:39])(=[O:37])=[O:38])=[CH:34][CH:35]=1.[O:1]([C:8]([O:10][CH2:11][CH2:12][N+:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])([CH3:27])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC#N
Solvent: CCOCC
Product: C[N+](C)(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
To a 250 ml round-bottomed flask fitted with a reflux condenser, magnetic stirrer, and argon inlet are added N,N-bis[2((phenoxycarbonyl)oxy)ethyl]-N-methylamine (25.00 g, 69.6 mmol), acetonitrile (100 ml), and methyl p-toluenesulfonate (12.95 g, 69.6 mmol). After addition is complete, the mixture is heated to reflux for 2 h. The cooled mixture is treated with ether (500 ml). The product precipitates from the mixture and dried to give 5 as a white powder, 31.14 g (81%): mp 117°-118° C.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH:15]=[CH2:16].[Si:18]([O:25][CH:26]1[CH2:30][C:29](=[O:31])[CH:28]=[CH:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[CH:32](=[O:36])[CH2:33][CH2:34][CH3:35].[Cl-].[NH4+]>CCOCC.C(OCC)(=O)C.C1C=CC=CC=1>[CH2:14]([CH:27]1[CH:26]([O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:30][C:29](=[O:31])[CH:28]1[CH:32]([OH:36])[CH2:33][CH2:34][CH3:35])[CH:15]=[CH2:16]
Reactant: [Li]CC=C
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: CCCC=O
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CCC1C(O[Si](C)(C)C(C)(C)C)CC(=O)C1C(O)CCC
Reaction time: 0.17 h
Yield: 44 %

Procedure:
266 mg (2.2 mmoles) of 2-bromopropene was dissolved in 5 ml of dry ether, and the solution was cooled to -95° C. Then, 3.0 ml (4.8 mmoles) of t-butyllithium (as 1.60M pentane solution) was added, and the mixture was stirred at -78° C. for 2 hours to form a 2-propenyllithium solution. 300 mg (2.05 mmoles) of cuprous iodide was taken into a reaction vessel. The reaction vessel was purged with argon, and 30 ml of dry ether and 1.02 ml (4.1 mmoles) of tributyl phosphine were added. The mixture was stirred for 10 minutes. The mixture was added to the 2-propenyllithium solution prepared above, and the mixture was stirred for 5 minutes. A solution of 425 mg (2.0 mmoles) of 4-t-butyldimethylsilyloxy-2-cyclopentenone in 5 ml of dry ether was added. The mixture was stirred at -78° C. for 10 minutes and -40° C. for 20 minutes. A solution of 148 mg (2.05 mmoles) of butanal in 5 ml of dry ether was added, and the mixture was stirred at -40° C. for 1 hour. 50 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ether. The etheric layers were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and then subjected to silica gel column chromatography (silica gel 50 g; eluent, benzene:ethyl acetate=10:1→3:1 to give 287 mg (yield 44%) of 3-(2-propenyl)-4-t-butyldimethylsilyloxy-2-(1-hydroxybutyl)cyclopentanone. The resulting compound had the following spectral data.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][N:7]=1.[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br-:19].[CH2:12]([N:7]1[C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[N+:10]([CH3:11])[N:9]=[CH:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cn1ncnc1C1OCCO1
Product: C[n+]1ncn(Cc2ccccc2)c1C1OCCO1
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
A reaction mixture of 6.27 g (40.4 mmol) of 5-(1,3-dioxolan-2-yl)-1-methyl-1,2,4-triazole and 6.91 g (40.4 mmol) of benzyl bromide was heated on a steam-bath with stirring for 4 h. The mixture was cooled to room temperature, triturated with ether and decanted to afford 11.3 g (85.7%) of 4-benzyl-5-(1,3-dioxolan-2-yl)-1-methyl-1,2,4-triazolium bromide (Formula VI: A=1-methyl-1,2,4-triazole; Y=5-(1,3-dioxolan-2-yl); R1 =R6 =H; Z- =Br-).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]C(C)=CC=O.C([O:37][C:38](=[O:41])CC)C.Cl.CCN(C(C)C)C(C)C>>[CH3:28][C:23]([CH3:24])=[CH:22][CH2:21][N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:38]([OH:41])=[O:37])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Reactant: CC(C)=CC=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCN(C(=O)Nc1ncc(SCCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enal and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.043 g, 0.10 mmol) and EtOH (4.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 2%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.023 g, 40%); 1H-NMR (500 MHz, DMSO-d6) 2.66 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2C6H4Cl), 3.66 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4CH2N and 2,6-C6H4CH2N), 7.40 (m, 4H, C6H4Cl), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.54 (br s, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3C=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([OH:36])[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:36][C:28]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Product: COc1cc(Oc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
Preparation analogously to Example 22 from Example 50A (50 mg, 0.14 mmol) and 3,4,5-trimethoxyphenol (50 mg, 0.29 mmol).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[C:24](C(O)=O)[CH:23]=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2:35][CH2:36][C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:24]1[CH:23]=[CH:22][C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:20]([CH3:19])[CH:25]=1)=[O:7])=[O:18]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)c(C)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 95% purity by HPLC. MS(ESI+): m/z=472.