Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O-])=[O:21])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65])([O-:50])=[O:49].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][C:20]([N:61]3[CH2:60][CH2:59][CH:58]([NH:57][C:54]4[CH:55]=[CH:56][C:51]([N+:48]([O-:50])=[O:49])=[C:52]([C:64]([F:67])([F:65])[F:66])[CH:53]=4)[CH2:63][CH2:62]3)=[O:21])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CCC(CCC(=O)[O-])CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2CCC(CCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 3-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-propionic acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 146) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stirring is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (6 mg; 0.011 mmol). The structure was confirmed using Protocol I-D. Calculated mass=561; observed mass=561; HPLC retention time=1.67 min.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:7]=1[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O>CO>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][CH2:8][C:7]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:6]=1[O:5][CH3:4]
Reactant: COc1cccc(OC)c1CNCc1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1CNCc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
At 60° C., 2.3 mL hydrazine hydrate was added by drops to a suspension of 3.58 g (11.84 mmol) (2,6-dimethoxybenzyl)(2-nitrobenzyl)amine (Example 1.1), 3.5 g activated carbon and 50 mg FeCl3×6H2O in 60 mL methanol and then the mixture was stirred for 1 hour at 60° C. Cooling, filtering the reaction mixture through Celite and evaporating yielded 2.78 g of the target product as a clear oil. ESI-MS [M+H+]=273.15.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([O:14]C)=[CH:12][CH:13]=1.I[CH3:18]>CC(OC)(C)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH3:18])[CH:9]=1
Reactant: COc1ccc(CC(=O)c2ccco2)cn1
Reactant: CI
Solvent: COC(C)(C)C
Product: Cn1cc(CC(=O)c2ccco2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 287.1 %

Procedure:
To a solution of 1-furan-2-yl-2-(6-methoxy-pyridin-3-yl)ethanone (7) (800.0 g, content 625.6 g, 2.88 mol) obtained in Example 1 in N-methyl-2-pyrrolidine (NMP) (1.88 L) was added iodomethane (122.6 g, 0.86 mol), and the reaction mixture was stirred at 100° C. for 3 hours and then at room temperature for 17.5 hours. To the reaction mixture was added dropwise MTBE (6.6 L) over a period of 77 minutes, followed by stirring for 1 hour while cooling in an ice bath. The precipitated crystals were collected by filtration and washed with MTBE (2.0 L), and then dried under reduced pressure at 50° C. for 3 hours to give 692.0 g of a crude product of the title compound as a dark brown powder (content 536.4 g, yield 85.7%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]1[S:15][CH:14]=[N:13][C:12]=1[CH2:16][OH:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:10]([C:11]1[S:15][CH:14]=[N:13][C:12]=1[CH2:16][OH:17])#[CH:9]
Reactant: C[Si](C)(C)C#Cc1scnc1CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1scnc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
Potassium carbonate (39 mg) was added to a solution of 6.02 g of [5-[2-(trimethylsilyl)ethynyl]thiazol-4-yl]-methanol in 12 ml of methanol, and the mixture was stirred at room temperature for 10 min. A 10% aqueous citric acid solution (6 ml) was added thereto, and the mixture was stirred for 30 min. The reaction mixture was then extracted with 90 ml of ethyl acetate. The organic layer was washed with 12 ml of 5% sodium bicarbonate water and 12 ml of 20% brine in that order and was treated with 0.8 g of activated carbon and anhydrous magnesium sulfate. Toluene (15 ml) was added to the organic layer, the mixture was concentrated, and the precipitated solid was collected by filtration to give 3.11 g of 5-ethynyl-4-hydroxymethylthiazole.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][N:24]([CH:26](N(C)C)N(C)C)[CH3:25]>C1(C)C=CC=CC=1>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:19])[C:16]([O:17][CH3:18])=[CH:23][N:24]([CH3:26])[CH3:25])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)COC)c2C1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)C(=CN(C)C)OC)c2C1

Procedure:
A solution of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene (1.0 g) and tris(dimethylamino)methane (1.5 ml) in toluene (25 ml) was heated to reflux for 1.5 hours. The reaction was concentrated to give crude 2-di-n-propylamino-8-(1-oxo-2-methoxy-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene (1.2 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:40][OH:41]>C1COCC1.C(O)(C)(C)C>[OH:41][NH:40][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][NH:14][C:12]([C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Reactant: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a solution of 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoic acid obtained in Reference Example 44 (90.0 mg, 0.236 mmol) in THF (2 mL) were added DMF (0.02 mL) and oxalyl chloride (59.9 mg, 0.472 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added a mixed solution of 50% aqueous hydroxylamine solution (0.5 mL), tert-butanol (0.5 mL) and THF (0.5 mL) at 0° C., and the mixture was stirred for 15 min. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm) to give a yellow powder. The obtained powder was recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow powder (8.0 mg, 9%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([O:8][CH:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC(C)C
Reactant: OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)COC(C)OCc1ccccc1
Temperature: 40 °C

Procedure:
A 250 ml. round-bottom flask equipped with a magnetic stirrer, condensor, mantle, and addition funnel was charged with 52.5 g. of benzyl alcohol and 4 drops of 36% hydrochloric acid. The mixture was heated to 40° C. and 50 g. of isobutyl vinyl ether was added dropwise, over a one-half hour period. GLC analysis showed the reaction to be complete at this point. Saturated sodium carbonate solution was added to quench (10 ml.) and the organic phase was dried over sodium sulfate prior to distillation on a concentric tube column:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CCCC(N)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,3-dimethylcyclohexyl)amine hydrochloride (10.0 g, 0.060 mol) and N,N-diisopropylethylamine (15.8 g, 0.12 mol) in acetonitrile (125 mL) at ice bath temperature was added a solution of benzyl chloroformate (11.4 g, 0.067 mol) in acetonitrile (25 mL), dropwise. The mixture was stirred overnight, gradually warming to ambient temperature, and concentrated in vacuo. The residue was partitioned between ethyl acetate/5% citric acid solution and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, adsorbed onto silica gel and purified by flash chromatography (CH2Cl2/hexanes) affording the title compound as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.85 (s, 6H), 0.92-1.02 (m, 3 H), 1.25 (d, 1 H), 1.36-1.52 (m, 3 H), 1.76 (br. d, 1 H), 3.36-3.44 (m, 1 H), 4.96 (s, 2H), 7.10 (d, 1 H), 7.27-7.36 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:35][C@@H:36]1[CH2:41][CH2:40]C[NH:38][CH2:37]1.CCN(C(C)C)C(C)C.[OH-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([N:38]3[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Reactant: O[C@@H]1CCCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(N3CCC(O)C3)c3ccccc3n2)CC1
Temperature: 110 °C
Yield: 24.7 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (150 mg, 0.315 mmol) in DMSO (3.0 mL) was added (R)-3-hydroxypiperidine (68 mg, 0.5 mmol) and DIEA (65 mg, 0.5 mL). The mixture was heated at 110° C. for 18 hours. The crude reaction mixture was treated with lithium hydroxide (3.0 mL 0.25 M) for 4 hours. The reaction was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-hydroxypyrrolidin-1-yl)quinoline (41.0 mg); NMR (DMSO-d6) 1.2 (t, 3), 2.00-2.20 (m, 4), 2.45 (m, 2), 3.30-3.75 (m, 8), 4.05 (q, 2), 4.60 (s, 1), 5.11 (m, 1), 7.39 (s, 1), 7.65 (m, 1), 7.95 (m, 1), 8.28 (m, 1), 8.58 (br s, 1), 9.75 (m, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.[H-].[Na+].O>CN(C)C=O>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCBr)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 59.2 %

Procedure:
2.05 g (5.26mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 50 mL of dimethylformamide under argon atmosphere, 3.6 mL (26.3 mmol) of 1,5-dibromopentane and 631 mg (15.8 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred at room temperature for 1.2 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=60:l) to give 1.68 g of 5-(5-bromopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])=[N:9][C:5]=2[CH:4]=1.C([O:23]CC)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])=[O:23])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Reactant: CCOCC
Product: COc1ccc2[nH]c(S(=O)Cc3ccccc3N)nc2c1

Procedure:
The title compound was prepared by the method of Example 3 using 1.20 g of the title product of Example 11 instead of the title product of Example 2. Trituration with diethylether gave 1.04 g of the title compound: m.p. 147-148° C. Analysis. Calc'd. for C15H15N3O2S: C, 59.78; H, 5.02; N,13.94; S, 10.64. Found: C, 59.30; H, 4.95; N, 13.55; S, 10.73.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[H][H]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH2:9][CH2:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN2C(=O)C3=C(C=CCC3)Oc3ccccc32)cc1
Yield: 94 %

Procedure:
Compound 416 (0.364 g, 0.912 mmol) was dissolved in ethanol (10.0 mL) and the palladium on charcoal (0.037 g, 10% w/w) was added. The reaction mixture was stirred over 1 atmosphere of hydrogen at room temperature for 1 hour. The catalyst was filtered and the filtrate was concentrated to afford title compound 417 (346 mg, 95%) that was used crude for next step. MS (m/z): 402.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 10 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
587 g (2 mols) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one were dissolved in 3 liters of methanol. A total of 80 g (2 mols) of sodium borohydride was added, in portions of 5 g each, to this solution at 0° to 10° C., while stirring and cooling with ice, and the mixture was stirred at 5° to 10° C. for 2 hours and then at room temperature for 12 hours. It was then cooled to 10° C. and 300 g (3 mols) of concentrated aqueous hydrochloric acid were added at 10° to 20° C. After stirring at room temperature for six hours, the resulting suspension was diluted with 3.8 liters of water which contained 400 g (4.8 mols) of sodium bicarbonate. The precipitate thereby formed was filtered off. 502 g (85% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 112°-117° C. were obtained. ##STR12##
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[CH2:39][CH2:38][N:37]3[C:30](=[CH:31][C:32]4[CH2:33][C:34]([CH3:41])([CH3:40])[CH2:35][C:36]=43)[C:29]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]([O:26][CH3:27])=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[N:20]=2)[CH:17]=1)(=O)C.O.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:28]2[CH2:39][CH2:38][N:37]3[C:30](=[CH:31][C:32]4[CH2:33][C:34]([CH3:40])([CH3:41])[CH2:35][C:36]=43)[C:29]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]([O:26][CH3:27])=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[N:20]=2)[CH:17]=1
Reactant: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2COC(C)=O)cc1Nc1ccnc(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc1Nc1ccnc(C)n1
Yield: 91.3 %

Procedure:
A mixture 222b (283.5 mg, 0.50 mmol) and lithium hydroxide monohydrate (630 mg, 15.0 mmol) in i-propanol/THF (1:1, 10 mL) and water (2.5 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was diluted with water (3 mL). It was then extracted with dichloromethane (3×20 mL). The combined organic extract was concentrated under reduced pressure to afford 222c (240 mg, 92%) as a white solid. MS-ESI: [M+H]+ 526.2
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:15][NH:16][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
4.0 g (23 mmole) of 3-phenylfuran-2,5-dione was added to a 100 ml single-necked round bottom flask followed by 2.9 g (27.6 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (95%). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 degree (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45 degree. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of Milli-Q water, and dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of white solid. Yield, 91%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]>ClCCl>[NH2:9][CH2:14][CH2:13][CH2:12][NH:11][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:36])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCN)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 155 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (497 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1,3-propyldiamine (0.251 mL, 3.0 mL). The mixture was stirred over night. The mixture was concentrated and separated by flash chromatography to afford the title compound (395 mg, 78%). LC-MS m/z 510 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].OC1C=C(C=C(OC)C=1)C=O.Cl[Si](C(C)C)(C(C)C)C(C)C>>[Si:17]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: COc1cc(O)cc(C=O)c1
Product: COc1cc(C=O)c(F)cc1O[Si](C)(C)C(C)(C)C

Procedure:
The same procedure was carried out as in Example (4a), except that 2-fluoro-4-hydroxy-5-methoxybenzaldehyde [CAS No. 79418-77-2] and t-butylchlorodimethylsilane were used instead of respectively the 3-hydroxy-5-methoxybenzaldehyde and chlorotriisopropylsilane, to give the title compound as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([OH:51])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.O.C([O-])(=O)C.[NH4+]>CC#N.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[Sc+3]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:51])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:36])=[O:32])=[CH:49][CH:50]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of N-({4-[(2R,3R)-3-{[(2R)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6,N6-dimethyl-L-lysine (11.0 mg, 0.013 mmol) in MeCN (1 ml) were added scandium tris(trifluoromethanesulfonate) (0.5 mg, 0.00102 mmol) and water (2 μl, 0.131 mmol). The reaction mixture was stirred for 3 hours. Additional Sc(OTf)3 (0.7 mg, 0.00142 mmol) and water (2 μl, 0.131 mmol) were added and the mixture was stirred for 1 hour. Additional Sscandium tris(trifluoromethanesulfonate) (6.0 mg, 0.01219 mmol)) and water (4 μl, 0.262) were added and the reaction mixture was stirred for 1 hour. Ammonium acetate buffer (0.1M, 1 ml) was added. The resulting solution was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 20 to 43% MeCN was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. H-NMR (500 MHz, DMSO-d6): 1.21-1.31 (m, 2H), 1.33-1.44 (m, 2H), 1.51-1.60 (m, 1H), 1.63-1.71 (m, 1H), 2.16 (s, 6H), 2.25 (bs, 2H), 2.81-2.94 (m, 2H), 3.01-3.15 (m, 2H), 3.78 (d, 2H), 4.07 (bs, 1H), 4.25 (d, 0.5H) 4.26 (d, 0.5H), 4.44-4.50 (m, 2H), 4.52 (s, 2H), 4.59-4.66 (m, 1H), 5.01-5.05 (b, 1H), 6.64 (dd, 1H), 6.97-7.02 (m, 3H), 7.11-7.18 (m, 3H), 7.21-7.26 (m, 2H), 7.37 (d, 2H), 7.98 (bs, 1H), 8.26 (t, 1H). M/z: 721.40 (M−1)