Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=3)=[CH:11][N:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(c1ccc(-c2cccc(OC)c2)cn1)n1ccnc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(c1ccc(-c2cccc(O)c2)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 2-(1-(1H-imidazol-1-yl)propyl)-5-(3-methoxyphenyl) pyridine (0.05 g, 0.17 mmol; prepared as described in Example 7) in dichloromethane (1 mL) was added BBr3 (0.064 g, 0.25 mmol) under nitrogen at 0° C. The reaction was stirred at this temperature for 1 h, allowed to warm to rt and then maintained at rt for another 1 h. The contents were diluted with dichloromethane (100 mL) and then distilled off to obtain crude product. Ice-cold water (100 mL) and dichloromethane (50 mL) were then added to the crude product, the mixture was shaken, and the DCM layer was discarded since the product was in the aqueous layer. To this aqueous layer was added ethyl acetate (100 mL) and saturated sodium bicarbonate solution (150 mL). The organic phase was washed with brine solution (2×50 mL), the layers were separated, and the organic layer was dried over sodium sulphate and distilled off to get the crude product. The product was recrystallized with dichloromethane and hexane to give 3-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)phenol (20 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.78 (d, 1H), 7.99 (d, 1H), 7.92 (s, 1H), 7.36 (d, 2H), 7.26 (t, 1H), 7.09 (d, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 6.81 (d, 1H), 5.38 (q, 1H), 2.33 (m, 2H), 0.81 (t, 3H); LC-MS m/z calcd for [M+H]+ 280.14. found 280.0.
Reaction SMILES: [F:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]=O>C(O)CCC.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[N:7]=1
Reactant: Nc1ccc(F)nn1
Reactant: O=CCCl
Solvent: CCCCO
Solvent: CCOCC
Product: Fc1ccc2nccn2n1

Procedure:
6-Fluoro-pyridazin-3-ylamine [108784-42-5] (10 g, 89 mmol) was combined with a 50% (w/v) aqueous solution of chloroacetaldehyde [107-20-0] (23 mL, 177 mmol) in n-butanol (150 mL) and stirred at reflux for 1 h. The cooled reaction solution was reduced in volume and diluted with diethyl ether to precipitate a brown solid, which was collected by filtration, to yield 12.0 g. LRMS (ESI) m/z 138.0 [(M+H)]+, calc'd for C6H4FN3: 137.12.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH2:16]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cc(Cc2ccccc2)ccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(Cc2ccccc2)ccn1)C(=O)OCC
Yield: 97.6 %

Procedure:
Diethyl malonate (1.15 mL, 7.60 mmol) was added to a solution of sodium ethoxide (0.106 g of sodium in 5.0 mL of EtOH). To the clear solution was then added gradually a solution of 4-benzyl-2-(chloromethyl) pyridine (0.59 g, 2.7 mmol) in EtOH (5 mL). After the mixture had been heated at reflux for 4.5 h, the EtOH was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with NH4Cl (2×50 mL)), dried over Na2SO4 and was concentrated under reduced pressure. The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a colorless oil (0.9 g, 98%) 1H NMR (CDCl3) δ1.12 (t, J=7.2 Hz, 4H), 1.28 (t, J=7.2 Hz, 2H), 3.25-3.40 (m, 2H), 3.92 (s, 2H), 4.00-4.30 (m, 5H), 6.93 (d, J=4.8 Hz, 1H), 7.00 (s, -H), 7.15 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 3H), 8.38 (d, J=5.1 Hz, 1H); IR (film) 2984, 1752, 1736, 1606 cm−1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25](O)=[O:26])#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: N#Cc1cc(C(=O)O)cc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: N#Cc1cc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)cc(-c2noc(C(F)(F)F)n2)c1
Yield: 30 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-cyano-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (25 mg, yield 30%): 1H NMR (400 MHz, MeOD) δ 8.63 (t, J=1.6 Hz, 1H), 8.52 (t, J=1.5 Hz, 1H), 8.25 (t, J=1.6 Hz, 1H), 7.87-7.85 (m, 2H), 7.81 (s, 1H), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 1H), 3.97-3.92 (m, 2H), 3.71 (s, 2H), 3.62-3.58 (td, J=11.4 Hz, 2.1 Hz, 2H), 2.48-2.44 (d, J=13.3 Hz, 2H), 2.11-2.04 (ddd, J=14.3 Hz, 10.5 Hz, 4.3 Hz, 2H). MS (ESI) m/z: Calculated for C26H20F3N5O3S: 539.12. found: 540.0 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:23]1[C:32]2[CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]=[CH:28][C:27]=2[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:33][C:30]1([CH3:34])[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:6]3[CH2:7][C:8]4[CH:13]=[C:12]([C:14]5[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=5)[CH:11]=[CH:10][C:9]=4[O:3][CH2:4][CH2:5]3)[C:32]=2[CH2:31]1
Reactant: CC1(C)C=Cc2ncnc(Cl)c2C1
Reactant: Nc1cc(-c2ccc3c(c2)CNCCO3)cnc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)C=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Temperature: 90 °C
Yield: 74 %

Procedure:
To a slurry of 5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine dihydrochloride (0.92 g, 2.8 mmol) and 4-chloro-6,6-dimethyl-5,6-dihydroquinazoline (0.55 g, 2.8 mmol) in NMP was added diisopropylethylamine (2.4 mL, 14 mmol) and the reaction mixture was heated (90° C.) for 12 hours. The resulting dark red solution was loaded directly on to a column of dry silica and elution with MeOH (w/8% NH4OH v/v) in CH2Cl2 (0-5%) provided 5-[4-(6,6-dimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (0.86, 74% yield) as a brown solid. MS (EI) for C24H26N6O: 415.1 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd].[OH-].[OH-].[Pd+2]>[C:27]1([CH3:32])[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH:10]2[CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)[CH2:21][CH2:22]1
Reactant: Cc1ccccc1C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: Cc1ccccc1C1CCN(CC2CNCC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 15 mg of 1-Benzyl-3-(SR)-(4-(2-tolyl)-piperidin-1-ylmethyl)-4-(SR)-phenylpyrrolidine (from Example 20), 35 mg of ammonium formate and 8 mg of 10% Pd on carbon in 1.5 mL of MeOH using a procedure analogous to that described in Example 30, Step A (except Pd on carbon was substituted for 20% Pd(OH)2) to provide the title compound, which was taken onto Step B without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:28])=[O:27]>>[CH3:39][O:38][C:36]([CH2:35][CH:30]1[CH2:31][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:33][CH2:34][N:29]1[S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:27])=[O:28])=[O:37]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: COC(=O)CC1CNCCN1S(=O)(=O)c1ccc2ccccc2c1
Product: COC(=O)CC1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with methyl 2-[l-(2 -naphthylsulphonyl)piperazin-2-yl]acetate to give 2-methoxycarbonylmethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 90% yield as a glass;
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[O:21]=[C:22]([CH:43]1[O:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[CH2:45][O:44]1)[CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[O:21]=[C:22]([CH:43]1[O:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[CH2:45][O:44]1)/[CH:23]=[CH:1]/[C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C1OCc2ccccc2O1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: c1ccccc1
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)C3OCc4ccccc4O3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1

Procedure:
Under an argon atmosphere, 7 g. of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one, E. J. Corey et al., J. Amer. Chem. Soc. 91, 5675 (1969), and 11.2 g. of [2-oxo-2-(1,3-benzodioxan-2-yl)-ethylidene]-triphenylphosphorane were agitated at room temperature for 16 hours in 300 ml. of benzene. The reaction mixture was then evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/20-60% ethyl acetate as the eluent. Yield: 5 g. of an oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH:15]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14])([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(N)cc1O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.40 mL, 4.48 mmol), 5-amino-2-isopropylphenol (339 mg, 2.24 mmol) and 37% HCl solution (0.37 mL, 4.48 mmol) in 10% aqueous EtOH solution (10 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69% yield (360 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:15](OCC)=[O:16].O.[OH-].[Na+]>C1COCC1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[CH2:15][OH:16]
Reactant: CCOC(=O)[C@@H](OC1CCCCO1)[C@@H](C)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CO)OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In a 50 ml flask were charged 1.2 g of lithium aluminum hydride and 50 ml of THF, and a solution of 7.85 g of the compound obtained in Step 2 in 20 ml of THF was added thereto dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. Then, 1.2 ml of water and 20 ml of THF were added thereto dropwise over 15 minutes. To the reaction mixture was further added dropwise 3.6 ml of a 4% sodium hydroxide aqueous solution under cooling with ice over 40 minutes, followed by filtration through zeolite. The filtrate was distilled under reduced pressure to remove the solvent, and the resulting crude product was purified by silica gel column chromatography to obtain 5.9 g (20.9%) of the titled compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5]CC[CH2:2]1.[NH2:10][C:11]1[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][N:15]=1.NC1C=CC(C(OC)=O)=CC=1>>[CH3:5][CH:1]([CH3:2])[CH2:6][C:7]([NH:10][C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)=[O:8]
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1cnc(N)s1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)CC(=O)Nc1ncc(C(=O)O)s1

Procedure:
The title compound was prepared as described in Example 52A, substituting 3-methylbutanoyl chloride for 2-cyclopentylacetyl chloride and methyl 2-aminothiazole-5-carboxylate for methyl 4-aminobenzoate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=O.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>O>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]1[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=1
Reactant: Nc1ccccc1N
Reactant: CN(C)CCCC(=O)O
Agent: Cl
Solvent: O
Product: CN(C)CCCc1nc2ccccc2[nH]1

Procedure:
Grams 10 4-dimethylaminobutyric acid hydrochloride are heated up till melting together with 6.45 g o-phenylendiamine then it is allowed to cool and 150 ml water are added thereto. The solution is washed with dichloromethane, made alkaline and extracted with dichloromethane. The extracts are collected together, filtered on charcoal, made anhydrous on sodium sulphate and evaporated to dryness. A thick oily reddish residue is obtained, which is triturated with 200 ml diethyl ether to give 5.8 g 2-(3-dimethylaminopropyl)benzimidazole melting at 117°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:19])([CH3:18])[CH2:15][CH2:16]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:27]>C1C=CC=CC=1>[Br:27][CH2:16][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([OH:19])[CH3:18]
Reactant: BrP(Br)Br
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(O)(CCBr)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 2.6 g. of 3-(4'-fluoro-4-biphenylyl)-1,3-butanediol in 10 ml. of pyridine is added dropwise, at -5°, while stirring, to a mixture of 1 g. of PBr3, 1 ml. of pyridine and 3 ml. of benzene. The reaction mixture is then stirred for 24 hours at 20° and worked up in the customary manner to give 1-bromo-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 72° -74°.
Reaction SMILES: [CH3:1][NH:2][C:3](=S)[NH:4][NH2:5].[CH2:7]([O:9][C:10](=[O:16])[CH:11](Cl)[C:12]([CH3:14])=O)[CH3:8]>C1COCC1>[CH2:7]([O:9][C:10]([C:11]1[C:12]([CH3:14])=[N:5][NH:4][C:3]=1[NH:2][CH3:1])=[O:16])[CH3:8]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CNC(=S)NN
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n[nH]c1NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 1 g of 4-methylthiosemicarbazide (9.51 mmol) and 1.565 g of ethyl-2-chloro-acetoacetate (9.51 mmol) in THF (20 ml) was stirred for 30 min at RT and then heated to reflux for 1 h. The yellow solid that precipitated was filtered off, washed with acetone and then dissolved in hot (95° C.) water. The precipitating sulfur was filtered off, the aqueous solution was cooled to 0° C., vigorously stirred and 5 ml of an aqueous ammonium hydroxide solution (25%) were added. A white precipitate formed and the suspension was stirred for an additional hour at RT. The precipitate was then filtered off and dried to give 1.04 g (60%) of 3-methyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid. MS (ISP) 184.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10])[CH3:4].Br[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[CH2:3]([O:5][C:6](=[O:12])[CH:7]([O:11][CH2:16][C:15]([CH3:17])=[CH2:14])[CH2:8][CH:9]=[CH2:10])[CH3:4]
Reactant: C=CCC(O)C(=O)OCC
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(=C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a cold (00C) stirred suspension of NaH (55% disperson in oil, 227.9 mg, 5.2 mmol, 1.3 eq) in THF (20 mL) was added drop wise a solution of 2-hydroxy-pent-4-enoic acid ethyl ester (0.576 g, 4.0 mmol) in THF (20 mL) and stirred for 1 h. The reaction mixture was then treated with 3-bromo-2-methylpropene (0.81 g, 6.0 mmol, 0.61 mL), slowly warmed up to rt, and stirred for 1 h. It was carefully quenched with saturated NH4Cl solution. Reaction mixture was extracted with EtOAc (3×20 mL) organic solution was washed with brine, dried (Na2SO4), concentrated. Purification of the residue on silica gel column chromatography using 5% EtOAc-Hexane furnished 2-(2-methyl-allyloxy)-pent-4-enoic acid ethyl ester (0.521 g, 66%) as oil. NMR 1H (CDCl3, 400 MHz): 5.9-5.78 (m, 1H), 5.16-5.06 (m, 2H), 4.97 (s, 1H), 4.91 (s, 1H), 4.26-4.16 (m, 2H), 4.072 (d, J=12.3, 1H), 3.93 (t, J=6.5, 1H), 3.813 (d, J=12.4, 1H), 1.15 (s, 3H), 1.28 (t, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:18])[C:9]([C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[N:6]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:18])[C:9]([C:11]3[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=3)=[O:10])[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nccnc1C(=O)N(C)Cc1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nccnc1C(=O)N(C)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A mixture of N-((2-aminothiazol-4-yl)methyl)-N,3-dimethylpyrazine-2-carboxamide (555 mg, 1.84 mmol) and DMAP (20 mg) in pyridine (10 mL) was cooled to 0° C. and a solution of phenyl chloroformate (433 mg, 2.8 mmol) in THF was added drop wise. The mixture was stirred overnight and all volatiles were removed in vacuo at 30° C. The residue was triturated with TBME to afford (4-{[Methyl-(3-methyl-pyrazine-2-carbonyl)-amino]-methyl}-thiazol-2-yl)-carbamic acid phenyl ester (125 mg) as a tan colored solid (purity 96%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][N:14]=2)=[N:11][CH:12]=1)(C)C.[F-].[K+]>CO.C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][N:11]=2)=[N:14][CH:15]=1)#[CH:20]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(-c2ccc(C#C)cn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 (390 mg, 1.12 mmol) was dissolved in a mixture of 40 ml MeOH and 10 ml THF; then KF powder (400 mg, 6.88 mmol) was added and the solution was stirred at room temperature overnight. Subsequently, the solvents were removed under reduced pressure. The residue was redissolved in 200 ml CH2Cl2 and washed four times with 100 ml H2O each, in order to remove inorganic salts. The organic phase was dried over Na2SO4, concentrated under reduced pressure and purified by silica flash column chromatography (eluent: CH2Cl2) to yield a colorless powder of 204 mg (1.0 mmol, 81%) pure 5. 1H NMR (CDCl3, 250 MHz): δ=8.76 (d, 2H, JHH=1.0 Hz, bpy-H), 8.39 (d, 2H, JHH=6.0 Hz, bpy-H), 7.90 (dd, 2H, JHH=1.1 Hz, 5.1 Hz, bpy-H), 3.31 (s, 2H, bpy-CCH).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:17][CH:18]=2)[C:13]1=[O:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:17][CH:18]=2)[C:13]1=[O:38]
Reactant: COC(=O)CC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 18 (0.080 g, 0.145 mmol) was treated with TFA (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.8:1.2, to yield the product 23 (0.040 g, 62%) as a brown solid: mp 225-227° C. IR (KBr) 3067, 1739, 1673, 1574, 1535, 1511, 1202, 1134, 722 cm−1; 1H NMR (CD3OD, 300 MHz) 8.52 (d, J=2.1 Hz, 1H), 8.29 (d, J=6.8 Hz, 1H), 7.43 (m, 5H), 4.50 (t, J=2.1 Hz, 2H), 3.78 (s, 3H), 3.10 (m, 2H), 2.22 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 191.6, 169.9, 166.8, 164.9, 155.4, 138.8, 137.9, 135.7, 134.9, 132.2, 129.6, 127.2, 125.0, 124.8, 124.1, 123.9, 118.6, 109.6, 52.9, 42.5, 38.2, 28.6; ESIMS m/z (relative intensity) 420 (MH+, 100); HRESIMS calcd for C23H21N3O5 420.1559 (MH+), found 420.1554 (MH+); HPLC purity: 100% (1% TFA in MeOH—H2O, 50:50).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[CH2:72]([C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-{[methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (206 mg, 0.71 mmol) in DMF (5 mL) is added diisopropylethylamine (174 μL, 1.1 mmol), HATU (323 mg, 0.85 mmol), then (2R,3S)-3-amino-1-[(3-ethylbenzyl)amino]-4-phenylbutan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (292 mg, 0.79 mmol). The reaction is stirred 4 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 569.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5]Cl.[C-:11]#[N:12].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [C-]#N
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CC#N)cc1C
Yield: 100 %

Procedure:
A mixture solution of 3,4-dimethylbenzyl chloride 10 g (64.7 mmol) in dimethyl formamide (15 ml) was treated with sodium cyanide (15.85 g, 323.8 mmol) for 16 hrs at 100° C. The mixture was diluted with H2O and extracted with CH2Cl2 several times. The combined organic layers were washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:10) as an eluant to give compound 2.