Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:20]([C:23]1[NH:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])[CH3:21].[I-].[Na+].[OH-].[Na+]>O.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][N:24]3[CH:25]=[CH:26][CH:27]=[C:23]3[C:20](=[O:22])[CH3:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)c1ccc[nH]1
Reactant: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(Cn3cccc3C(C)=O)cs2)cc1OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
In a mixed solvent consisting of 2 ml of dimethylformamide and 0.2 ml of water were dissolved 200 mg of 2-(3,4-diethoxyphenyl)-4-chloromethylthiazole, 73 mg of 2-acetylpyrrole, 200 mg of sodium iodide and 200 mg of sodium hydroxide. The solution was stirred at 80° C. for 4 hours. The reaction mixture was subjected to distillation to remove the solvent. To the residue were added 30 ml of dichloromethane and 20 ml of water, and phase separation was conducted. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from methanol to obtain 60 mg of 2-(3,4-diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthiazole as white acicular crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N12CCCN=C1CCCCC2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Sc1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc(Br)cc1)(C(C)C)C(C)C

Procedure:
To a solution of 45 grams of 4-bromothiophenol in 250 mL of THF was added 53 mL of triisopropylsilyl chloride and 38 mL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) under a nitrogen atmosphere. The reaction mixture heated spontaneously to reflux. The reaction mixture was allowed to cool and was diluted with 500 mL of hexanes. The resultant white suspension was filtered through a pad of Celite® (diatomaceous earth), and the filter cake was washed with additional hexanes and 100 mL of ether. The filtrate was washed with ice-cold 0.1 N aqueous HCl, water, aqueous NaHCO3, and saturated aqueous NaCl, dried over MgSO4, and concentrated under vacuum to obtain 82 grams of the title compound of Step A as a clear oil. 1H NMR (CDCl3, 300 MHz) δ 1.1 (m, 18H), 1.2 (m, 3H), 7.3-7.4 (m, 4H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:9][C:7]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: OC1CCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.543 g of cyclopentyl alcohol in 15 ml of methylene chloride is added to a 0° C. solution of 1.0 ml of a 10% toluene solution of phosgene in toluene in 10 ml of methylene chloride. The reaction is allowed to warm to room temperature and is stirred for 3 hours. The reaction is concentrated at reduced pressure, diluted with 15 ml of toluene and reconcentrated to dryness to give the product.
Reaction SMILES: [C:1]([NH2:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCCCCCCCCC(N)=O
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCCCCCCCCC(=O)NC(NC(=O)CCCCCCCCC)c1ccc(N(CC)CC)cc1
Yield: 56 %

Procedure:
Compound 55 was prepared from decanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 56%. 1H NMR (400 MHz, DMSO) δ 8.99 (d, J=9.6 Hz, 1H), 8.38 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 5.84 (d, J=8.4 Hz, 1H), 3.27-3.30 (m, 4H), 2.33 (t, J=7.2 Hz, 4H), 2.14 (t, J=7.2 Hz, 4H), 1.50-1.55 (m, 4H), 1.24-1.28 (m, 24H), 1.06 (t, J=7.2 Hz, 6H), 0.87 (t, J=7.2 Hz, 6H). LC-MS (ESI): m/z 502.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([N+:29]([O-])=O)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[C:16]([NH2:29])[CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1N
Yield: 66 %

Procedure:
360 mg of 10% palladium-carbon were added to 15 ml of ethyl acetate solution of 3.61 g of t-butyl 4-[2-(4-chlorobenzenesulfonamido)ethyl]-2-nitrophenoxyacetate and stirred at one atmospheric pressure in the presence of hydrogen gas. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was subjected to silica-gel column chromatography, whereupon 2.23 g (yield 66%) of t-butyl 4-[2-(4-chlorobenzenesulfonamido)ethyl]-2-aminophenoxyacetate were obtained from the fraction as eluted with hexane/ethyl acetate (2/1, v/v) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:41])[C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:31](=[O:41])[C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:29][CH:30]=1
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CCO)CC2)ccc1OCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cc1cc(C(=O)N2CCN(CCOC(=O)c3ccc4c(c3)OCO4)CC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
1-[4-(4-fluorobenzyloxy)-3-isobutylbenzoyl]-4-(2-hydroxyethyl) piperazine (1.95 g) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.04 ml) and then, while being cooled with ice, piperonyloyl chloride (0.93 g) was added thereto dropwise. After being stirred for 12 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1), thereby yielding 1.92 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:22]O>>[Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([O:10][CH3:22])=[O:9]
Reactant: Cc1cccc2sc(C(O)C(=O)O)c(Br)c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1sc2cccc(C)c2c1Br
Yield: 88 %

Procedure:
A solution of (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-hydroxy-acetic acid (23g) (270 mg, 0.9 mmol) and sulfuric acid (500 μL) in methanol (5 mL) was refluxed for 1 hour. The reaction mixture was then concentrated and the residue was diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×20 mL), a saturated aqueous solution of sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired product (23h) as a orange solid (250 mg, 0.79 mmol, 88%) without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1ccc(Br)cc1
Product: CCOC(=O)C(C)(C)Sc1ccc(Br)cc1
Yield: 89.7 %

Procedure:
Following the procedure indicated in Example 49b 47 g of a limpid pale yellow oil are prepared from 29 g (0.150 mol) of p-bromothiophenol and 32.2 g (0.165 mol) of ethyl 2-bromo-2-methylpropionate; subsequent purification of this oil (by distillation under reduced pressure) gives 40.8 g of ethyl 2-(p-bromophenylthio)-2-methylpropionate.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:21][O-:22].[Na+]>CN(C=O)C.O>[CH3:18][CH:17]([N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:22][CH3:21])[C:3]=2[CH3:20])[CH2:12][CH2:13]1)[CH3:19]
Reactant: C[O-]
Reactant: Cc1c(N2CCN(C(C)C)CC2)ccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc(N2CCN(C(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 175.3 %

Procedure:
To a solution of 1-(3-chloro-2-methyl-4-nitrophenyl)-4-(1-methylethyl)piperazine (12.6 g, 42.4 mmol, 1 equiv) in 120 mL of DMF was added sodium methoxide (1.12 g, 21 mmol, 0.5 equiv) at 0° C. After stirring for 1 hour at room temperature, additional sodium methoxide was added (4.61 g, 85 mmol, 2 equiv, ×2) at 0° C. The mixture was warmed to 35° C. overnight. The next morning, the mixture was diluted with water, dried, and taken to a residue under reduced pressure. Recrystallization from ethyl acetate afforded 1-(1-methylethyl)-4-[2-methyl-3-(methyloxy)-4-nitrophenyl]piperazine (10.8 g, yield 87.1%) of sufficient purity for use in subsequent chemical transformations. 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (d, J=6.53 Hz, 6H), 2.27 (s, 3H), 2.68-2.74 (m, 4H), 2.98-3.09 (m, 4H), 3.89 (s, 3H), 6.78 (d, J=9.2 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].O[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCCCCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
2-(5-methyl-2-phenyloxazol-4-yl)ethanol (1.02 g), 3-hydroxybenzaldehyde (0.73 g) and triphenylphosphine (1.57 g) were dissolved in dichloromethane (10 ml) and thereto was added 1, 1′-(azodicarbonyl)dipiperidine (1.74 g) at 0° C. and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added hexane and the solid was filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methanol:chloroform=1:100) to give the title compound (1.30 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:24][S-:25].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:25][CH3:24])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reaction time: 2.5 h
Yield: 20.9 %

Procedure:
The procedure as in Example 27, a was followed using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (3.5 g, 8.10 mmol, Example 118, step b) and sodium thiomethoxide (560 mg, 8.10 mmol as 1M solution in EtOH). The reaction was allowed to stir for 2.5 hours and was quenched with acetic acid. The resulting mixture was dissolved into EtOAc, and aqueous work up with brine and saturated NaHCO3 resulted in isolation of a mixture. This mixture was purified by SiO2 flash column chromatography (Biotage—40 M, 100% hexanes to 25% EtOAc in hexanes). The product was isolated as a yellow solid (750 mg, 21%). ESI-MS (m/z): Calcd. for C12H10BrClNO4S3: 441.8 (M+H); found: 442.1. 1H-NMR (CD3OD+CDCl3): δ 8.93 (m, 1H), 8.50 (m, 1H), 8.06 (s, 1H), 3.91 (m, 3H), 2.67 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC#N>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)c1ccccc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a stirring solution of (7S)-7-amino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (8.0 g, 21.6 mmol) in dry MeCN (100 mL) and to this solution was added benzoyl chloride (2.78 mL, 23.8 mmol) and triethylamine (6.1 mL, 43.2 mmol). The solution was stirred at 0° C. for 1 h, then at RT for 2 h. The solvent was removed, and residue was dissolved in 400 mL EtOAc, and stirred with 100 mL 0.5 M NaHCO3 for 1 h. The aqueous layer was removed, and the organic layer was washed with 100 mL 0.5 M NaHCO3, then with 50 mL water. The solution was dried over anhydrous Na2SO4. The product (8.1 g) was obtained after column purification (EtOAc as eluent) in 78.8% yield as a thick oil. 1H NMR (CDCl3) δ 9.40 (1H, s), 8.80 (1H, d), 8.22 (1H, d), 8.0–7.0 (10H, m), 5.0 (1H, m), 2.2–1.2 (19H, m). MS (ESI): (MH+) 476.1.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[N:15][C:14]([O:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][N:12]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[Pd]>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[CH2:19][CH2:18][O:17][C:14]1[N:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: [H][H]
Reactant: O=C(Nc1cnc(OCCC2CCCCO2)cn1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(OCCC2CCCCO2)cn1

Procedure:
A solution of {5-[2-(tetrahydro-pyran-2-yl)-ethoxy]-pyrazin-2-yl}-carbamic acid benzyl ester (560 mg, 1.5 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was treated with 10% palladium on activated carbon (110 mg) in methanol (5 mL). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. for 2 h, at which time, thin layer chromatography indicated complete removal of the protection group. The reaction mixture was filtered and concentrated in vacuo to afford 5-[2-(tetrahydro-pyran-2-yl)-ethoxy]-pyrazin-2-ylamine as an oil which was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([NH2:7])=[O:6])[CH3:4].[O:8]=[CH:9][CH2:10][CH2:11][C:12](OCC(C)C)=O>>[O:6]=[C:5]1[C@@H:3]([CH3:4])[N:2]2[C:9](=[O:8])[CH2:10][CH2:11][C@H:12]2[NH:7]1
Reactant: CC(C)COC(=O)CCC=O
Reactant: CC(N)C(N)=O
Agent: Cl
Product: C[C@@H]1C(=O)N[C@@H]2CCC(=O)N12

Procedure:
DL-Alaninamide hydrochloride (6.9 g, 0.055 mol) and isobutyl 4-oxobutanoate (7.3 g, 0.046 mol) were reacted together according the procedure of Example 2 to give the title compound, 1.7 g (24%), m.p. 84°-86°. NMR (DMSO-d6): deltaH =8.55 (bs, 1H, NH); 5.20 (t, J=5 Hz, NCHNH); 3.92 (q, J=6.5 Hz, 1H, CHCH3); 2.82-1.50 (c.a., 4H, CH2CH2); 1.17 (d, J=6.5 Hz, 3H, CHCH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 111 (M--CHNO+, 98 (M--C3H4O)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=O.CC(=O)OCC>CO.[OH-].[Na+]>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(F)cc3F)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
The 2-trifluoroacetamido-3-(2,4-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (9.24 g, 20.8 mmol) was dissolved in 250 ml of MeOH and 170 ml of 1N NaOH. The solution was stirred at RT under N2 for 2 weeks. The precipitant was filtered and the filter cake was dissolved in 900 ml of EtOAc. The solution was washed with brine (3×50 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystalized from EtOAc/hexane to give 2 crops yielding 5.57 g. (76.8%). EA, MS(FD).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.[CH2:13]([O:15][C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:27])[C:17](=[CH:23][NH:12][C:11]1[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]
Reactant: Nc1ccnn1Cc1ccco1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)OCC

Procedure:
163 g of 1-(2-furyl)methyl-5-aminopyrazole (1 mol) and 216 g of ethoxymethylene malonic acid diethyl ester (1 mol) are heated to 130° (bath temperature) until the theoretical amount of alcohol is distilled off. The remaining oil, [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]malonic acid diethyl ester, is recrystallized from methanol, yield 280 g (84%), m.p. 84°-86 °.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1>C(#N)C>[OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1
Reactant: c1ccc2c(c1)OCC1OC21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN([C@@H]2c3ccccc3OC[C@H]2O)CC1

Procedure:
To 3 g of the compound obtained in Step B of Example 4, dissolved in 45 ml of acetonitrile, there are added 4 g of tert-butyl piperidin-4-ylcarbamate (20.2 mmol). The mixture is then heated at reflux for 12 hours and subsequently evaporated to dryness. A yellow oil is obtained which is purified by flash chromatography on silica (eluant: dichloromethane/ethanol 95/5) to yield the expected product in the form of a pale-yellow meringue.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](I)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 7-benzyloxy-4-iodo-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (165 mg, 0.32 mmole), piperidine (95 μl, 0.96 mmole) and triethylamine (89 μl, 0.64 mmole) in ethanol (1.6 ml) was heated at 130° C. in a CEM microwave synthesizer for 30 min before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a green oil (24 mg). MS: (+) m/z 474.55 (M+1).
Reaction SMILES: [F-].[K+].[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:30]#[C:31][Si](C)(C)C)=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:30]#[CH:31])=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCOC)nc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
Potassium fluoride (22 mg, 0.38 mmol) was added to a stirred solution of the title compound from Example 14 (90 mg, 0.19 mmol) in aqueous N,N-dimethylformamide (2 mL N,N-dimethylformamide/0.2 mL water) at 0° C. After 10 min the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, 1 N hydrochloric acid (3 times) and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound as a white solid (75 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.O.[NH4+:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:21])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccnc3)oc12
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccnc3)oc12

Procedure:
Methyl 2-(pyridin-3-yl)benzo[d]oxazole-7-carboxylate (135 mg, 0.53 mmol) in ammonium water (15 mL) was stirred at 25° C. overnight. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(pyridin-3-yl)benzo[d]oxazole-7-carboxamide a solid (39 mg, yield 31%). 1H-NMR (400 MHz, DMSO-d6) δ 7.50-7.54 (t, J=8 Hz, 1H), 7.65-7.69 (q, 1H), 7.65-7.69 (q, 1H), 7.85-7.87 (d, J=8 Hz, 1H), 7.91-7.93 (d, J=8 Hz, 2H), 7.99-8.01 (d, J=8 Hz, 1H), 8.64-8.66 (d, J=8 Hz, 1H), 8.81-8.82 (d, J=4 Hz, 1H), 9.46-9.47 (s, J=4 Hz, 1H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1C=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:13]1([NH:16][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Cn1c(C=O)cc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(NC2CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-methylindole-2-carboxaldehyde (1.5 g, 10 mmole), cyclopropylamine (1.14 g, 20 mmole), and glacial acetic acid (0.6 mL, 10 mmole) in MeOH (30 mL) was added NaBH3CN (0.69 g, 11 mmole). The reaction was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOWCH2Cl2) gave the title compound (1.3 g. 65%) as a semi-solid: MS (ES) m/e 201 (M+H)+.