Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]=1)=[O:7])[CH3:4]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:12]([Br:1])=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]=1)=[O:7])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Bromine (15 ml, 294 mmol) was added in one portion to a cooled (ice/water bath) stirred solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (26.6 g, 73.6 mmol) in acetic acid (300 ml). After 45 minutes, the reaction was concentrated in vacuo, the solids slurried in diethyl ether (100 ml), filtered and dried in vacuo to afford the title compound (I-1a) as a light-yellow colored solid, 29.6 g.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[CH3:11][CH:12]([CH3:16])[C:13](Cl)=[O:14]>CN(C=O)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:11][CH:12]([C:13]1[O:14][CH:5]=[N:4][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:16]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)C(=O)Cl
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C(C)C
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium methoxide (1.86 g) in DMF (30 ml) was added methyl isocyanoacetate (2.38 ml) dropwise at −50° C. and the mixture stirred for 30 min at −50° C. 2-Methylpropanoyl chloride (3.36 ml) was added gradually to the mixture at −50° C. and the mixture stirred for 2 h at −50° C. The mixture was diluted with DCM (50 ml) and saturated sodium bicarbonate solution (50 ml) was added and the organic layer collected using a hydrophobic frit. The aqueous layer was washed with DCM (2×50 ml) and separated by hydrophobic frit. The combined organic phases were concentrated in vacuo. This was purified by chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, followed by 0-20% methanol. The residue was distilled using a Kugelrohr to give the title compound (553 mg) as yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[C:18](\[C:22]#[N:23])/[C:19]([NH2:21])=[O:20])=[C:9]1OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-]>CO>[NH2:23][C:22]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[N:27]=1
Reactant: CCOc1c(/C=C(\C#N)C(N)=O)c2ccccc2n1Cc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 2.00 g, 5.79 mmol) in MeOH (150 mL) was added NH4OH (30% weight solution of NH3 in water, 100 mL). The reaction was stirred at RT overnight. The reaction was concentrated under reduced pressure and the crude solid was triturated with H2O. The solid was filtered and triturated again with ether. A yellow solid was collected by suction filtration to yield 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide 1.23 g, 63%). NH4OAc standard conditions. DAD Retention time=7.25 min. M+H=317. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.62 (br s, 2H), 7.40 (d, J=7.7 Hz, 1H), 7.31-7.16 (m, 9H), 5.52 (s, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].[F:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>O1CCCC1>[F:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([OH:24])[CH:10]([CH:11]([CH3:13])[CH3:12])[C:9]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(C)C
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
Lithium diisopropylamide (22.2mL of 1.8M solution, 40 mmol) was added to a solution of ethyl isovalerate (5.2g, 40 mmol) in 40 mL of tetrahydrofuran at -40° C. After stirring for 0.5 hours and cooling to -70° C., 4,4'-difluorobenzophenone (4.36 g, 20 mmol) was added and the mixture stirred for 3 hours during which time the temperature was allowed to warm to -20° C. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 5.3 g of the title product; m.p. =118°-120° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:17]([CH2:26][CH3:27])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH2:26][CH3:27])[N:18]([CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:39]([NH:38][CH:35]([CH3:37])[CH3:36])=[O:40])=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(CCCNC(=O)NC(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 22.4 %

Procedure:
7-(3-Aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and isopropyl isocyanate (128 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0° C. and the reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×20 mL). The combined organic fractions were sequentially dried (MgSO4), filtered and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA over 2000 mL). The desired product was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 10% methanol in dichloromethane over 1500 mL). A final purification by recrystallization from acetonitrile provided 142 mg of N-{3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}-N′-isopropylurea as a white solid, mp 213-216° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25]([C:27]1([CH2:41]I)[CH2:31][CH2:30][N:29]([C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:28]1)=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25]([C:27]1([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][N:29]([C:32](=[O:40])[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
4′-Hydroxy-4-biphenyl carbonitrile (329 mg, 1.68 mmol) and potassium carbonate (317 mg, 2.30 mmol) were added to a stirred solution of 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (620 mg, 1.53 mmol) (see Preparation 12) in dimethylformamide (7 mL). The reaction mixture was heated at 80° C. for 18 hours then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (2000 mL), dried over magnesium sulfate then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 3:1→1:1 heptane:EtOAc to afford the title compound as a white solid (517 mg, 71%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH3:9])(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[NH2:7][C@@H:8]([C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH3:9]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)c1nc(CO)co1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (137 mg, 0.51 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.2 ml, 15.6 mmol) was slowly added. The reaction was stirred at room temperature for 1.5 h then concentrated to afford [2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate as a brown oil which was used without further purification.
Reaction SMILES: [C:1]([C:3]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[S:4]1)#[N:2].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(O)C>[C:26]([NH:30][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2([C:1]#[N:2])[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[S:4]2)=[CH:20][CH:19]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CN1C(=O)C(C#N)(c2ccc(OCC3CO3)cc2)Sc2ccccc21
Reactant: CC(C)(C)N
Solvent: CCO
Product: CN1C(=O)C(C#N)(c2ccc(OCC(O)CNC(C)(C)C)cc2)Sc2ccccc21
Yield: 74.8 %

Procedure:
To a stirred suspension of 2-cyano-3,4-dihydro-2-[4-(2,3-epoxypropoxy)phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (1.2 g, compound No. 23) in ethanol (15 ml), tert-butylamine (3.6 ml) is added. The mixture is refluxed for 1.5 hours, and concentrated in vacuo to give 1.3 g (74.8%) of the titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12](\[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[N:19][CH:20]=2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:28][C:25]1[CH:26]=[CH:27][C:22](/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12](/[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[N:19][CH:20]=2)\[CH2:13][CH3:14])=[CH:23][CH:24]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)nc1
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)nc1

Procedure:
Following the same procedure as described in example 11, step D, (Z)-5-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl)pyridin-2-ol (0.02 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (brs, 1H), 7.13 (dd, J=9.2 Hz, 2.8 Hz, 1H), 6.96 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 4H), 6.12 (d, J=9.2 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.93 (t, J=5.6 Hz, 2H), 2.40 (s, 3H), 2.29 (q, J=7.2 Hz, 2H), 0.90 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[C:5]1([C:11]2([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CCOCC.CO>[CH3:19][CH:18]([N:2]([CH3:3])[CH3:1])[CH2:17][C:11]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1
Reactant: CNC
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(CC1(c2ccccc2)C=CCC=C1)N(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 50 ml. of methanol, 10 ml. of dimethylamine and 1 g. of molecular sieve 3 A are added dropwise at about -5° C. 10 ml. of 5 N methanolic hydrochloric acid and subsequently at 0° C. a solution of 5.3 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in 20 ml. of methanol. 1.1 g. of sodium cyanoborohydride are then added at 0° C. and the mixture is stirred at room temperature for 4 days. The mixture is worked-up as follows: Ether and ice-water are added to the mixture and the phases are separated. The ether phase is extracted with dilute aqueous hydrochloric acid. The acid extracts are made alkaline with concentrated ammonia and extracted with ether. The combined ether phases are filtered and concentrated. There is obtained crude α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is dissolved in ether, converted with hydrogen chloride into the hydrochloride and recrystallized from methylene chloride/ether. According to melting point and mixed melting point, the thus-obtained product is identical with that obtained in accordance with Example 3.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CC(O)C>[CH2:24]([O:23][CH2:22][CH2:21][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:13]1)[CH3:25]
Reactant: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCn1cc(C2CCNCC2)c2ccccc21
Temperature: 97.5 °C

Procedure:
4 g of 4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester and 3.81 g of potassium hydroxide 85% were added to 14 g of 2-propanol and the mixture was heated at 95-100° C. for 16 hours. The solvent was distilled off and water was added. The mixture was extracted with toluene and the organic layer was separated, washed with water and concentrated. The residue was disolved in a mixture of 10 mL of ethyl alcohol 96% and 6 mL of 2-propanol and 1.4 g of fumaric acid were added. The mixture was refluxed for 30 minutes. After cooling at 0-5° C. for 30 minutes the formed solid was isolated by suction filtration. 4.05 g of a white solid were recovered as a salt of the product with fumaric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(N)c1
Yield: 93 %

Procedure:
3.0 g of 3,4-diaminobenzoic acid was suspended in methanol, and 1.86 ml of thionyl chloride was then added dropwise. Afterward, thionyl chloride was further added as much as 0.5 ml twice, and the suspension was then heated under reflux for 11 hours. Next, thionyl chloride and methanol were distilled off, and the residue was dissolved in methylene chloride, washed with a 0.5N aqueous sodium hydroxide solution and a saturated sodium chloride solution, and then dried over sodium sulfate. After the solvent was distilled off, the residue was sludged with n-hexane to obtain 3.04 g (93%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[O:29][C:30]([F:33])([F:32])[F:31]>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:25])=[CH:22][C:21]=1[O:29][C:30]([F:31])([F:33])[F:32]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccc(F)c(OC(F)(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(F)c(OC(F)(F)F)c1
Yield: 43 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-fluoro-3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a brown solid (25 mg, 43%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=8.0 Hz), 7.44 (t, 1H, Harom, J=8.0 Hz), 7.59 (s, 1H, Harom), 7.63 (d, 1H, Harom, J=9.0 Hz), 7.70 (t, 1H, Harom, J=9.0 Hz), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 8-06-8.13 (m, 2H, Harom), 10.47 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH:26]1([N:29]([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]([CH3:37])[C:30]2[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:35]=2)[CH2:28][CH2:27]1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Reactant: CN(c1ccc(N)cn1)C1CC1
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23ClN4O2 (m/e) 410, obsd 411 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33]O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC2CCCN(C(=O)OC(C)(C)C)C2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in step c of Example 3, N-(tert-butoxycarbonyl)-3-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step a of Example 2, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added and the reaction mixture was extracted into ethyl acetate (3×50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo The residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a colorless syrup (875 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.28 (m, 1H), 1.45 (s, 9H), 1.64-1.96 (m, 4H), 2.23 (s, 3H), 2.87 (M, 2H), 3.69 (m, 2H), 3.90 (d, 2H), 6.46 (s, 1H), 6.52 (s, 1H), 6.58 (s, 1H), 7.40 (t, 1H), 7.62 (m, 2H), 7.96 (d, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol), and sodium bicarbonate (52.3 g, 622 mmol) were dissolved/suspended in water (182 mL) and acetone (112 mL). The flask was cooled in an ice bath and a solution of benzoyl chloride (17.7 mL, 152 mmol) in acetone (56 mL) was added drop-wise over 1 hour. After 16 hours the acetone was removed on the rotovap. Water (400 mL) was added and the resulting mixture acidified using 6 M HCl to pH <2. The aqueous layer was washed with 200 mL CH2Cl2 three times. Aqueous sodium hydroxide (5M) was added to pH >12, and this solution was extracted three times with 200 mL of CH2Cl2. The combined organics were dried (MgSO4) and evaporated to give a thick yellow oil. MS (M+H)+=205.1
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:21]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of methyl 6-chloro-5-nitronicotinate (3 g, 13.85 mmol) in THF (60 mL) and DMF (30.0 mL) was added ethyl 2-hydroxyacetate (1.573 mL, 16.62 mmol) and potassium carbonate (5.74 g, 41.6 mmol). The reaction was stirred at room temperature for 24 hours. TLC analysis of the reaction mixture indicated partial consumption of starting material. Ethyl 2-hydroxyacetate (1 mL, 10.57 mmol) and potassium carbonate (2 g, 14.5 mmol) were added and the reaction was stirred at room temperature for 72 hours. TLC analysis of the reaction mixture indicated nearly complete consumption of starting material. The reaction mixture was partially concentrated under reduced pressure for removal of THF. The resulting red solution was diluted with H2O (200 mL) and 1N HCl was added to adjust the pH to 7. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide methyl 6-(2-ethoxy-2-oxoethoxy)-5-nitronicotinate (2.43 g, 8.55 mmol, 61.7% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[ClH:15].N1C=CC([C:21]([NH2:23])=[NH:22])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:15].[NH2:23][C:21]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[NH:22]
Reactant: N=C(N)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (8.93 g, 44.6 mmol) and pyrazole carbox-amidine hydrochloride (6.536 g, 44.6 mmol) was added Hunig's base (7.77 ml, 44.6 mmol) and DMF (25 ml). The reaction was heated at 60° C. for 15 hours. The reaction was then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separated out as a white solid, which was filtered, washed and dried (10.9 g, 88%). M.p.=169-172° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.09 (d, J=8.8 HZ, 1H), 6.9-7.9 (br. s, 3H), 3.83 (d, J=13.6 Hz, 2H), 3.63 (m, 1H), 2.88 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for C11H22N4O2.1.06HCl.0.2H2O: C, 46.39; H, 8.31; N, 19.68. Found C, 46.43; H, 8.31; N, 20.68.