Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:19]>C(O)(C)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=4)=[C:16]([Cl:15])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: ClCCCn1ccc2ncnc(Cl)c21
Solvent: CC(C)O
Product: FC(F)(F)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 88.5 %

Procedure:
A mixture of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidine (789 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) and isopropyl alcohol (5 mL) was stirred at 80° C. for 4.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (40 mL×3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80) to give the title compound (1.46 g).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]([C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:15])[NH2:13].C(OC(OCC)OCC)C>O>[O:15]1[CH:1]=[N:13][N:12]=[C:14]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccc(C(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Product: O=C(O)c1ccc(-c2nnco2)cc1
Temperature: 100 °C
Yield: 379.7 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:4]=1)#[N:2].Br[CH2:36][CH2:37][OH:38].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:36][CH2:37][OH:38])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])=[C:5]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:4]=1)#[N:2]
Reactant: OCCBr
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (74 mg, 150 μmol) was initially charged in dry DMF (2 ml), 2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:3). The product-containing fractions were combined and concentrated, the residue was taken up in a little acetonitrile, water was added and the mixture was lyophilized. The title compound was obtained as a colorless solid (63 mg, 78% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:18][C:19]1[NH:20][C:21](=[O:36])[C:22]2[N:23]=[CH:24][N:25]([C:34]=2[N:35]=1)[C@@H:26]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[CH2:27]1)(=[O:17])[CH:14]([CH3:16])[CH3:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:32][CH2:31][C@H:30]2[O:33][C@@H:26]([N:25]3[C:34]4[N:35]=[C:19]([NH:18][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[NH:20][C:21](=[O:36])[C:22]=4[N:23]=[CH:24]3)[CH2:27][C@@H:28]2[OH:29])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-isobutyryldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/sodium bicarbonate mixture and evaporation to dryness, the product is taken up in chloroform. This product was not used because it was too insoluble.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[N:11]O)[C:6]=2[CH:13]=1.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28]N[CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[S:10][CH2:9][CH2:8][CH:7]2[N:11]1[CH2:28][CH2:29][C:24]2([N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][NH:22][C:23]2=[O:30])[CH2:25][CH2:26]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ON=C1CCSc2ccc(Cl)cc21
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCSc3ccc(Cl)cc31)CC2

Procedure:
The title compound, m.p. 164-166° C. dec. and MS: m/e=414.2 (M+H+) was prepared in accordance with the general method of example 11 from 6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]=[CH:13][CH:12]=[N:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:15]([S:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([S:17]([C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[N:14]=[CH:13][CH:12]=[N:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: Brc1cccc2[nH]c3nccnc3c12
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1cccc(-c2cccc3[nH]c4nccnc4c23)c1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
Compound 80 (50 mg, 0.2 mmol), 3-ethanesulfonyl-phenylboronic acid (65 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), and potassium carbonate (83 mg, 0.6 mmol), were combined in dioxane (2 mL) and H2O (0.2 mL) in a sealed tube under nitrogen. The reaction was heated at 150° C. in the microwave for 20 min and then concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CH2Cl2) gave 46 mg (68%) of the title compound as a light orange solid. 1H NMR (400 MHz, CH3OD) δ 8.42 (t, 1H, J=2.8 Hz), 8.31 (d, 1H, J=2.8 Hz), 8.24 (d, 1H, J=2.8 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.60-7.75 (m, 3H), 7.31 (dd, 1H, J=7.2, 1.2 Hz), 3.33 (q, 2H, J=7.2 Hz), 1.37 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C18H15N3O2S, 338; found 338.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:28])([CH3:27])[CH2:11][C:12](=[O:26])[C:13](NC3C=CC=C4C=3C=CC=N4)=[O:14])[C:4]=2OC1.CC(C1C=CC=CC=1)(C)CC(=O)C(N)=[O:34]>>[CH3:27][C:10]([C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH3:28])[CH2:11][C:12](=[O:26])[C:13]([OH:14])=[O:34]
Reactant: CC(C)(CC(=O)C(N)=O)c1ccccc1
Reactant: CC(C)(CC(=O)C(=O)Nc1cccc2ncccc12)c1cccc2c1OCO2
Product: CC(C)(CC(=O)C(=O)O)c1ccccc1

Procedure:
According to the instructions for 4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide (Example 12) after chromatography on silica gel, 370 mg of N-(quinolin-5-yl)-)-4-methyl-2-oxo-4-phenylpentanamide is obtained from 515 mg of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159). Flash point: 98–99° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1>>[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH:22]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: CCOC(=NC(=O)c1cccc(C)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and m-toluoyl chloride, there is obtained ethyl N-(m-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepin-6-carboximidate m.p. 102°-105° C.;
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>CO>[C:6]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11]
Reactant: COCOc1cccc(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(O)c1-c1ccccc1
Yield: 98.9 %

Procedure:
A solution of 16 (400 mg, 1.46 mmol) in MeOH (12.0 mL) at room temperature was treated dropwise with 3 M HCl (430 μL, 11.7 mmol), then heated to reflux for one hour. Water (15 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 17 as an orange amorphous solid (269 mg, 99%): 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, J=7.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.46-7.44 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 2H), 4.84 (s, 1H), 4.83 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[S:18]1(=[O:26])(=[O:25])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>C1COCC1.O>[O:25]=[S:18]1(=[O:26])[CH2:23][CH2:22][C:21](=[CH:9][C:7]#[N:8])[CH2:20][CH2:19]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCS(=O)(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCS(=O)(=O)CC1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at 0° C. and THF (8 mL) was added. Diethyl (cyanomethyl)phosphonate (0.56 mL, 3.5 mmol) was added slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide (0.50 g, 3.4 mmol) in THF (5 mL). After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)CC(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CN(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(isobutyl(methyl)amino)quinoxaline-6-carboxylate (80 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (34.8 mg, 0.87 mmol 1), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-3-(isobutyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (50.0 mg, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>O=[Pt]=O.C1(C)C=CC=CC=1>[NH2:19][C:10]1[CH:11]=[C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1

Procedure:
(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.200 g, 0.569 mmol) in 1:1 THF:toluene (5 mL) was reacted with PtO2 (1% w/w) on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The product was concentrated to give the title compound. ES/MS calcd. for C15H17BrNO2+ 322.0. Found m/z=322 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=O)=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:16][F:29])=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Solvent: ClCCl
Product: FCSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 20 (390.9 g, 1.11 mol) and SbCl3 (7.62 g, 0.0334 mol) in anhydrous dichloromethane (2.27 L) at −15° C., diethylamino sulfurtrifluoride (DAST) (258 ml, 2.0 mol) was added drop-wise. The reaction mixture was stirred for 3 hours at −20° C. and then allowed to warm up to room temperature overnight. The reaction was quenched with 1N NaOH solution until pH 3-4 at −20° C., and then solid NaHCO3 was added to pH=8. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to provide 330 g of the desired product as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4]([C:7]2[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][NH:9][CH:8]=2)=[N:3]1
Reactant: [Li]c1ccccc1
Reactant: CC1(C)COC(c2cccnc2)=N1
Solvent: C1CCOC1
Product: CC1(C)COC(C2=CNC=CC2c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a cooled (-78° C.) solution of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)pyridine [Hauck A. E., et al., J. Chem. Soc. Perkin I 1980:2070-2076] (140.0 g, 0.79 mol) in 500 mL dry tetrahydrofuran (THF), phenyllithium (1.42 mol, 1.8 eq) is added under a nitrogen atmosphere until gas chromatography (GC) analysis indicates no more starting material is present. The reaction mixture is stirred for 10 minutes and then quenched with 500 mL water at -78° C. After warming the reaction mixture to room temperature with a water bath, 700 mLof diethyl ether is added to the mixture. The resulting solid is filtered, rinsed once with chilled methanol, and then dried at 40° C. in a vacuum oven overnight to yield 166.6 g (0.65 mol) of 1,4-dihydro-3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-4-phenylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:31][CH3:32])[CH:21]=3)[N:16]([CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:24]([CH2:31][CH3:32])=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][CH3:30])[CH:21]=3)[N:16]([CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC(CCC)n1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2cc(-c3c(CC)cccc3CC)ncc21
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)n1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2cc(-c3c(CC)cccc3CC)ncc21
Reaction time: 18 h

Procedure:
The 4-[5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) is dissolved in EtOH (2 mL), 10% Pd/C (5 mg) is added, and the mixture is shook in a parr-reactor under 50 psi of H2 over 18 h. Filter, remove solvents and chromatograph the residue affords 4-[5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil: 1H NMR (CDCl3) 8.80 (s, 1H), 7.36 (s, 1H), 7.27 (t, J=7 Hz, 1H), 7.13 (d, J=12 Hz, 2H), 7.04 (s, 1H), 4.36 (m, 1H), 4.21 (m, 1H), 2.96 (m, 1H), 2.92 (m, 1H), 2.34 (m, 4H), 2.03 (m, 1H), 1.86 (m, 4H), 1.63 (m, 2H), 1.49 (s, 9H), 1.28 (m, 4H), 1.02 (t, J=8 Hz, 6H), 0.90 (t, J=8 Hz, 6H); LCMS m/z 532.39 (2.58 min).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the tiitle compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s). Procedure for the Preparation of 3-methyl-5-(2-morpholin-4-ethoxy)-2-nitro phenylamine
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH2:36])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:1].[ClH:49].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCC(CCN2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCN3CCCCC3)C2)c2ccccc21
Yield: 43 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[2-(piperidin-l-yl)ethyl]-piperidin-l-yl]ethanamine in a yield of 43% of theory. The dihydrochloride melted at 204°-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:41])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 98 %

Procedure:
The compound of example 47 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2-phenoxy phenyl isocyanate.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]([NH2:19])=[S:18].C([O-])(=O)C.[Na+]>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[N:16]=1
Reactant: O=C(CCl)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C(=O)c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
A mixture of chloromethyl-(4-nitrophenyl)diketone (2 g), thiourea (1.5 g) and sodium acetate (1.6 g) in ethanol (20 ml) was heated at 50° C. for 4 hours with stirring. The mixture was concentrated in vacuo and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure give 2-amino-4-(4-nitrobenzoyl)thiazole (0.71 g, yield: 32.4%).