Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([O:29]C)=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:35]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.N>ClCCl>[NH3:9].[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([NH2:35])=[O:29])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 139.3 %

Procedure:
A solution of methyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxylate (Preparation 72) (200 mg, 0.47 mmol) in dichloromethane (10 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol), N-methylmorpholine (77 μl, 0.70 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (134 mg, 0.70 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. Concentrated ammonia solution (0.88, 50 μl, 1.00 mmol) was then added and the mixture was stirred for 17 hours. The mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (97:3:0.3) to afford the title compound as a white solid (140 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][CH2:7]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To DMF (5.0 ml) was added sodium hydride (53 mg, 1.3 mmol) and the solution stirred at room temperature for 30 min. 5-Bromoindoline (240 mg, 1.2 mmol) was added and the solution was stirred at room temperature for 30 min. Methanesulfonyl chloride (94 ul, 1.2 mmol) was added and the solution stirred at room temperature overnight, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2% CH3OH/CHCl3 to give the title compound (202 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:4].[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[NH:29][C:28]1[N:24]([CH3:23])[N:25]=[C:26]([CH3:30])[CH:27]=1)=[O:4]
Reactant: Cc1cc(N)n(C)n1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cc(C)nn1C)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (step D3) and 2,5-dimethyl-2H-pyrazol-3-ylamine [3524-32-1] were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a foam. ESI-MS: tR=1.29 min, [M+H]+ 479/481/483 (LC-MS 1); TLC: Rf=0.31 (1:1 CH2Cl2/EtOAc).
Reaction SMILES: [Mg].CI.[CH2:4]([O:11][C:12]1[CH:21]=[CH:20]C(C(OC)=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].C[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:27]([C:26]([OH:25])([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(C)(C)C
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Under argon 6.63 g of magnesium (273 mmol) was suspended in 15 mL of tert-butyl methyl ether. A solution of 38.68 g of methyl iodide (273 mmol) in 145 mL of tert-butyl methyl ether was added during 45 min under stirring while maintaining the temperature at 40° C. Then stirring was continued at 40° C. for 1.5 h and then the mixture was cooled to room temperature. A solution of 30.0 g of methyl 4-benzyloxybenzoate (124 mmol) in 120 mL of tetrahydrofuran was then added during 1 h. The temperature was kept at 20° C. After complete addition, the reaction mixture was heated to 42° C. and stirred 3 h at this temperature. After cooling to room temperature, the reaction mixture was poured into a mixture of 300 mL of 10% aqueous ammonium chloride and 100 g of ice and extracted with ethyl acetate. The organic phases were washed with water and saturated aqueous sodium bicarbonate, combined, dried and evaporated to give the crude product as an oil which partially crystallised. The product was dissolved at 25° C. in diethyl ether. When crystals started to separate the solution was cooled to 18° C. After 30 min hexane was added. The suspension was then stirred for 1 h at 5° C. The crystalline 2-(4-benzyloxy-phenyl)-propan-2-ol was collected on a filter and washed with hexane.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][N:27]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=2)[CH2:26][CH2:25]1
Reactant: CC1(N)CCNCC1
Reactant: Cc1cc(Cl)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC(C)(N)CC2)ncn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a mixture of 4-methylpiperidin-4-amine bis(4-methylbenzenesulfonate) (3.91 g, 8.53 mmol) and 4-chloro-6-methylpyrimidine (1.10 g, 8.53 mmol) in NMP (35 mL) was added K3PO4 (3.12 g, 17.9 mmol) and the reaction mixture was stirred at 80° C. for 18 hours. After cooling to room temperature, 0.5 M aqueous K3PO4 was added and the mixture extracted twice with dichloromethane. The combined organic layers were extracted twice with HCl (1 N). The combined aqueous layers were made alkaline with NaOH (6 N), extracted twice with dichloromethane and the organic layers washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70 g, 0 to 100% ethyl acetate in heptane; then 0 to 50% methanol in ethyl acetate, containing 10% triethylamine) afforded the title compound (1.09 g, 62%) as a light yellow semisolid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1>[Pd].CO>[CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: C=Cc1cccc(-n2nnn(C)c2=O)c1COC
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(-n2nnn(C)c2=O)c1COC
Temperature: 25 °C

Procedure:
A mixture of 1-(2-methoxymethyl-3-ethenylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one described in Reference Preparation example 2219.7 g, palladium fibroin complex 3.02 g and methanol 1 L was stirred at room temperature under hydrogen atmosphere for eleven hours. The reaction mixtures were filtered and the filtrates were concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methoxymethyl-3-ethylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 19.3 g.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([NH:40][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)NC2CCCCC2)CC1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g, 0.33 mmole, described as intermediate 7 above) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. Cyclohexyl isocyanate (0.050 rmL, 0.35 mmole) was added dropwise and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (25 mL) and water (25 mL). The layers were separated and the organic layer washed with water (25 mL) and brine. The combined organic washings were extracted three times with EtOAc (25 mL), then dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 7:3 EtOAc-hexane) to give 0.16 g (100% yield) of 1-{(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-3-cyclohexyl-1-methyl-urea. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C@H:14]2[CH2:16][C@@H:15]2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].B(O)(O)[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1.N#N.[OH-].[Na+]>COCCOC.O.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>[OH:10][CH2:9][C@H:8]([NH:11][C:12]([C@H:14]1[CH2:16][C@@H:15]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(N[C@@H](CO)c1ccc(Br)cc1)[C@H]1C[C@@H]1c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc([C@H](CO)NC(=O)[C@H]3C[C@@H]3c3cccs3)cc2)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
A mixture of (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid [(R)-1-(4-bromo-phenyl)-2-hydroxy-ethyl]-amide (560 mg, 1.53 mmol), K3PO4 (650 mg, 3.0 mmol)) and p-tolylboronic acid (310 mg, 2.3 mmol) in DME/H2O (3/1, 2 ml) was passed through N2 and then Pd(PPh3)4 (178 mg, 0.153 mmol) added. The mixture was stirred in a sealed tube at 85° C. for 1.5 h. The reaction mixture was poured 1N NaOH and extracted with EtOAc (3×). The combined EtOAc layer was dried over MgSO4. After removal of the solvent, the residue was subjected to silica column (50% EtOAc in DCM and then 10% MeOH in DCM). The product obtained was further purified by crystallization (iPrOH/EtOAc) and Prep HPLC to give the titled compound (275 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.6 (d, J=8.1 Hz, 2H), 7.5 (d, J=7.8 Hz, 2H), 7.4 (d, J=8.1 Hz, 2H), 7.2 (d, J=7.6 Hz, 2H), 7.1 (t, J=5.4 Hz, 1H), 6.8-7.0 (m, 2H), 5.0 (dd, J=5.4, 1.9 Hz, 1H), 3.7-3.8 (m, 2H), 2.5-2.7 (m, 1H), 2.4 (s, 3H), 2.1 (t, J=8.7 Hz, 1H), 1.4-1.6 (m, 1H), 1.2 (ddd, 1H). LRMS (ESI)=378, [(M+1)+ calcd for C23H24NO2S 377.5].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(OC1C=CC=C(C(C)(C)C=CCCCCC)C=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC(C)(C)c1cccc(O)c1
Agent: CCCCCC=CC(C)(C)c1cccc(OCc2ccccc2)c1
Product: CCCCCCC(C)(C)c1cccc(O)c1

Procedure:
In like manner, 2-(3-hydroxyphenyl)-2-methylnonane is prepared in 82% (7.8 g.) yield from 13.0 g. (0.0406 mol.) of 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene. It is obtained as an oil having the characteristics:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH:23]([CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([CH:26]1[CH2:31][CH2:30][CH:29]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)C1CCC(=O)CC1
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.0 g of 1-[4-(4-phenyl-1-piperidinyl)phenyl]-2-propanone and 16 ml of dimethylformamide dimethylacetal is stirred at room temperature overnight, followed by heating at 45°-60° C. for six hours. The solvent is evaporated and the residue triturated with two 100 ml portions of hexane. The solid is filtered and dried to give 3.5 g of orange powder, mp 93°-100° C. Upon standing overnight at 0° C., the filtrate gave an additional 0.7 g of the product, mp 103.5°-105° C. This material is used directly for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[C:23]1[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=1.C1OCCOCCOCCOCCOCCOC1>[Cu].ClC1C=CC=CC=1Cl>[C:23]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: c1ccc(-c2cc3ccccc3n2-c2ccccc2)cc1
Temperature: 185 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of dry o-dichlorobenzene containing 2-phenylindole (1 mmole) was added K2CO3 (1.5 mmole), 4-iodotoluene (1 mmole), copper powder (1.5 mmole) and 18-crown-6 (0.02 mmole), the reaction mixture was stirred under argon at 185° C. overnight. After cooling to room temperature, the reaction mixture was washed with hexane. The solid mixture was dissolved in EA, the K2CO3 and copper powder was removed by filtration. EA solution was evaporated under reduced pressure to give brown-red crude solid. Further purification by column chromatography on silica gel with hexane as an eluent gave a pale yellow solid of 1,2-diphenylindole (75% yield). The solid product (1 mmole) was dissolved in DMF (10 ml), a mixture of POCl3 (1.2 mmole) and DMF (1.2 mmole) was added dropwise. After stirring at 75° C. for 1 h, the reaction mixture was added into saturate NaHCO3 solution. The precipitated solid was collected by filtration and washed with ethanol to give a pale gray solid of 1,2-diphenylindole-3-carboxaldehyde (90% yield). A dry DMF solution of the aldehyde (2 mmole) was added o-aminothiophenol (2.1 mmole) and Ac2O (0.5 ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred water and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford compound 1-4(32% yield). 1H-NMR (CDCl3, TMS) δ(ppm)=2.4 (s, 3H, Ar—CH3), 7.1-7.6, 8.2 (m, d, 17H, aromatic H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:17]1([NH:20][C:21]([NH2:23])=[NH:22])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:17]1([NH:20][C:21]2[N:23]=[C:5]([C:7]3[CH:8]=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:22]=2)[CH2:19][CH2:18]1
Reactant: N=C(N)NC1CC1
Reactant: CN(C)/C=C/C(=O)c1cnn2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnn2ncc(-c3ccnc(NC4CC4)n3)c2c1
Temperature: 165 °C
Yield: 75 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-pyrazolo[1,5-b]pyridazin-3-yl-2-propen-1-one (43 mg, 0.20 mmol) in DMF (2 mL) was added N-cyclopropylguanidine.0.5H2SO4 (160 mg, 0.80 mmol) and potassium carbonate (110 mg, 0.80 mmol). The reaction was heated at an oil bath temperature of 165° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was purified by flash column chromatography (0-10% gradient MeOH/CH2Cl2) to give the title compound as a yellow solid (38 mg, 75%). 1H-NMR (400 MHz, d6-DMSO) δ 9.13 (dd, 1H, J=9.0, 1.6 Hz), 8.77 (s, 1H), 8.53 (dd, 1H, J=4.4, 1.6 Hz), 8.24 (d, 1H, J=5.2 Hz), 7.38 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 2.72 (m, 1H), 0.71 (m, 2H), 0.47 (m, 2H), MS (ESI) (M+H)+ 253.
Reaction SMILES: N1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:4][N:3]=N1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([C:11]1[O:16][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:4][N:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1nnn[nH]1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(C(C)(C)C)o1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of ethyl tetrazole-5-carboxylate (8.53 g, 60 mmol) and pivaloyl chloride (7.23 g, 60 mmol) in dry toluene (240 ml) is refluxed for 16 hours. After the solution has cooled to room temperature, it is washed two times with 1 N sodium hydroxide solution (20 ml) and then once with water (20 ml). The organic phase is dried over magnesium sulphate and the solvent is evaporated in vacuo to give ethyl 5-tert-butyl-[1,3,4]oxadiazole-2-carboxylate as a red oil (6.96 g, 59%), which is used in the following stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C([Li])(C)(C)C.[CH:26](=[O:29])[CH2:27][CH3:28].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH:26]([OH:29])[CH2:27][CH3:28]
Reactant: O=C(O)c1cc(Cl)c(Cl)s1
Reactant: CCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1sc(C(=O)O)cc1Cl
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4,5-dichloro-thiophene-2-carboxylic acid in THF (25 mL) at −53° C. is treated with LiHMDS (2.5 mL, 1 M THF) and then cooled to −78° C. for 10 min. Tert-butyl lithium (3.2 mL, 1.7 M Pentane, 5.4 mmol) is added dropwise for 12 min., then treated with propanal (0.25 mL, 3.4 mmol). After 5 min. the reaction is warmed to rt and stirred overnight. The reaction mixture is then acidified with 1 N HCl (10 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are dried over MgSO4, filtered, and concentrated to provide crude 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid as a brown syrup (0.280 g), which is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)C>[CH3:1][NH:2][C:3]([NH:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: NC1CCCCC1
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)NC1CCCCC1
Yield: 67.3 %

Procedure:
In 500 ml of ethyl ether is dissolved 57 g of methyl isocyanate and, then, 99 g of cyclohexylamine is added dropwise, whereupon crystals separate. The crystals are washed with ether. By the above procedure is obtained 105 g of N-methyl-N'-cyclohexylurea. melting point: 160°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15].[Br:18]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]([OH:17])([CH3:15])[CH3:16])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Br:18]
Reactant: COC(=O)c1ccc(N)c(NCC(C)(C)O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(N)c(NCC(C)(C)O)c1
Yield: 26.9 %

Procedure:
To a solution of methy 4-amino-3-[(2-hydroxy-2-methylpropyl)amino]benzoate (1.5 g, 6.30 mmol) in DCM (12.59 mL) added bromine (0.324 mL, 6.30 mmol) drop-wise. The reaction was complete upon total addition of bromine. Reaction mixture was quenched with sodium sulfite and diluted with EtOAc. The aqueous layer was washed with EtOAc (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (0.538 g): LC-MS [M]=317.2.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CN(C)C=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CCNCC
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCCc1nnc2c(N(CC)CC)nc3ccccc3n12
Yield: 78 %

Procedure:
4-Chloro-1-n-propyl-[1,2,4]-triazolo[4,3-a]quinoxaline (1.23 g., 0.005 mole), the product of Example 5, and 1.1 g. (0.015 mole) of diethylamine in N,N-dimethylformamide (15 ml.) were stirred at room temperature for 2 hours. The reaction mixture was then poured over ice. The precipitate was removed by filtration, washed with water and air dried. Recrystallization (twice) from ethanol/water afforded 1.1 g. (78% yield) of pure 4-diethylamino-1-n-propyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 92°-94° C. Mass spectrum: m/e, 283 (P).