Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:25])[C:26]3[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl {[4-(4-oxo-1-piperidinyl)benzoyl]amino}acetate (which was obtained in Example 162) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.35 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.90 (m, 5 H), 2.91 (s, 3 H), 3.63 (s, 3 H), 3.70–3.85 (m, 2 H), 3.95(d, J=5.7 Hz, 2 H), 4.49 (dd, J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.96(d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.71 (d, J=8.9 Hz, 2 H), 8.60 (t, J=5.8 Hz, 1 H); MS (ES) m/z: 521.3 (MH+); HRMS Calcd. for C25H37N4O7S (M+): 520.2064. Found: 520.2054.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.N1C=CC=CC=1.[Cl:28][CH2:29][C:30]1[S:31][CH:32]=[C:33]([C:35](Cl)=[O:36])[N:34]=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]([NH:21][C:35]([C:33]2[N:34]=[C:30]([CH2:29][Cl:28])[S:31][CH:32]=2)=[O:36])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(N)cc(Br)cc32)cc1
Reactant: O=C(Cl)c1csc(CCl)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CCl)n4)cc(Br)cc32)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
A three necked rounded bottomed flask was charged with 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-amine (12.7 g), anhydrous DCM (100 ml) and pyridine (7.5 ml) then placed under a nitrogen atmosphere and cooled to −10° C. A suspension of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (9.39 g) in anhydrous DCM (75 ml) was added in one portion. The reaction mixture was stirred at room temperature for ˜4 hrs. Additional 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.36 g) in anhydrous DCM was added in one portion and the reaction was stirred overnight. The suspension was filtered, washing sparingly with DCM, then dried on the vacuum pump to give title compound (15.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([OH:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(Br)ccc2OCc2ccccc2)cc1

Procedure:
A solution of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol (7.00 g), potassium carbonate (3.80 g) and benzyl bromide (3.27 ml) in DMF (10 ml) was stirred at 60° C. for 5 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane→hexane:ethyl acetate=10:1) to give the title compound (8.31 g) as a brown oil.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>O>[CH2:9]([O:8][C:6]([CH2:5][NH:4][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 25 °C

Procedure:
A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3×100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([CH:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:4]1[CH:9]=[CH:8][C:7]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH:22]3[CH2:21][CH2:20][C:19]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:24][CH2:23]3)[CH2:30][CH2:29]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: BrCCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
4-Bromoethylbenzene (s4) (30.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 124 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s5) (38.6 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (1.6 g) and toluene (300 ml) were added to the residue, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (0.3 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and by recrystallization from heptane, and then dried to give 8-(trans-4-(4-ethylphenyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane (s6) (33.2 g). The yield based on the compound (s1) was 62.3%.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])C=CC=CC=1.C([SiH](C(C)C)C(C)C)(C)C>C(Cl)Cl>[SH:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:18]([OH:20])=[O:19]
Reactant: O=C(O)CCC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CCC(CCCS)C(=O)O
Reaction time: 1 h
Yield: 69 %

Procedure:
2.46 mmol of 6-[(triphenylmethyl)thio]-1,3-hexanedicarboxylic acid (IV) (1.1 g) with 5 mmol triisopropylsilane (0.79 g) was dissolved in a mixture of 3 ml CH2Cl2/3 ml trifluoroacetic acid and left to stand at room temperature for 1 hour. The mixture was then evaporated to dryness and washed 3× with hexane. The remaining oily residue was dissolved in water, filtered and lyophilized to yield 0.35 g of 2-(3-sulfanylpropyl)pentanedioic acid (V) (76%), 13C-NMR (MeOH) δ 25.2(t), 28.8(t), 32.4(t), 33.0(t), 33.2(t), 45.9(d), 177.2(s), 179.6(s).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[CH:16][CH2:17][CH2:18][CH2:19]C34CC5CC(OC(O5)O3)C4)[C@H:11]2[N:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-:54].[Na+].[O:56]1[CH2:61]COCC1>>[O:37]=[C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:12]2[CH2:13][S:14][C:15](=[C:16]([CH2:17][CH2:18][CH3:19])[C:61]([OH:56])=[O:54])[C@H:11]2[N:10]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1N(Cc2ccccc2)[C@@H]2C(=CCCCC34CC5CC(C3)OC(O5)O4)SC[C@@H]2N1Cc1ccccc1
Reactant: C1COCCO1
Reactant: [OH-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
839 mg (1.62 mmol) of cis-1,3-dibenzyl-4-(4-(2,4,10-trioxaadamantyl)-butylidene)-hexahydro-1H-thieno[3,4-d]imidazol-2-one (prepared in accordance with Example 3) are treated with 4.6 ml of dioxan, 4.6 ml of 0.2N sulphuric acid as well as 20 mg of p-toluenesulphonic acid and the mixture is heated to boiling under an argon atmosphere for 2.5 hours. The mixture is subsequently made alkaline with 1.54 ml of 2N sodium hydroxide solution and boiled under reflux for a further 45 minutes. After cooling to room temperature the solution is extracted with ethyl acetate and the extract is discarded. The aqueous phase is acidified with dilute hydrochloric acid and again extracted with a total of 200 ml of ethyl acetate. The combined extracts are washed once with saturated sodium chloride solution and dried over sodium sulphate. After removing the solvent there are obtained 622 mg (89% of theory) of cis-2-oxo-1,3-dibenzyl-hexahydro-1H-thieno[3,4-d]imidazol-4-ylidenepentanoic acid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[OH:33])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[CH3:11].[Cl:34][C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[ClH:34].[CH2:10]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[O:33][C:35]3=[O:37])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)[CH3:11]
Reactant: CCO[C@H]1CC[C@H](N2CCC(Nc3cc(C)ccc3O)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCO[C@H]1CC[C@H](N2CCC(n3c(=O)oc4ccc(C)cc43)CC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (0.24 mL, 1.37 mmol) was added to a solution of 2-({1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}amino)-4-methylphenol (D29, 215 mg, 0.648 mmol) in dichloromethane (8 mL) at rt under argon. The reaction was cooled to 0° C. and the triphosgene (79 mg, 0.267 mmol) was added. The mixture was stirred for 30 min at 0° C., followed by a further 15 min at rt. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a white solid. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give the free base of the title compound as a white solid. The free base was dissolved in diethyl ether (1.5 mL) at 25° C. HCl (0.207 mL, 0.207 mmol, 1 M in diethyl ether) was then added and the reaction was stirred for 15 min. The solvent was removed by rotary evaporation to give 3-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-one hydrochloride (E10, 39.3 mg, 14% yield) as a white solid.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=O)[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:24][OH:25].CC([O-])=O.[Na+]>CO>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=[N:24][OH:25])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: NO
Reactant: CC(=O)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone (1.32 g, 4.2 mmol) in MeOH (50 mL) at RT was added hydroxylamine hydrochloride (877 mg, 12.61 mmol) followed by NaOAc (3.45 g, 42.0 mmol). The reaction mixture was stirred at 80° C. for 1 h then concentrated tinder reduced pressure. Water (100 mL) was added to the reaction mixture, and the mixture extracted with EtOAc (50 mL×3). The combined organic layers were concentrated under reduced pressure to afford 1.35 g (97.6%) of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone oxime as yellow solid: MS (ESI) m/z: 320.1 [M+1]+.
Reaction SMILES: ClC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[C:10](OC)[CH:11]=2)[C:6](CC2C=CC(OC)=C(OC)C=2)=[N:5][CH:4]=1.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(N(CC)CC)C>CS(C)=O.O>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: c1ccc2cnccc2c1

Procedure:
A mixture of 1.16 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 0.8 of 1-(para-methoxyphenyl)piperazine hydrochloride, and 1.3 ml of triethylamine in 10 ml dimethylsulfoxide was heated at 80° for one hour under argon. The cooled solution was then diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated. The residue was crystallized from ethanol to give 1.3 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-[[4-methoxyphenyl)-1-piperazinyl]methyl]isoquinoline as a yellow solid, mp 176°-177°. Recrystallization from ethanol provided the analytical sample, mp 176-177°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
The mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (300 mg), 3-[(methyloxy)carbonyl]benzoic acid (180 mg), HBTU (417 mg) and DIPEA (690 μL) in dichloromethane (DCM, 25 mL) was stirred at room temperature overnight. It was concentrated. Separation via CombiFlash (MeOH, DCM) then afforded the desired product (670 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>COCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[N:4][CH:3]=[C:2]2[NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: FC(F)(F)c1ccc2nncc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CC(C)(C)OC(=O)CNc1cnnc2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8 mL vial, was placed a solution of 4-chloro-6-(trifluoromethyl)cinnoline (as prepared in the previous step, 260 mg, 1.12 mmol, 1.00 equiv) in 2-methoxyethyl ether (2 mL), tert-butyl 2-aminoacetate (187 mg, 1.12 mmol, 1.10 equiv) and triethylamine (339 mg, 3.36 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 4 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate, and the combined organic layers washed with 2×10 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[H-].[Na+].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH:24]=[CH2:25]>O>[CH2:24]([C:23]([CH2:22][CH2:21][CH:20]=[CH2:19])=[CH:10][C:8]([O:7][CH3:6])=[O:9])[CH3:25]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C=CCCC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=CC(=O)OC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (25 mL) solution of trimethyl phosphonoacetate (4.67 g, 25.1 mmol) was added dropwise at 0° C. over 1 hour to a tetrahydrofuran (25 mL) suspension of sodium hydride (1.04 g, 63%, 27.4 mmol). To the mixture, tetrahydrofuran (25 mL) was further added, and the mixture was then stirred at 0° C. for 1 hour. To this solution, a tetrahydrofuran (25 mL) solution of 6-hepten-3-one (2.56 g, 22.8 mmol) was added dropwise at 0° C. over 20 minutes, and the mixture was stirred at room temperature for 2.5 hours and subsequently stirred at 65° C. for 3 hours. The mixture was treated with water, and volatile portions were then distilled off under reduced pressure, followed by extraction with hexane. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (3.04 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:17].CCOCC.[OH2:26]>[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[C:1]([C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([OH:17])=[O:26]
Reactant: Cc1ccc(OCc2ccccc2)cc1
Reactant: O=S(=O)(O)O
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-methylphenoxy phenyl methane (2g) was suspended in aqueous sodium dichromate solution (20ml. 50%) and concentrated sulphuric acid (10ml) added dropwise with stirring. The mixture was stirred at room temperature overnight then warmed on a water bath for 1hr. The mixture was cooled, diluted with water and the 4-carboxyphenoxy phenyl methane (m.p. 188°) isolated with ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Reactant: OCCCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CCCO)CC4)n3)ccc21

Procedure:
88 mg (0.25 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazine are irradiated in the microwave at 140° C. for 2 h with 42 μl (0.50 mmol) of 3-chloropropan-1-ol in 2 ml of ethanol and 70 μl (0.50 mmol) of triethylamine. The reaction mixture is evaporated and purified by means of preparative HPLC.
Reaction SMILES: C(C1C=C([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])N(C2C=C(C=CC=2)C(OCC)=O)N=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11](=[O:12])[NH2:10])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc(Cl)cc1
Yield: 226.1 %

Procedure:
To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added LiAlH4 powder (413 mg, 10.9 mmol) at −10° C. under N2. The mixture was stirred for 2h and excess LiAlH4 was quenched by adding ice. The solution was acidified to pH=7 with dilute HCl. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200+100 mL). The filtrate was concentrated to yield 1-{3-tert-butyl-1-[3-hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.40 g, 97%). 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.47 (s, 1H), 7.47–7.27 (m, 8H), 6.35 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 399 (M+H+).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[C:27]3[C:22]([N:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[C:27]3[C:22]([N:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4nccnc4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2,7′-biquinoxaline-6-carboxylate (90 mg, 0.23 mmol) in methanol (30 mL) and water (1 ml), was added sodium hydroxide (54 mg, 1.35 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 ml), adjusted the pH value to 6 with HCl (3N) and filtered to give 3-(isopropyl(methyl)amino)-2,7′-biquinoxaline-6-carboxylic acid as a light yellow solid (43.6 mg, 50%).