Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine as starting material. Product as an oil (20 mg, 62%). LC/MS (Method B) 2.89 min, [M+1]+ 461. Potency class A.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]1.[OH-].[Na+]>FC(F)(F)C(O)=O>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:16]4([CH2:17][CH2:18][CH2:19][O:14][CH2:15]4)[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCCOC1
Reactant: NCCc1coc2cc(I)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2c3c(oc2c1)C1(CCCOC1)NCC3

Procedure:
A solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (1.00 g, 3.48 mmol) and dihydro-pyran-3-one (1.05 g, 10.4 mmol) in trifluoroacetic acid (4.00 mL) was heated at 80° C. for 15 h. The reaction mixture was cooled down, 1M aqueous NaOH was added and the mixture was extracted with DCM. The solvent was evaporated and the residue was purified by silica gel chromatography eluting with DCM-MeOH—NH4OH to afford the title product. mp 131-137° C. dec.; MS m/z 370 [M+H]+
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:2])[CH3:3])[S:14][C:13]=2[CH:15]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Yield: 89.2 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.065 mmol) in DCM (1.5 mL) at 0° C. was added BBr3 (1.0 M in heptane, 0.196 mL, 0.196 mmol) dropwise. After 1 h at 0° C. the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (25.8 mg, 0.058 mmol, 89% yield). LC/MS (m/z, M-H): 443.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:18](O)=[O:19].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]2[NH:9][C:18](=[O:19])[CH:13]3[CH2:14][O:15][CH2:16][CH2:17][N:12]3[C:6]=2[N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)c1N
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1NC(=O)C1COCCN21
Temperature: 100 °C
Yield: 4.1 %

Procedure:
A round-bottom flask was charged with crude 2,4-dichloro-6-methylpyrimidin-5-amine (6.644 g, 37.3 mmol), morpholine-3-carboxylic acid hydrochloride (7.51 g, 44.8 mmol), DIPEA (26.1 mL, 149 mmol) and DMSO (49.0 mL). The flask was heated overnight at 100° C. The mixture was subsequently cooled to room temperature and then poured into ice. The solution was stirred while slowly warmed to room temperature. The mixture was subsequently filtered, and the filtrate was purified by preparatory HPLC using a gradient of 15-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a white solid (387 mg, 4.1%). 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.54 (s, 1H), 2.87-2.99 (m, 1H), 3.43-3.52 (m, 1H), 3.91 (dd, J=11.72, 3.42 Hz, 1H), 4.10-4.22 (m, 2H), 4.29 (dd, J=10.74, 3.91 Hz, 1H), 10.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C10H11ClN4O2, 255.06. found 255.5.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17](=[N:36][OH:37])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:41][C:42]([NH2:44])=[O:43].Cl>CN(C)C=O.O.C(OCC)(=O)C>[NH2:44][C:42](=[O:43])[CH2:41][O:37][N:36]=[C:17]([C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1
Reactant: CCOC(=O)CCc1cc(C(=NO)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Reactant: NC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=NOCC(N)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
In 5 ml of N,N-dimethylformamide is dissolved 2.0 g of ethyl 3-{5-[(2,4-diisobutoxyphenyl)-(hydroxyimino)methyl]-2-isobutoxyphenyl}propanoate, to which is added 0.19 g of 60% sodium hydride. The mixture thus obtained is stirred at ambient temperature for 30 minutes. Then, 1.07 g of 2-bromoacetamide is added and the mixture thus obtained is stirred at ambient temperature for one hour and further at 80° C. for 15 minutes. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 1.09 g of ethyl 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoate as a colorless oily product.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:35]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:34])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:35][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:34])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]
Reactant: C=CCCCc1ccc(C)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCc1ccc(C)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
Step AL (2): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-methyl-2-(pent-4-enyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (65 mg, 0.102 mmol) in DME (7.0 mL) and water (4.5 mL) was added barium hydroxide monohydrate (625 mg, 3.3 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(5-methyl-2-(pent-4-enyl)benzylamino)butan-2-ol double trifluoroacetate salt (22 mg, 35%) as a colorless oil. LC-MS (M+H)+=389.63.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:14])=[CH:11][C:10](=[O:15])[CH2:9]1>O1CCCC1.C(OCC)C.[Cu]I>[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:1])([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Reactant: [Li]C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(C)(C)CCC1CC(=O)CC(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (6.O g, 0.032 mol) in tetrahydrofuran (120 mL) cooled to 0~C was added a methyllithium solution (45 mL of a 1.4 M solution in diethyl ether, 0.063 mol). After stirring 0.5 hour, 3-(3-methoxy-3-methylbutyl)-5-methylcyclohex-5-en-1-one (2.0 g, 0.0095 mL) in tetrahydrofuran (80 mL) was slowly added. After stirring 2.5 hours, the mixture was added to ice cold dilute hydrochloric acid. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5,5-dimethylcyclohexan-1-one, bp0.5 125-130~C (1.3 g); NMR (CDC13)δ0.9(s,3H), 1.1(s,3H), 1.1(s,6H), 1.2-1.6(m,6H), 1.6-2.5(m,5H), 3.2(s,3H); IR(neat) 2960, 1715, 1365, 1085 cm-1. MS(m/e) 41, 55, 73, 138, 161, 211, 212.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]#[N:23]>CN(C)C=O>[C:22]([CH2:21][CH2:14][O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:23]
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: N#CCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC)c1OCCC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 57.1 g (0.31 mole) of 2-hydroxy-3-methoxybenzoic acid, methyl ester, 95.5 g (0.69 mole) of anhydrous potassium carbonate, and 23.9 ml (28.5 g; 0.38 mole) of chloroacetonitrile in 260 ml of N,N-dimethylformamide is heated on the steam bath for three hours. The mixture is cooled, added to 1700 g of ice/water, stirred for 1 hour, and the precipitated crude product is filtered and washed with water. Recrystallization from aqueous methanol yields 52.5 g 77% yield) of the 2-cyanoethoxy-3-methoxybenzoic acid, methyl ester, mp 77°-78° C. (See U.S. Pat. No. 4,420,476 for mp of 74°-75° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:15]([OH:22])[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1>N1C=CC=CC=1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(O)c1cccnc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide (1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and treated with CrO3 (0.75 g, 7.5 mmol, 2.39 eq). The mixture was stirred under N2 at room temperature for five hours, diluted with 20 mL 1:2 EtOAc/H2O, and filtered through Celite. The aqueous phase was separated and discarded, then the organics dried under vacuum yielding product (680 mg, 70%). 1H NMR (CDCl3) δ 11.06 (s,1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz, 1H) 8.73 (d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz, 2.0 Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.B1C2CCCC1CCC2>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:12]([OH:13])[C:11]3[CH:14]=[C:15]([CH2:18][CH3:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(O)c1cc(Cl)cnc1C=C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (20 mg, 0.075 mmol) was dissolved in 1 mL of tetrahydrofuran. Rh(COD)2BF4 (3 mg, 0.007 mmol) was added followed by a dropwise addition of 9-BBN (0.44 mL of 0.5 M in THF, 0.22 mmol) and the reaction was stirred overnight. The reaction was cooled to 0° C. and quenched by the simultaneous addition of 1M sodium hydroxide (2.5 ml) and 30% aqueous hydrogen peroxide (0.75 mL) and stirred for 5 hours. The resulting solution was poured into ethyl acetate and brine and extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (0-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H); 8.03 (s, 1H); 7.54 (s, 1H); 7.28 (m, 2H); 7.17-7.14 (m, 2H); 5.31 (s, 1H); 2.70 (q, 2H); 1.25 (t, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C16H15ClNO) [M+H]+, 272.1; found 272.1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[CH2:29]([OH:32])[C:30]#[CH:31]>N(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:31]#[C:30][CH2:29][OH:32])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Preparation No. 4 (0.494 g) in Et2NH (12.9 mL) is added CuI (10.8 mg) and (Ph3P)2PdCl2 (39.7 mg). DMF (2 mL) is added to solubilize the reactants. To this solution is added propargyl alcohol (0.066 mL) and the reaction is stirred at room temperature for 2 days. The reaction mixture is concentrated to remove Et2NH. The resulting residue is partitioned between CH2Cl2 (3×) and H2O. A brown solid precipitated from the CH2Cl2 layer is filtered and collected to obtain pure product as indicated by NMR. The organic layers are combined, dried over Na2SO4, and concentrateed to obtain a brown residue. The residue is placed under high vac to remove residual DMF. The residue is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2C12 and 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to obtain a creme solid. The two crops yielded 325.4 mg (79%) of the desired product as a tan solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.[CH3:12][NH:13][C:14]([NH:16][CH3:17])=[O:15].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19]>CO>[S:18]([O-:22])([O-:21])(=[O:20])=[O:19].[CH3:12][N+:13]1[C:14](=[O:15])[N:16]([CH3:17])[CH:5]=[CH:4][CH:3]=1.[CH3:12][N+:13]1[C:14](=[O:15])[N:16]([CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: COC(CC(OC)OC)OC
Reactant: CNC(=O)NC
Solvent: CO
Product: Cn1ccc[n+](C)c1=O
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Yield: 76.6 %

Procedure:
82.1 g (0.5 mol) of 1,1,3,3-tetramethoxypropane and 39.7 g (0.45 mol) of 1,3-dimethylurea were dissolved in 400 ml of methanol, 49.0 g (0.5 mol) of concentrated sulfuric acid was added dropwise thereto at room temperature, and the mixture was allowed to undergo the reaction at 50° C. for 30 minutes. After completion of the reaction, this was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain 59.7 g (yield 69%) of the title compound (purity 99.8%, melting point 203-205° C.).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])[NH:3]1.[NH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:30](O)=[O:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:30]([N:9]1[CH2:8][CH2:7][C:6]2([N:5]=[C:4]([CH2:12][N:13]3[C:14](=[O:19])[CH2:15][CH2:16][C:17]3=[O:18])[NH:3][C:2]2=[O:1])[CH2:11][CH2:10]1)=[O:31]
Reactant: Nc1sc2ccccc2c1C(=O)O
Reactant: O=C1CCC(=O)N1CC1=NC2(CCNCC2)C(=O)N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CN1C(=O)CCC1=O)NC2=O

Procedure:
5A (1.0 equivalent) in DMF (0.12 M) along with a 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 equivalent) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with brine and dried over Na2SO4, and volatiles removed under reduced pressure. Residue purified by LCMS to afford 1-((8-(2-aminobenzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)pyrrolidine-2,5-dione (5B).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:21])(=O)=O.C[O:24][C:25]([C:27]#[C:28]C(OC)=O)=[O:26].OS(O)(=O)=O>>[OH:8][CH2:7][C:3]1[C:2]2[N:1]([N:21]=[C:27]([C:25]([OH:24])=[O:26])[CH:28]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)C#CC(=O)OC
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc2c(CO)cccn2n1

Procedure:
In Scheme I, dicarboxylic acid dimethyl ester 1 is prepared by reaction of the 3-pyridylcarbinol analogue with O-mesitylenesulfonylhydroxylamine in the presence of acetylene dicarboxylic acid dimethyl ester. Reaction of 1 with aqueous H2SO4 affords the 4-hydroxymethylpyrazolo[1,5-a]pyridine-2-carboxylic acid analogue, which is converted to the ethyl ester 2 by reaction with acetyl chloride in absolute ethanol. Oxidation of 2 with Jones reagent yields carboxylic acid 3, which is converted to amide 4 by reaction with an appropriate amine in the presence of BOP.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([C:12]3([C:20]([F:23])([F:22])[F:21])[O:19][CH:13]3C(OCC)=O)=[CH:6][C:5]=2[O:4]1>C(O)C.O>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[O:19])=[CH:6][C:5]=2[O:4]1
Reactant: CCOC(=O)C1OC1(c1ccc2c(c1)OCO2)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=CC(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
Into a solution of 9.5 g of potassium hydroxide in 80 ml of ethanol and 20 ml of water, 24.0 g of ethyl 3-(3,4-methylenedioxyphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 17 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 2 with 10% HCl and extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (140°-160° C.) to obtain 7.7 g of the desired aldehyde (b.p. 121°-122° C./18 mmHg).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:6]([O-:9])=[O:7])=[C:14]([OH:18])[CH:13]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1O
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 18.2 %

Procedure:
To a solution of concentrated sulfuric acid (32.6 mL) in water (105 mL) was added potassium nitrate (51.5 g, 509 mmol) at 10° C. The reaction mixture was stirred for 5 min before adding 3-bromophenol (49.35 g, 285 mmol) dropwise so that the temperature of the reaction was maintained around 10° C. The reaction mixture was stirred at ambient temperature for an additional 2 h, diluted with water (350 mL) and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 19:1 hexanes/ethyl acetate) to give 5-bromo-2-nitrophenol (11.3 g, 18%) as a yellow-green solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.44 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.7, 2.1 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 61 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg, 5.62 mmol) to provide 1.37 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide as a white powder, m.p. 149–151° C. Analysis: Calculated for C22H25N5O3S: % C, 60.12; % H, 5.73; % N, 15.93. Found: % C, 60.40; % H, 5.82; % N, 15.85.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([O-:5])=O.[Na+].[CH3:18][N:19]1[CH:23]=[C:22]([C:24]2[N:29]=[N:28][C:27]([NH:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=2)[CH:21]=[N:20]1.N1C=CN=C1.S(Cl)(Cl)=O>C(#N)C>[F:16][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([N:28]1[N:29]=[C:24]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:25]=[CH:26]/[C:27]/1=[N:30]\[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:5]
Reactant: O=C([O-])C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)cn1
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cn1cc(-c2cc/c(=N\NC(=O)OC(C)(C)C)n(C(=O)C(F)(F)c3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
900 mg (3.67 mmol) of sodium difluoro(quinolin-6-yl)acetate was dissolved in acetonitrile (27 mL). 1.17 g (4.04 mmol) of tert-butyl 2-[6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl]hydrazinecarboxylate was added and 300 mg (4.41 mmol) of 1H-imidazole was added at once. 0.561 mL (7.71 mmol) of thionyl chloride was added over 5 minutes at room temperature. The mixture was stirred for 2 hours at room temperature, giving tert-butyl (2E)-2-{2-[difluoro(quinolin-6-yl)acetyl]-6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-ylidene}hydrazinecarboxylate. Then, 0.722 mL (11.0 mmol) of methanesulphonic acid was added at room temperature and stirred for 16 h. The resulting solids were filtered off under argon atmosphere, yielding 6-{1,1-difluoro-2-[(6E)-6-hydrazono-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-1(6H)-yl]-2-oxoethyl}quinoline and used as such in the next step.