Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[C:13]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature 14 hours before partitioning between EtOAc (120 mL) and water (100 mL). The organics were washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH2Cl2, 0→5→25→35 min) yielded 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brown solid: 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.50 (2H, d, J 8.0 Hz, 2H of C6H4CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH2C6H4CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m, 2H of pip); m/z 399, 401 [M+H]+. To a mixture of the 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100 mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixture was degassed by bubbling argon through the mixture. Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture further degassed before sealing the reaction and heating to 105° C. for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH—CH2Cl2 (3×15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by RP-HPLC to yield Compound 165: 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H of OC6H4CN, 2H of CH2C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 522 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](I)[CH3:18]>CC(=O)CC.O>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc(C=O)cc1O
Yield: 43.5 %

Procedure:
Anhydrous potassium carbonate (2.25 g, 16.3 mmol) was added to 3,4-dihydroxybenzaldehyde (1.5 g, 10.8 mmol), in butanone (30 ml), at room temperature. The reaction was stirred for 10 min after which ethyl iodide (0.872 ml, 10.8 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×25 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60, v/v) with an increasing gradient of ethyl acetate) afforded 0.78 g (43%) of 3-hydroxy-4-ethoxybenzaldehyde as a white solid.
Reaction SMILES: O.[OH-].[Li+].[I-:4].[C:5]1([NH:11][C:12](=[O:40])[NH:13][CH2:14][CH2:15][CH2:16][NH+:17]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CO>[I-:4].[C:5]1([NH:11][C:12](=[O:40])[NH:13][CH2:14][CH2:15][CH2:16][NH+:17]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CCC[NH+](CCCNC(=O)Nc2ccccc2)CCc2ccc(Cl)cc2)cc1
Agent: [I-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCCC[NH+](CCCc1ccc(C(=O)O)cc1)CCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 69.4 %

Procedure:
Lithium hydroxide monohydrate (4 mg, 0.095 mmol) was added to a solution of [3-(phenylureido)propyl][2-(4 chlorophenyl)ethyl][4-(methoxycarbonyl)benzyl]ethylammonium iodide (28 mg, 0.044 mmol) in 10% water/methanol (1.3 ml). After stirring at RT for 26 h, the reaction mixture was concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 33% methanol/chloroform to afford [3-(phenylureido)propyl][2-(4-chlorophenyl)ethyl][4-(carboxy)benzyl]ethylammonium iodide (19 mg, 70%): MS(ES+) m/e 496 [M-I]+; 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.38 (m, 2H), 7.30 (m, 4H), 7.24 (m, 2H), 6.97 (m, 1H), 4.59 (s, 2H), 3.31 (m, 8H), 3.15 (m, 2H), 2.15 (m, 2H), 1.48 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2CC2(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N1CC2CC2(c2ccc(N)cc2)C1

Procedure:
A solution of 3-acetyl-1-(p-nitrophenyl)-3-azabicyclo[3.1.0]hexane in tetrahydrofuran is hydrogenated at atmospheric pressure and ambient temperature using a 5% palladium on charcoal catalyst. Filtration and evaporation of the filtrate under reduced pressure gives 3-acetyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [F:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[O:28][C:13]3=[CH:14][N:15]=[C:16]([C:18]4[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH:23]=4)[CH:17]=[C:12]3[CH2:11]2)[CH2:6][CH2:5]1>[Pd].CO>[F:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[O:28][C:13]3=[CH:14][N:15]=[C:16]([CH:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)[CH:17]=[C:12]3[CH2:11]2)[CH2:6][CH2:5]1
Reactant: CC(C)(F)CN1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(F)CN1CCC(C2Cc3cc(C4CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-[1-(2-fluoro-2-methyl-propyl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine (50 mg) and 10% palladium on carbon (15 mg) in methanol (5 mL) is shaken under hydrogen atmosphere (3.5 bar) at room temperature. The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 3): tR=0.58 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]([NH:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C[C@@H](N)c1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 83 %

Procedure:
Using a procedure analogous to that used to prepare 34B, 39A (2.75 g, 10 mmol) was reacted with N-(Benzyloxycarbonyloxy)succinimide to afford 39B (3.1 g, 83%) as a white solid. MS (ESI) m/z 395.13 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:32][CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1sc(-c2cc(Nc3cccc(O)c3)ccc2C)c(-c2cccnc2)c1C#N
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2cc(Nc3cccc(OCCCO)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 5-[5-(3-hydroxyphenylamino)-2-methyl-phenyl]-2-methylsulfanyl-4-pyridin-3-yl-thiophene-3-carbonitrile (330 mg, 0.77 mmol) in DMF (anhydrous, 5 mL) was added 3-bromo-propan-1-ol (214 mL, 1.54 mmol). The reaction was stirred at 70° C. in the presence of excess K2CO3 overnight then cooled to ambient temperature and partitioned between water and DCM. The mixture was extracted with DCM (30 ml×3) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (2% MeOH-DCM) afforded desired product (370 mg, 99%). 1H NMR (CDCl3): δ 8.6 (d, 1H), 8.5 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (s, 1H), 7.3–7.2 (m, 3H), 7.0 (d, 1H), 6.6 (d, 1H), 4.1 (t, 2H), 3.9 (t, 2H), 2.7 (s, 3H), 2.0 (m, 2H), 1.5 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([OH:19])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28](=[O:30])[CH3:29].O1C2C=CC=CC=2C=C1>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[CH:11]=[C:27]([C:28](=[O:30])[CH3:29])[O:19][C:13]=2[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: COc1cc(O)c(C=O)c(OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)c2cc(C(C)=O)oc2c1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
A solution of 2-(benzyloxy)-6-hydroxy-4-methoxybenzaldehyde (Example 1C, 3.46 g, 13.4 mmol) in N,N-dimethylformamide (50 mL) was treated with powdered anhydrous cesium carbonate (4.58 g, 14.05 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with chloroacetone (1.74 g, 18.7 mmol) added dropwise over 5 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting aldehyde left by tlc and formation of the intermediate alkylated aldehyde). The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (300 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. This syrup was diluted with tetrahydrofuran (50 mL) and ethyl acetate (50 mL), treated p-toluenesulfonic acid monohydrate (0.2 g) and stirred at 20° C. for 1 h (tlc indicated complete cyclization of the intermediate alkylated aldehyde to the benzofuran). The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4×12 cm, elution toluene-ethyl acetate 2-4%) gave 3.51 g (88% yield) of the title benzofuran as a yellow solid. Recrystallization from ethyl acetate (10 mL) and hexane (20 mL) gave the title material as large yellow prisms (3.15 g). LC (Method D): 2.148 min. HRMS (ESI) calcd for C18H17O4 [M+H]+ m/z 297.1121, found 297.1092. 1H NMR (CDCl3, 600 MHz) δ 2.51 (s, 3H), 3.82 (s, 3H), 5.13 (s, 2H), 6.37 (d, J=1.77 Hz, 1H), 6.63 (broad s, 1H), 7.34 (broad t, 1H), 7.39 (broad t, 2H), 7.44 (broad d, 2H), 7.55 (d, J=0.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][OH:13])[CH2:2][CH:3]=[CH2:4].[CH2:14]([O:17][C:18]1([CH3:47])[CH2:23][CH2:22][N:21]([C:24]2[N:29]3[N:30]=[C:31]([CH2:33]I)[CH:32]=[C:28]3[N:27]=[C:26]([CH3:35])[C:25]=2[C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:20][CH2:19]1)[CH:15]=[CH2:16].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:17][C:18]1([CH3:47])[CH2:19][CH2:20][N:21]([C:24]2[N:29]3[N:30]=[C:31]([CH2:33][O:13][CH2:12][C:6]4[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=4[CH2:1][CH2:2][CH:3]=[CH2:4])[CH:32]=[C:28]3[N:27]=[C:26]([CH3:35])[C:25]=2[C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:22][CH2:23]1)[CH:15]=[CH2:16]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCCc1cc(F)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCc1cc(F)ccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
A mixture of (2-(but-3-en-1-yl)-4-fluorophenyl)methanol (43.8 mg, 0.243 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (142 mg, 0.243 mmol) in DMF (5 mL) at 0° C. was added NaH (9.72 mg, 0.243 mmol) and the reaction was stirred at 0° C. for 3 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 20% EtOAc/hexane to isolate (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.079 mmol, 32.3% yield) as an oil. LCMS (M+1)=637.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][OH:14].C[O-].[Na+]>O>[CH3:13][O:14][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1cc([N+](=O)[O-])ccc1O

Procedure:
18.7 g (0.1 mol) of 2-chloromethyl-4-nitrophenol and 50 ml of pure methanol were mixed together and refluxed for 2 hours 30 minutes. 37 ml of sodium methoxide (0.2 mol, 5.4 N solution in MeOH) were added and the mixture was refluxed for another 30 minutes. The resulting mixture was cooled in an ice bath and diluted with 350 ml of water, and the insoluble matter formed was filtered off. The filtrate was acidified with acetic acid (10 ml). The crystalline product was filtered off by suction, reslurried in ice-cold water and then dried over P2O5 at 40° C. 11.4 g of crude products were isolated and then recrystallized from 15 ml of isopropyl acetate to give 7.5 g of expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:14])=[O:7]
Reactant: NCc1cccnc1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (102 mg, 0.3 mmol), 3-aminomethyl pyridine (0.036 ml, 0.36 mmol) in DMF 3.0 mL was added EDC (86.3 mg, 0.45 mmol), HOBt (60.8 mg, 0.45 mmol) and DIPEA (0.078 ml, 0.45 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-3-ylmethyl-benzamide as a white-solid (71.4 mg, 55% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.[CH3:13][C:14]([N:16](C)C)=O.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:13][C:14]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:16]=1
Reactant: C/C(=N/O)c1ccc(O)cc1O
Reactant: CC(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (ice-water) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) and dimethylacetamide (11 mL) in acetonitrile (65 mL) was added phosphorous oxychloride (5.6 mL, 60.3 mmol) dropwise. The temperature was not allowed to exceed 10° C. during the reaction. After 1 hour stirring at room temperature the yellow slurry was poured into a mixture of aqueous NaHCO3 and ice. The resulting precipitate was filtered off and dried to give the sub-title compound (6.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:20]([C:21]1[N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: c1ccncc1
Reactant: C[C@@H](CO)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3ccccc3c2n1[C@@H](C)CO
Temperature: 90 °C
Reaction time: 20 h
Yield: 609.3 %

Procedure:
A suspension of (2S)-2-[(3-aminoquinolin-4-yl)amino]propan-1-ol (0.98 g, 4.49 mmol) in 50 mL of toluene was treated with triethyl orthopropioate (1.1 mL, 5.39 mmol) and pyridine HCl (52 mg, 0.45 mmol), and heated to 90° C. under an atmosphere of N2. After ˜20 hours, the reaction was allowed to cool back to ambient temperature and the solvent was removed under reduced pressure to give an orange solid. Chromatography (AFC, SiO2, 20-40% CMA/CHCl3) gave (2S)-2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (0.70 g) as a white solid.
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[NH2:17][C:18](=O)[C@@H:19]([NH:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[N:32]([CH3:36])[C:31]=3[CH:37]=2)=[CH:23][CH:22]=1.C(N(CC)CC)C.O>ClCCl>[C:18]([C@@H:19]([NH:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[N:32]([CH3:36])[C:31]=3[CH:37]=2)=[CH:23][CH:22]=1)#[N:17]
Reactant: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)cc3)cc21
Reaction time: 3 h
Yield: 75.1 %

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (137 mg) was added to a solution of (S)-tert-butyl 2-((S)-1-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (120 mg) and triethylamine (0.128 ml) in dichloromethane (1 mL) and stirred for 3 h. Water was added and the mixture was extracted with DCM (3 times). The organic layers were dried over (magnesium sulfate), evaporated and purified by flash silica chromatography eluting with acetone 1:2 isohexane/acetone to give the subtitle compound (87 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C1COCC1.CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CCc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 15.8 h
Yield: 94.2 %

Procedure:
[4-(3,3-Dimethyl-but-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (37b, 2.50 g, 9.15 mmol) was treated with 1:1 THF/MeOH (50 mL) and Pd/C (0.5 g, 10%), shaken for 15.8 hours under an atmosphere of H2 (51.4 psi). More Pd/C (0.5 g, 20%) was added and the reaction was stirred for an additional 1.13 hours, then filtered and concentrated. The crude material was chromatographed on silica gel eluting with 1:9 EtOAc/Hexane to give 2.39 g (94%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)([CH3:11])[CH3:10].[OH-].[K+].C(O)C1C=CC=CC=1>CCOCC>[CH:9]([NH:12][CH2:13][CH:14]([OH:16])[CH2:15][O:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CC(O)C1
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: OCc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(OCC(O)CNC(C)C)cn1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of 6.1 g of 6-methyl-3-pyridinol, 5.5 g of 1-isopropyl-3-azetidinol, 0.3 g of potassium hydroxide and 25 ml of benzyl alcohol is stirred for 16 hours under nitrogen in a bath at 150° C. After cooling, the reaction mixture is diluted with 50 ml of ether and extracted with 30 ml of 4 N hydrochloric acid. The aqueous phase is separated off, rendered alkaline with concentrated sodium hydroxide solution and extracted with 100 ml of methylene chloride. 3-(3'-Isopropylamino-2'-hydroxy-propoxy)-6-methyl-pyridine is isolated from the crude product thus obtained by bulb tube distillation at 130°-140° C. bath temperature and 0.04 mm Hg. It is identical in its properties with the product obtained in Example 19.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH3:23])(Br)[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Br)CCc1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: COC(=O)C(C)=CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 160 °C
Yield: 53.7 %

Procedure:
A mixture of 1.46 g of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate and 7.3 ml of quinoline was heated at 160°C for 3 hours and after cooling to room temperature, 73 ml of 2N hydrochloric acid were added thereto. The mixture was extrated with methylene chloride and the organic phase was washed with 2N hydrochloric acid, with aqueous saturated sodium bicarbonate solution and then with water. The solution was dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over magnesium silicate and eluted with methylene chloride to obtain 615 mg of methyl 4-(m-benzoylphenyl)-2-methyl-2-butenoate in the form of an oil.