Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:22])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:21])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:22])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:21][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCC1CCc2c(O)cccc2C1)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 74 %

Procedure:
A suspension of (1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl N,N-diphenylcarbamate (67 mg), ethyl bromoacetate (33 mg) and potassium carbonate (37 mg) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 5.5 hours and then extracted with ethyl acetate. The extract was washed with water and brine (twice), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford [5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl]methyl N,N-diphenylcarbamate (61 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Br)cccc1-c1ccccc1

Procedure:
A mixture of the product from Example 114A (2.2 g, 7.5 mmol), phenylboronic acid (919 mg, 7.5 mmol), sodium carbonate (7.55 mL, 2 M aqueous solution, 15.1 mmol) tetrakis(triphenylphosphine)palladium(0) (261 mg, 0.23 mmol) and 50 mL of toluene were refluxed for 16 hours under nitrogen. The reaction was cooled and partitioned between 50 mL of water and 50 mL of ethyl acetate. The aqueous portion was separated and extracted with 2×25 mL of ethyl acetate and the combined organic extracts were washed with 2×25 mL of water and 1×25 mL of brine and dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (95:5 hexane:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.63 (s, 3H) 7.35-7.60 (m, 6H) 7.71-7.79 (m, 2H); MS (DCI+) m/z 308.0 [M+NH4]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O.CN(C)C=O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[N:7]([CH3:16])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cn1c(=O)c2ccccc2n(CCCBr)c1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ccccc2n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-bromopropyl)-3-methyl-2,4(1H,3H)-quinazolinedione (1.68 g), 1-diphenylmethylpiperazine (1.56 g), anhydrous potassium carbonate (2.33 g) and N,N-dimethylformamide (8 ml) was stirred for 3 hours at 60° C. After cooling, water was added to the reaction mixture and then the mixture was extracted twice with chloroform. The chloroform layer was washed with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oily residue. This oily residue was dissolved in methanol and then conc.hydrochloric acid solution was dropwise added to the solution to give a crystal, which was collected by filtration, washed with water and dried. This crude crystal was recrystallized from a mixture of methanol and water, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-3-methyl-2,4(1H,3H)quinazolinedione.2HCl.0.5H2O (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26]O)=[CH:23][C:22]=3[CH2:28][CH3:29])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26][N:55]4[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]4)=[CH:23][C:22]=3[CH2:28][CH3:29])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-{5-[3-chloro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methanol (0.15 g, 0.34 mmol) that was obtained in Example 16 (16b), carbon tetrabromide (0.16 g, 0.51 mmol), triphenylphosphine (0.13 g, 0.51 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.073 g, 0.51 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.84 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 5:15) as the eluent to afford the title compound (0.16 g) in a yield of 88% as a colourless oily product.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)C.O.Cl>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: CC(O)Cn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)Cn1c(N)c(N=O)c(=O)n(C)c1=O

Procedure:
To 79 g (0.4 mol) of 6-amino-1-(2-hydroxypropyl)-3-methyl- 2,4-(1H, 3H)-pyrimidinedione (IV), dissolved in 500 ml of ethanol, was added 30 g NaNO2 (0.43 mol) which was dissolved in water, whereafter 36 ml conc. hydrochloric acid was added. The red crystals were dissolved through boiling and the sodium chloride was filtered off. The red filtrate was used for synthetizing 5,6-diamino-1-(2-hydroxypropyl)-3-methyl-2,4-(1H, 3H)-pyrimidinedione (VI) NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:69]([NH2:73])([CH2:71][CH3:72])[CH3:70]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:73][C@H:69]([CH2:71][CH3:72])[CH3:70])[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(Cl)n1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
Add 6-chloropyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (2.44 g, 10 mmol), palladium acetate (224 mg, 1.0 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (623 mg, 1.0 mmol), cesium carbonate (4.95 g, 15.2 mmol) in toluene (70 mL) in a sealed tube. Degas the tube for 5 min with nitrogen, add (S)-sec-butylamine (1.2 mL, 11.8 mmol) and seal the tube. Heat to 80° C. overnight. Cool to room temperature and filter the mixture through a filtering agent. Wash with ethyl acetate. Dissolve the solid in water and extract with ethyl acetate. Combine all organic solutions, concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (2.5 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.[N+:10]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:12])=[O:11]>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:14]([CH2:13][N+:10]([O-:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: C[NH2+]C
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1
Yield: 51 %

Procedure:
Dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole) carbon disulfide (7.6 grams, 0.10 mole), and β-nitrostyrene (14.9 grams, 0.10 mole) were dissolved in methanol (50 ml.). A rapid exothermic reaction ensued and the product precipitated. The reaction temperature was held to 35° C. with ice cooling. After several hours at 25° C., the product was filtered off, washed with methanol, and dried in air. The crude product, melted at ca. 103° C.-110° C. and weighed 22.9 grams (85%). Recrystallizations from hot methanol and from acetone-2-propanol solution (without heating) gave 13.8 grams of α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 104° C.-108° C. (prior sintering). The infrared spectrum was essentially identical to the spectrum of analytically pure material.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[C:13]([Cl:26])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:26][C:13]1[C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:15][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[CH:12]=1
Reactant: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 139.8 %

Procedure:
The above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.897 g, 2.36 mmol) was dissolved in 4.8 mL of THF/ethanol=1/1 and treated with 1.18 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 3 h at ambient temperature and was then neutralized by adding 1.77 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded finally 1.161 g of the title compound as off-white solid, contaminated with innocuous inorganic salts.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: N[C@H]1CC[C@H](CO)CC1
Agent: Cl
Product: OC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.093 g, 0.31 mmol) was reacted with trans-(4-aminocyclohexyl)methanol hydrochloride (0.077 g, 0.47 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.011 g, 9%) as a light yellow solid. MW=393.35. 1H NMR (DMSO-d6, 500 MHz) δ 13.44 (s, 1H), 7.99-7.96 (m, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.55 (br s, 1H), 7.10 (s, 1H), 4.45-4.43 (m, 1H), 3.84-3.80 (m, 1H), 3.28-3.23 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H); 1.92-1.90 (m, 2H), 1.79-1.77 (m, 2H), 1.45-1.34 (m, 3H), 1.16-1.10 (m, 2H); APCI MS m/z 357 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
4′-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl piperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride (5.61 g) in CH2Cl2 (60 mL) were stirred for 24 hours. The reaction was quenched with methanol and poured into ether. The solution was washed with water and brine, concentrated, and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: O=[C:2]([CH:18]([C:20](OCC)=O)C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl.[OH2:26]>>[O:26]=[C:18]([CH3:20])[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O
Reactant: CCOC(=O)C(C)C(=O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 14.2 g of 3-(2'-oxo-3'-ethoxycarbonyl-butyl)-benzophenone and 142 ml of 6N hydrochloric acid was refluxed with stirring of 17 hours and after cooling to 20°C, the mixture was diluted with 140 ml of water and extracted 3 times with 50 ml of methylene chloride. The organic phase was washed with 50 ml of an aqueous saturated sodium bicarbonate solution and twice with 50 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 10.76 g of 3-(3'-oxo-butyl)-benzophenone which was utilized as is for the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[C:24]([CH3:26])[N:25]=4)[CH:22]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:28].[ClH:28].[CH3:26][C:24]1[N:25]=[C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:8]4([NH2:7])[CH2:9][CH2:10]4)=[N:12][CH:13]=3)=[CH:22][N:21]2[CH:23]=1
Reactant: Cc1cn2cc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)nc3)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cn2cc(-c3ccc(C4(N)CC4)nc3)ccc2n1
Reaction time: 1 h

Procedure:
{1-[5-(2-Methyl-imidazo[1,2-a]pyridin-6-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (21 mg, 0.06 mmol) was dissolved in 0.5 mL of CH2Cl2 and 1 mL of 4M HCl in dioxane was added. The resulting suspension was stirred for 1 h. The mixture was concentrated to yield crude 1-[5-(2-methyl-imidazo[1,2-a]pyridin-6-yl)-pyridin-2-yl]-cyclopropylamine dihydrochloride. The material was used in subsequent reactions without purification.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccncc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(pyridin-4-yloxy)ethylamine (540 μl) and sodium hydrogencarbonate (1.32 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(pyridin-4-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (23 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([CH3:13])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68316.4 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09 mmol), 6-methylnicotinic acid (313 mg, 2.28 mmol), BOP-Cl (581 mg, 2.28 mmol), and triethylamine (0.757 mL, 5.43 mmol) in DCM (5 mL) was stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was then added. The reaction was stirred for an additional 10 minutes and then poured into water. The mixture was then filtered, washed with DCM, washed with 10:1 DCM:MeOH and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide (260 g, 68.5% yield) as a solid
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:28](=[O:29])[CH2:27][CH2:26][O:25][CH3:24])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: COCCC(=O)Cl
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)CCOC)C2)cc1

Procedure:
62 mg (0.18 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 33 mg (0.27 mmol, 1.5 eq.) of methoxypropionyl chloride were reacted according to General Method 2. Yield: 65 mg (91% of theory)
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][C:6]1=[O:16])[CH3:4].I[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CN(C=O)C.O.CCOC(C)=O.[Cu](I)I>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:1][CH2:2][CH:3]([N:5]3[CH:10]=[C:9]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)[CH:8]=[CH:7][C:6]3=[O:16])[CH3:4])=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: CC(CO)n1cc(-c2cccs2)ccc1=O
Reactant: COc1ccc2c(I)ccnc2c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCC(C)n3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 140 °C
Yield: 17.4 %

Procedure:
To a solution of 1-(1-hydroxypropan-2-yl)-5-(thiophen-2-yl)pyridin-2(1H)-one (0.052 g, 0.22 mmol) and 4-iodo-7-methoxyquinoline (0.063 g, 0.22 mmol) in 3.0 mL of DMF was added cesium carbonate (Cs2CO3, 0.072 g, 0.22 mmol), 1,10-phenanthroline (0.020 g, 0.11 mmol) followed by copper iodide (CuI) (0.021 g, 0.11 mmol) in a microwave vial. The mixture was heated to 140° C. for 45 minutes. The mixture was then diluted with 40 mL of water and 60 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a MS-triggered Prep-HPLC to give light organic film 1-(1-(7-methoxyquinolin-4-yloxy)propan-2-yl)-5-(thiophen-2-yl)pyridin-2(1H)-one (0.015 g, 17% yield). MS (ESI pos. ion) m/z (MH+): 393.1. Calc'd Exact Mass for C22H20N2O3S: 392.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][N:11]2C(OCC1C=CC=CC=1)=O.C1CCC=CC=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][NH:11]2
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2CCN3C(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: C1=CCCC=C1
Product: COc1ccc(CN2C(=O)[C@H]3NCC[C@H]32)cc1OC

Procedure:
This compound was prepared analogously to Example 2 from benzyl (1S,5R)-6-(3,4-dimethoxybenzyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate by treatment with Pd/C and cyclohexadiene.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[Cl:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH:32]=O>>[Cl:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: O=CCc1ccc2c(c1Cl)COC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3Cl)COC4=O)CC1=O)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (4-Chloro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:7]3[O:6][CH2:5][CH2:4][C:3]([CH:2]=[O:1])=[CH:9][C:8]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CO)CCO3)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
Into a solution of 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (0.21 g) in dichloromethane (10 ml) were added manganese dioxide (687 mg), and the resulting mixture was stirred at room temperature for 3 hours. An insoluble material was removed by filtration, and the filtrate was evaporated to remove dichloromethane. The residue was recrystallized from ethyl acetate/hexane to obtain 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (192 mg) as colorless crystals.