Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:55][CH:56]=[CH2:57].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:57][CH:56]=[CH2:55])[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6cccc(O)c6)c5)nn34)c(Cl)c21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol) in DMF (2 mL) was added K2CO3 (38.1 mg, 0.276 mmol) followed by 3-bromoprop-1-ene (0.017 mL, 0.207 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (50 mL), washed with brine, dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (5-30% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (40 mg, 0.058 mmol, 41.9% yield) as white solid. 28 mg of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.84 (dt, J=7.7, 1.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.03-6.97 (m, 2H), 6.96-6.92 (m, 2H), 6.17-6.00 (m, 2H), 5.50-5.44 (m, 1H), 5.39-5.29 (m, 3H), 5.25 (dd, J=10.2, 1.6 Hz, 1H), 5.09 (s, 1H), 4.62 (dt, J=5.3, 1.4 Hz, 2H), 4.27 (t, J=4.4 Hz, 2H), 3.67 (s, 3H), 3.27-3.17 (m, 2H), 2.86 (s, 3H), 1.19 (s, 9H). LCMS (M+H)=693.4.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[C:21]([F:30])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>CCO>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[C:21]([F:30])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(CNc4ccc(C(=O)O)c(F)c4)cc3c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A 100 mL 3-necked flask equipped with a magnetic stirrer was charged with 0.200 g of ethyl 4-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-2-fluorobenzoate, 18 mL of 1 N NaOH, and 20 mL of EtOH. After stirring overnight at RT, the solution was concentrated to 20 mL in vacuo and acidified to pH 2.5 by addition of concentrated HCl. The resulting precipitate was collected by vacuum filtration, washed with 15 mL of water, and dried in vacuo to afford 0.15 g (77%) of 4-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-2-fluorobenzoic acid as a white powder, m.p. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2C=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[Cl:18])=[CH:5][N:4]=1.O.N>C(COC)OC>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[C:15]([NH2:16])=[C:14]([Cl:18])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc3c(Cl)ncnc32)cn1
Agent: N
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Nc2ncnc(Cl)c2N)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
A mixture of 25 g of 5-(6-chloro-9H-9-purinyl)-2-pyridyl methyl ether, 250 mL conc. ammonia water and 500 mL dimethoxyethane was stirred at 70° C. for 4 hours, and the resulting suspension was filtered, to give 21.2 g of the title compound as white crystals (91% y.). (4) 8-Bromo-9-(6-methoxy-3-pyridyl)-9H-6-purineamine
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][C:13]1[C:12]2[C:16](=[CH:17][C:9]([Cl:8])=[CH:10][CH:11]=2)[NH:15][N:14]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: O=C(CCCCl)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 6 °C
Reaction time: 19 h

Procedure:
0.67 cm3 of 4-chlorobutyryl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, after cooling to about 6° C. in an ice bath, and the mixture is then allowed to return to room temperature over 19 hours. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 45° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The precipitate is filtered off and rinsed with 15 cm3 of ethyl acetate and 5 cm3 of dichloromethane. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 45° C.); after drying (90 Pa; 50° C.), 343 mg of 4-chloro-N-(6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a pale yellow solid melting at 220° C.
Reaction SMILES: [C:1]([NH2:8])(=[S:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[CH2:2]([C:1]1[S:7][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([OH:12])[N:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(N)=S
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: CCCCCc1nc(O)c(-c2ccccc2)s1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except thiohexanamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:27]([NH2:29])=[O:28].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.[Cl-].[Na+].O>[CH3:30][O:1][C:2]1[N:6]=[CH:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)c1c(O)ncn1Cc1ccc(NC(=O)c2cccc3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ncn(Cc2ccc(NC(=O)c3cccc4ccccc34)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
200 mg (0.517 mmol) of 5-hydroxy-3-{4-[(naphthalene-1-carbonyl)amino]benzyl}-3H-imidazole-4-carboxamide are dissolved in 5 ml of dry DMF in a round-bottomed flask under argon. 285 mg (2.07 mmol; 4 eq.) of potassium carbonate are then added. After one hour at room temperature, 440 mg (3.1 mmol; 6 eq.) of methyl iodide are added. After stirring for 24 hours at room temperature, the reaction medium is poured into brine and a precipitate appears. After stirring for 20 minutes, the precipitate is filtered off and then washed with water. After drying, 72 mg of a white solid are obtained.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>COCCOC.C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([C:5]2[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=2)[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108 %

Procedure:
A solution of sulfone 121 (0.184 g, 0.80 mmol) in ethyleneglycol dimethylether (5 mL) was treated with neat morpholine (0.3 mL, 3.4 mmol) and the mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with DCM and washed with saturated NaHCO3 in brine, dried over MgSO4, filtered, concentrated and stored under vacuum to give intermediate 122 (0.205 g, >99% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([O-:22])=[O:21])=[CH:16][CH2:15]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:23][CH2:24]3)[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C([O-])C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Yield: 104.7 %

Procedure:
tButyl 4-[[4-(4-pyridyl)piperazin-1-yl]methylene]cinnamate (200 mg) was stirred in trifluoroacetic acid (5 ml) for 2 hours. The solvent was removed by evaporation and the resulting oil was titriated with anhydrous ether to give the title compound (210 mg) as a white solid: NMR (d6DMSO) δ3.05-3.25(m,4H), 3.7-4.1(bm,4H), 4.25(s,2H), 6.6(d,1H), 7.25(d,2H), 7.5(d,2H), 7.6(d,1H), 7.75(d,2H), 8.35(d,2H); m/e 324(M+H)+ ; calculated for C19H21N3O2. 2CF3COOH.0.5H2O: C, 49.5; H, 4.25; N, 7.4. Found: C, 49.1; H, 4.2; N, 7.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH2:15][CH3:16])=[C:13]([O:17]C(=O)C)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH2:15][CH3:16])=[C:13]([OH:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: CCc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1c(CC(=O)OC)cc2ccc(F)cc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of (4-acetoxy-3-ethyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (50 mg, 0.164 mmol), sodium methoxide (13 mg, 0.247 mmol), and methanol (4 mL) was stirred at room temperature for 2 hours. After the reaction mixture was acidified with concentrated hydrochloric acid to pH 5, a precipitate formed, which was then collected by filtration, and dissolved in ethyl acetate (20 mL). The organic solution was dried over sodium sulfate, and concentrated in vacuo to afford the crude product of (3-ethyl-6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (42 mg, 97.7%) as a light yellow solid.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1>O.CN(C)C=O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH2:1])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCOc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CN)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 103.9 %

Procedure:
A solution of 1.25 g of sodium azide in 2.5 ml of water was added to a solution of 900 mg of p-chloromethyl(heptyloxy)benzene in 25 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 6 hours. After cooling, the reaction mixture was diluted with water, and the product was extracted with ether. The ether layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A solution of the thus-obtained residual oil in 10 ml of tetrahydrofuran was added dropwise at 0° C. over 5 minutes to a suspension of 200 mg of lithium aluminum hydride in 15 ml of tetrahydrofuran. The resultant mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Then, sodium sulfate decahydrate added to decompose the excess lithium aluminum hydride. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 860 mg of p-heptyloxybenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=O)[CH3:13].[NH2:16][C:17]1[C:22]([CH:23]=O)=[CH:21][CH:20]=[CH:19][N:18]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:23][C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)CCCCCCCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCCCCCc1ccc2cccnc2n1

Procedure:
A mixture of 13-2 (9.2 g, 43 mmol), 1-3 (5.3 g, 43 mmol), proline (2.5 g, 22 mmol), and ethanol (215 mL) was heated to reflux for 20 h. The cooled reaction mixture was concentrated and the residue purified by flash chromatography (silica, EtOAc) to give 13-3 as a yellow oil.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH2:6]1)C=C.I([O-])(=O)(=O)=O.[Na+].[C:32]([O:36]C)(C)(C)[CH3:33]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][CH:7]3[CH2:8][CH2:9][CH2:10][CH:5]([CH2:33][CH:32]=[O:36])[CH2:6]3)[N:14]=2)=[CH:24][CH:23]=1
Reactant: COC(C)(C)C
Reactant: C=CCOC1CCCC(OCc2nc(-c3ccc(F)cc3)oc2C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(CC=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 h, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5). This gives 1.4 g of [3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]-acetaldehyde as a yellow-brown oil. C20H25NO4 (343.42), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate=1:1)=0.25.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][OH:26]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:25][OH:26])[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: CC(=NO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 72 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and hydroxylamine hydrochloride in 72% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6), δ ppm 9.31 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30].Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3F)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4F)oc23)[C@@H]1CO

Procedure:
Compound of example 20 (0.07 g, 0.169 mmol) subjected to demethylation with pyridine hydrochloride (1 g, 8.65 mmol) as described in example 17 afforded the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]2[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[O:25])=[CH:19][CH:18]=1.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]4[CH:31]5[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]5)[CH2:27]4)=[O:25])=[CH:19][CH:18]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(N3CCOCC3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A mixture of 120 mg (0.58 mmol) of 4-morpholinophenylboronic acid, 120 mg (0.39 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 1.16 ml (1.16 mmol) of 1N sodium hydroxide solution, 30 mg (0.04 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 1 ml of DMF is heated at 80–85° C. for 40 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 80:20:2). The solvent is stripped off under reduced pressure, and final residues of solvent are removed under high vacuum. 100 mg (66% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][N:4]2[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
5-Bromo-2-butyl-3H-imidazole-4-carbaldehyde (38 g, 160 mmol) was dissolved in DMF (400 mL, 5 mol). Potassium carbonate (27 g, 200 mmol) was added followed by methyl 4-bromomethylbenzoate (38 g, 160 mmol) and the solution was stirred at room temperature overnight. The mixture was then concentrated and purified by silica gel chromatography (0-50% EtOAc:hexanes) to yield intermediate (9a) (32.2 g, 62.2 mmol). MS m/z: [M+H+] calcd for C17H19N2O3Br, 379.3. found 379.1. 1H-NMR (400 Mz, CD3OD) δ (ppm): 0.82 (t, 3H, J=5 Hz), 1.28 (m, 2H), 1.54 (q, 2H, J=5 Hz), 2.70 (t, 2H, J=5 Hz), 5.69 (s, 2H), 7.15 (d, 2H, J=5 Hz), 7.96 (d, 2H, J=5 Hz), 9.66 (s, 1H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 7.2 g. 3-propylthio-1,2,4-triazole, 6.8 g. diethylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 9 ml. dry triethylamine was refluxed under anhydrous conditions for 72 hours. The reaction mixture was worked up as described in Example 1 to produce a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 118° - 121°C./0.2 mm. (89.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-]=C=O.[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12>>[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: CC(C)(C)N=C=O
Agent: [N-]=C=O
Product: CC(C)(C)NC(=O)Nc1cccc(N2CN=c3occc3=C2N)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using t-butyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 326 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([Cl:28])[C:22]([F:29])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13]CCC(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:28][C:23]1[C:24]([N+:25]([O-:27])=[O:26])=[C:2]2[C:3]([C:4]([OH:5])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[N:13]2)=[CH:21][C:22]=1[F:29]
Reactant: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])c(Cl)c(F)cc2c1O

Procedure:
52 g of the product from Example 4 and 18.5 g of K2CO3 are heated at 140° C. for 4 hours in 160 ml of DMF. The mixture is subsequently poured onto ice and acidified, and the precipitated solid is isolated. It is dried and recrystallized from glycol methyl ether acetate. Yield: 35.8 g, melting point: 226°-8° C. (decomposes).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-nitro-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (71%, white crystals). HPLC-MS m/z=365.0 (M+1), Rt: 4.83 min. 4(300 MHz; CDCl3): 3.44 (s, 3H), 7.00 (d, 2H), 7.06 (d, 2H), 7.26-7.32 (m, 1H), 7.33-7.49 (m, 4H), 8.20 (dt, 2H).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([O:15][C:16](=[O:29])[CH:17]([N:21]=CC1C=CC=CC=1)[CH2:18][CH2:19][CH3:20])[CH3:14].ICCC>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16](=[O:29])[C:17]([NH2:21])([CH2:18][CH2:19][CH3:20])[CH2:2][CH2:1][CH3:3])[CH3:14]
Reactant: CCCC(N=Cc1ccccc1)C(=O)OCC
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCC(N)(CCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 10.4 ml of diisopropylamine in 200 ml of tetrahydrofuran was combined dropwise at 0° C. with stirring under a stream of dry nitrogen with 49 ml of a 1.6 molar solution of n-butyllithium in n-hexane. After cooling to -78° C., a solution of 18.31 g of the product from stage 2 in 80 ml of tetrahydrofuran was added dropwise. The entire reaction batch was stirred for 30 minutes and a solution of 8.8 ml of 1-iodopropane in 40 ml of tetrahydrofuran was then added dropwise. The reaction batch was stirred for 16 hours, wherein the temperature slowly rose to 20° C. The solvent was removed by distillation. The resultant orange-coloured residue was redissolved in 500 ml of 1 N hydrochloric acid. After 1 hour's stirring at 20° C., extraction was performed three times with 100 ml portions of diethyl ether. The phase acidified with hydrochloric acid was adjusted to a pH of between 10 and 12 with potassium hydroxide and then extracted three times with 100 ml portions of diethyl ether. The extracts were combined, washed twice with a saturated sodium chloride solution and dried over sodium sulphate. The crude product obtained after removing the solvent by distillation was purified by passage through a silica gel column with ethyl acetate. 9.84 g of 2-amino-2-propylpentanoic acid ethyl ester (67% of th.) were obtained in the form of a slightly coloured oil.