Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[NH:27])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:31])[CH:22]=[CH:21]4)=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: N=C(C=Cc1ccc(-c2ccc3[nH]ccc3c2)cc1)Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-c3ccc(C=CC(=N)Nc4ccc(Cl)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A mixture of 0.075 g (0.22 mmol) of 3-(4-bromo-phenyl)-N-(4-chloro-phenyl)-acrylamidine, 0.042 g (0.26 mmol) of 5-indoleboronic acid, and 0.013 g (0.011 mmol) of Pd(PPh3)4 in 3 mL of DME/water/ethanol (4/2/1) in a sealed tube was heated under microwave (45 W, 5 min). The reaction was diluted with 10 mL of saturated NaHCO3, and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 60% ethyl acetate in hexanes plus 1% NH4OH to give 0.036 g of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine. Method M: To a stirred solution of 0.10 g (0.27 mmol) of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine in 3 mL of DMF was added 0.011 g (0.28 mmol) of 60% NaH at 0° C. After 1 h, 0.018 mL (0.28 mmol) of iodomethane was introduced, the reaction was warmed to room temperature overnight and quenched with 10 mL of saturated NaHCO3. It was extracted with three 10 mL portions of dichloromethane. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed eluting with 40% ethyl acetate in hexanes to give 0.028 g of N-(4-chloro-phenyl)-3-[4-(1-methyl-1H-indol-5-yl)-phenyl]-acrylamidine.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[CH:16]=[C:15]3[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:33])([CH3:32])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=[CH:14]3)=[CH:19][CH:18]=2)=[CH:25][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 3-{[7-(4-chloro-3-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (36 mg), TFA (1 mL) and DCM (3 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (20 mg). LC MS ESI+: 433 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH2:23][N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:23][N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: NN1CCC(O)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 430.1150 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[N:12]=1>C(O)CC>[CH3:22][O:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1cccnc1
Solvent: CCCO
Product: COc1ccc2ccc(NC(=O)c3cccnc3)nc2n1
Temperature: 4 °C
Yield: 77.7 %

Procedure:
The prccedure is similar to that described in Example 1, but starting with nicotinic acid (7.4 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-methoxy-1,8-naphthyridine (7 g). After filtration, washing with water and drying, the crystallised solid formed during the reaction (10.3 g; m.p. 245° C.) is dissolved in boiling 1-propanol (900 cc). After being cooled for 3 hours at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-3-pyridylcarboxamide (8.7 g) is produced, m.p. 247° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9].[CH3:16]C(C)=O.CI.[ClH:22]>C(O)C.O>[ClH:22].[CH3:16][N:3]1[CH:2]([CH3:1])[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][CH:4]12
Reactant: CC(C)=O
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CI
Product: CCC1C(=O)N2C(C)CCCC2N(C)C1C
Reaction time: 24 h
Yield: 41 %

Procedure:
0.01 moles of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido(1,2-a)pyrimidine are dissolved in 20 ml. of acetone, 0.03 moles of methyl iodide are added and the mixture is kept in a bomb tube at 150° C. for 24 hours. The solution is evaporated to dryness, the residue is dissolved in 15 ml. of methanol and a solution of 0.05 moles of sodium tetrahydroborate(III) in 10 ml. of water is added. After 4 hours the methanol is distilled off and the aqueous phase is extracted with three 20-ml. portions of chloroform. The organic phase is dried, evaporated and added to the oily substance obtained are 10 ml. of ethanol saturated with hydrochloric acid. 1,2,6-trimethyl-3-ethyl-1,2,3,6,7,8,9,9a-octahydro-4-oxo-4H-pyrido(1,2-a)pyrimidine hydrochloride is obtained, while crystallizes when triturated with ether. The product obtained after recrystallization from a mixture of acetone and ether sublimates over 206° C. Yield: 41%.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:22])[CH2:5][CH:6]([OH:21])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19]>C(Cl)Cl.CCOCC.[O-2].[O-2].[Mn+4]>[OH:21][CH:6]([CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19])[CH2:5][C:4]([CH3:22])=[CH:3][CH:2]=[O:1]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC(O)CC(C)=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C=CC1=C(C)CCCC1(C)C)=CC(O)CC(C)=CC=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
1.22 g (4 mmol) of 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonatriene (I) was dissolved in 30 ml of methylene chloride, to which was then added 3.48 g (40 mmol) of manganese dioxide and the mixture was stirred at an ambient temperature for 24 hours. After the resulting mixture was diluted with ether, it is dried over anhydrous magnesium sulfate and filtered, followed by evaporation of ether to obtain 5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-nona-2,6,8-trienal (II) as a mixture of E and Z isomers in a yield of 90%.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>CO>[Cl:2][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH2:1])[C:8]=1[NH2:9]
Reactant: N
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CO
Product: Nc1ncnc(Cl)c1N
Temperature: 100 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a 7 N solution of ammonia in MeOH (40 mL) was added 4,6-dichloro-pyrimidin-5-ylamine (8.7 g, 53 mmol) and the solution was heated to 100° C. in a sealed tube. After 12 h, the resulting solution was cooled to rt and allowed to stand for 2 h. The colorless crystalline material that resulted was collected by filtration and washed with ice cold MeOH (10 mL) to give the title compound (5.4 g, 71%). MS (ESI): mass calcd. for C4H5ClN4, 144.0; m/z found, 145.0 [M+H]+. 1H NMR ((CD3)2SO): 7.64 (s, 1H), 6.70 (s, 2H), 4.93 (s, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][C:29]6=[O:41])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][NH:31][CH2:30][C:29]6=[O:41])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)=[O:45])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5=O)cn4)sc23)c(F)c1)NC1CC1
Yield: 69.5 %

Procedure:
A solution of 71 (60 mg, 0.095 mmol) and TFA (5 mL) in DCM (20 mL) was stirred at RT for 5 h. The TFA was removed by co-evaporation with DCM and MeOH, diluted with water, and the pH was adjusted to around 12 with 1N NaOH. The resultant gel was extracted with DCM with traces of MeOH. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 10 g column; 2% of ammonium hydroxide in MeOH/DCM; 0/100 to 10/90 over 20 CV, 10/90 to 20/80 over 10 CV then 20/80 over 5 CV), to afford the title compound 72 (35 mg, 0.066 mmol, 69% yield, traces of TFA) as a white sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (s, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.83 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (dd, J=8.9, 1.5 Hz, 1H), 6.65 (dd, J=5.3, 0.6 Hz, 1H), 6.58 (bd, J=2.7 Hz, 1H), 4.59 (s, 2H), 3.37 (s, 2H), 3.28 (t, J=5.5 Hz, 2H), 2.95 (t, J=5.4 Hz, 2H), 2.59-2.51 (m, 1H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H), one NH is missing. MS (m/z): 533.4 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]([CH3:38])[CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:26]=[C:25]([CH3:39])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]([CH3:38])[CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:26]=[C:25]([CH3:39])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N(C)Cc2ccncc2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N(C)Cc2ccncc2)n1
Reaction time: 8 h
Yield: 33 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0979 g, 0.1802 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). The reaction was left to stir overnight. The volatiles were evaporated, and the resulting material was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a beige solid (0.0273 g, 33%). LCMS: (M+H)+=460.7.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=4[CH:28]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:34])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:33].[Cl:33][C:30]1[CH:31]=[CH:32][C:26]2[O:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:16](=[O:34])[CH2:17]3)(=[O:23])=[O:22])=[CH:28][C:27]=2[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 193.7 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-chlorobenzofuran-2-sulfonyl)-2-piperazinone (270 mg) were added 4N hydrochloric acid in ethyl acetate (8 ml) and methanol (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give 4-(5-chlorobenzofuran-2-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (229 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[Br:7][C:8]1[S:12][C:11]([S:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Br)s1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidine (0.72 g, 8.41 mmol) was added to a solution of 5-bromothiophene-2-sulfonyl chloride (2 g, 7.65 mmol) in tetrahydrofuran (100 mL) at 0° C. followed by triethylamine (0.93 g, 9.18 mmol) added slowly. The resulting mixture was stirred at rt overnight and 100 mL of brine was added. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. Removal of the solvent gave the title compound as a slightly yellow solid (quantitative yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CC(O)C>[C:22]([C:21]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: COC(=O)C(Cl)C(=O)C(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C(C)(C)C
Yield: 77.1 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), methyl 2-chloro-4,4-dimethyl-3-oxopentanoate (950 mg, 4.9 mmol) produced above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11-B (vi), the title compound (330 mg, 76%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:20](=[O:21])[CH2:19][CH:16]1[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:12]=2)[C:14](=[O:23])[NH:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)NCc3ccccc3)C2=O)cn1
Yield: 30 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and benzyl amine. Yield: 30%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3 H), 2.41 (s, 3 H), 2.56-2.52 (m, 1H, J=16 Hz), 2.56-2.52 (m, 1H), 3.00-2.96 (m, 1H), 4.45-4.44 (d, J=5.6 Hz, 2H), 5.04 (s, 2H), 5.96 (bs, 1H), 6.36 (bs, 1H), 7.36-7.25 (m, 5H), 7.90 (s, 1H, 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.3 μM.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:24]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)oc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-oxazolyl]propionate (192 mg), lithium hydroxide hydrate (47.6 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (1.2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-oxazolyl]propionic acid (158 mg, yield 85%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 136–137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)([O:22][CH3:23])=[O:21].N1CCCC1.O1CCCC1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:20]([O:22][CH3:23])=[O:21])[CH:25]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)c1cccc(C=O)c1
Solvent: C1CCOC1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of 17 g of 6-benzyloxy-4-chromanone, 11.3 g of 3-carbomethoxybenzaldehyde, 14.4 g of pyrrolidine, 100 ml of tetrahydrofuran and 300 ml of methanol was stirred at room temperature overnight. The volatiles were evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel eluting with dichloromethane. The product fractions were combined and concentrated to an oil which crystallized upon trituration with methanol to give 17.2 g of title product, mp 109°-112° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[C:20]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:27][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 0 °C
Yield: 92.2 %

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [6 g; prepared as hereinbefore described in Example 1(iv)] and hexanoylmethylenetriphenylphosphorane (8.5 g.) in dry tetrahydrofuran (50 ml.) was heated to reflux under nitrogen for 16 hours. The solvent was removed in vacuo and the residue triturated with petroleum ether (b.p. 60°-80° C.), cooled to 0° C. for 1 day, filtered to remove triphenylphosphine oxide and the filtrate evaporated. The residue was again triturated with petroleum ether (b.p. 60°-80° C.) to remove further triphenylphosphine oxide, filtered, and evaporated to give 6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (7.5 g.), νmax 1620 cm-1, 1660 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[H-].[Na+].[CH3:33][CH2:34][OH:35]>>[CH2:34]([O:35][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)[CH3:33]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3ccccc3F)c2n1

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was placed in EtOH (10 mL) and the mixture stirred under Ar. Approximately 2 mL of the ethanol was distilled off to dry the mixture. When the mixture was cooled to 23°, some of the starting material sulfone crystallized out. NaH (11.5 mg, 0.46 mmol) was added. The reaction did not go to completion, so additional NaH (4 mg, 0.16 mmol) was added. The solvent was removed in vacuo, and the residue was flash chromatographed on silica gel eluted with 60-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 137-139°, LC MS m/z=394(MH+) Retention time=2.32 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:11][CH:12]=C.C[N+]1([O-])CC[O:19]CC1>CC(C)=O.O.C(OCC)(=O)C.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:11][CH:12]=[O:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cc(C)ccc1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)cc1CC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 2-allyl-4-methyl-benzoic acid methyl ester (0.980 g, 5.15 mmol) in acetone (20 mL) and water (2.0 mL) are added N-methyl morpholine oxide (0.89 g, 7.57 mmol) and OsO4 (1 mg). The resulting reaction mixture is stirred at room temperature for three hours. The reaction mixture is diluted with ethyl acetate (50 mL) and is washed with Na2S2O3 (1.0 M, 20 mL). The organic layer are concentrated and the residue is dissolved in THF (25 mL) and water (15 mL). To the solution, NaIO4 (3.24 g, 15.2 mmol) is added and the mixture is stirred at room temperature for two hours. The mixture is filtered and the filtrate is concentrated, diluted with ethyl acetate (60 mL), and washed with Na2S2O3 (1.0 M, 20 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is purified via flash chromatography eluting with 30-40% ethyl acetate in hexane to give the title compound (0.260 g, 26%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.94-7.92 (d, 1H), 7.15-7.13 (d, 1H), 7.00 (s, 1H), 3.99 (s, 2H), 3.81 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH:11]1([C:14]2([F:18])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][C:14]([CH:11]3[CH2:13][CH2:12]3)([F:18])[CH2:15]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: FC1(C2CC2)CNC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC1(C2CC2)CN(c2cc(Cl)nc(Cl)c2)C1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A solution of 2,4,6-trichloropyridine (3.0 g, 16.4 mmol), 3-cyclopropyl-3-fluoroazetidine hydrogen chloride (2.49 g, 16.4 mmol) and DIPEA (7.09 ml, 41.0 mmol) in ethanol (40 ml) was heated under reflux for 1 h. Reaction mixture cooled to room temperature then concentrated to dryness in vacuo. Crude product purified by flash chromatography on silica (0 to 100% EtOAc:petrol) to give title compound as a white solid (1.56 g, 36%). 1H NMR (CDCl3) 0.52-0.48 (2H, m), 0.72-0.67 (2H, m), 1.42-1.31 (1H, m), 3.91 (2H, ddd), 4.05 (2H, ddd), 6.20 (2H, s). ES+ 261.30.