Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH:59]=1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:67]3[CH2:68][CH2:69][N:64]([C:60]4[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=4)[CH2:65][CH2:66]3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: c1cncc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(c4cccnc4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), 1-pyridin-3-ylpiperazine (21 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[ClH:18].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:28])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: Cl
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc(Cl)cc1
Yield: 48.1 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (2.67 g; 10 mmole), methylene chloride (50 ml) and 4-chlorophenyl isocyanate (1.54 g; 10 mmole). Recrystallization from methanol provided the title compound (1.1 g; 25% yield) as colorless crystals, m.p. 241° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:34](=[O:33])[CH2:35][OH:36])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CO)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), acetoxyacetyl chloride (66 μL, 0.62 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C.for 5 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirred for 10 min to give the title compound. The reaction mixture was acidified with concentrated HCl and extracted with ethyl. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (217 mg, 78%) of the desired product as a yellow solid. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=7.6 and 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 7.22 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 467.0957 (M+H calcd for C22H19ClF3N2O4 requires 467.0980).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:22]3[CH:21]=CC=C[C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([Li])[CH2:24][CH2:25][CH3:26].[CH3:28]I.O>O1CCCC1.CCCCCC>[CH3:26][C:25]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:28])[N:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[C:22]=2[CH:21]=[CH:23][CH:24]=1
Reactant: CI
Reactant: [Li]CCCC
Reactant: CC(c1ccccc1)N1c2ccccc2Oc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc2c1Oc1c(C)cccc1N2C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 10 g (34 mmoles) of N-(αphenylethyl)phenoxazine in 100 ml of anhydrous tetrahydrofuran, under nitrogen, was cooled to -78° C. in a dry ice-acetone bath. 82 ml of a 1.4N solution (114 mmoles) of n-butyl lithium in hexane was slowly added to the cold solution while the temperature was maintained below 0° C. When the addition was completed, the reaction mixture was stirred for 4 hours at 0° C. Then 10.8 g (76 mmoles) of methyl iodide were added, the temperature was maintained at 0°-5° C. The resulting mixture was stirred for 16 hours at 0° C. and then poured into water and extracted with ethyl acetate (3.1 l). The combined extracts were dried and the solvent was removed. The residue purified by column chromatography on 450 g of silica gel, using hexane as eluant afford the pure 4,6-dimethyl-N-(α-phenylethyl)phenoxazine, as an oil, ir: 3837, 2940. 1640, 1600, 1570, 1470 cm-1 : nmr: (CDCl3) 1.90-1.83 ppm (d, 3H), 2.23 ppm (s, 6H), 5.20 ppm (c, 1H), 6.40-6.16 ppm (m, 2H), 6.80-6.53 ppm (m, 4H), 7.53-7.20 ppm (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]([CH3:20])[N:13]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:21][CH3:22])[C:12]1[N:17]=[C:16]([CH2:18][O:19][S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=[C:14]([CH3:20])[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(c1nc(C)cc(CO)n1)c1ccc(C(C)C)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1nc(C)cc(COS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimidinamine (1.57 g, 4.3 mmol), triethylamine(2.5 mL, 17 mmol) and dichloromethane (15 mL) at 0° C. under a nitrogen atmosphere was added methanesulfonyl chloride (0.54 g, 4.7 mmol) dropwise and the reaction mixture was stirred at 0° C. for 1.5 h. It was then washed successively with an ice-cold 1N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying the methylene chloride solution over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methanesulfonyloxymethyl-6-methylpyrimidinamine as a clear colorless oil (1.6 g): NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.5 (s, 1H), 5.05-4.9 (br s, 2H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 1H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.25 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 442, 444 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][N:4]=[C:5]([NH2:7])[NH2:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[S:20][C:19]([CH2:27][CH2:28]NC#N)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:17]=1.Cl.CON.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[ClH:1].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[S:20][C:19]([CH2:27][CH2:28][NH:6][C:5]([NH2:7])=[N:4][O:3][CH3:2])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]([C:32](=[O:37])[C@@H:33]([O:35][CH3:36])[CH3:34])[N:17]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC#N)c1ccccc1
Reactant: CON=C(N)N
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON=C(N)NCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 70 °C
Yield: 62 %

Procedure:
Preparation of 1-(2-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)-2-methoxyguanidine hydrochloride: To a solution of crude (2-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl)cyanamide (31 mg, 0.072 mmol) and methoxyamine hydrochloride (151 mg, 1.80 mol) in ethanol (3 mL) was added triethylamine (182 mg, 1.80 mmol). After heating to 70° C. in a sealed vessel for 16 hours, additional methoxyamine hydrochloride (151 mg, 1.80 mol) and triethylamine (182 mg, 1.80 mmol) was added, and the reaction mixture was heated to 70° C. in a sealed vessel for an additional 24 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The salts were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was chromatographed (4% methanol in dichloromethane with 0.5% NH4OH), and the isolated material was treated with excess HCl in MeOH then concentrated to afford the product as a mixture of diastereomers (23 mg, 62% yield). MS APCI (+) m/z 478 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 7.69-7.64 (m, 2H), 7.50-7.38 (m, 8H), 7.37-7.29 (m, 6H), 4.83-4.78 (m, 2H), 3.80-3.67 (m, 2H), 3.73 (s, 6H), 3.54-3.45 (m, 2H), 3.45-3.33 (m, 2H), 3.39 (s, 3H), 3.31 (s, 3H), 3.04-2.92 (m, 2H), 1.49 (d, 3H, J=7.1 Hz), 1.45 (d, 3H, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:14]=2)[CH:5]=1)([O-])=O.[H][H]>[Pd]>[CH:5]1[C:6]2[C:15](=[N:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:16]=[CH:17][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2nc3c(nc2c1)CCCC3
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc2nc3c(nc2c1)CCCC3
Yield: 94 %

Procedure:
A 18.0 g (0.078 mole) portion of 6,7,8,9-tetrahydro-2-nitrophenazine and 5 g of 5% Pd/C (50% H2O) were placed in a 1.7 liter stainless steel pressure bottle and subjected to hydrogenation at 40 psig. The hydrogen uptake was 18 lb (theory 17 lb). The reaction mixture was then filtered and concentrated. The filtrate was then concentrated to 1/3 volume, refrigerated, filtered, air dried, and dried to a constant weight at 60° to give 15 g (94%) of a yellow solid, m.p. 150°-152°.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9](O)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1CN=[N+]=[N-]
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N2C(=O)c3ccccc3C2=O)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of the compound 5 (658 mg) in tetrahydrofuran (15 mL), phthalimide (600 mg), triphenylphosphine (1070 mg) and 2.2 mol/L of a solution (2.0 mL) of diethyl azodicarboxylate in toluene were added at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→4:1) to obtain the title compound (508 mg) having the following physical properties.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>[Pd].O1CCCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:4]2[C:5]([NH:10][CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1NCC(O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8 g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml of tetrahydrofuran was hydrogenated in a large glass Parr bottle at room temperature. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. p-Chlorobenzoyl chloride (15.1 ml, 0.12 mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneously dropwise to the stirred filtrate at 12°-15° C. (ice-water bath) and the mixture was allowed to stir at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated and extracted with water (1×), 5% potassium hydroxide (2×), and water (2×). The methylene chloride layer was separated, dried, and evaporated to dryness. The residue was purified on a silica gel column (400 g) by eluting with 50% ethyl acetate/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-g sample was recrystallized from ethyl acetate/hexanes to give 2.71 g of solid, mp. 157°-159° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH2:7]([O:9][C:10](=[O:22])[CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH3:8]>>[CH2:7]([O:9][C:10]([C:11]1[C:12](=[O:13])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[C:3]2[C:17]=1[OH:18])=[O:22])[CH3:8]
Reactant: Nn1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2[nH]c1=O
Temperature: 170 °C
Yield: 8.1 %

Procedure:
A mixture of N-aminopyrrole (1.77 g, 20.56 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (14.4 g, 61.68 mmol) was subjected microwave heating at 170° C. for 30 min; then cooled, the reaction mixture was directly purified with silica gel column to give the desired product (372 mg) as brown solid. ESI (m/z): 223 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)[CH3:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1csc2[nH]c(=O)c(=O)[nH]c12
Solvent: CC(=O)O
Product: CCc1c(Cl)sc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 1 h

Procedure:
A solution of 7-ethylthieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 5.1 mmol) in 250 ml of acetic acid was stirred in a dry nitrogen atmosphere and sulphuryl chloride (0.41 ml, 5.1 mmol) was added dropwise. Stirring was continued for 1 h, the precipitate was filtered off, washed with water and dried at 100° C. under reduced pressure (30 Torr). Yield 0.77 g (65%) of the title compound. M.p. 282°-284° C. 1H-NMR (DMSO-D6, δ): 1.05 (t, 3H), 2.65 (q, 2H), 12.02 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH:14]=[CH2:15])[NH:9]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C(Cl)(Cl)Cl.Cl.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH:14]=[CH2:15])[N:9]2[C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:6][CH:7]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: C=CCCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (460 mg) and diisopropylamine (0.59 mL) in methylene chloride (10 mL), 4-pentenoyl chloride (0.37 mL) was added, and the reaction solution was stirred at room temperature for 1.5 hours. Chloroform and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 307 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Product: COc1ccc(CN(Cc2ccccc2)C(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 4-(chlorocarbonyl)benzoate and N-benzyl-1-(4-methoxyphenyl)methanamine. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72 (d, J=7.6 Hz, 3H), 4.26 (s, 1H), 4.30 (s, 1H), 4.50 (s, 1H), 4.55 (s, 1H), 6.89 (m, 2H), 7.02 (m, 1H), 7.10 (m, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.28 (m, 4H), 7.55 (m, 2H), 7.96 (m, 2H), 13.13 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(F)cc(F)c1

Procedure:
To the solution of 3,5-difluoroaniline (3.53 g, 26.8 mmol) in toluene/THF (1:1, 60 mL) is added acetonylacetone (3.24 mL, 26.8 mmol) and p-toluenesulfonic acid monohydrate (0.168 g). The reaction mixture is heated at reflux for 3 h, concentrated under reduced pressure, diluted with CH2Cl2 (60 mL), washed with water (3×10 mL) and saline (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge eluting with EtOAc/Hexanes (5/95-10/90) affords the title compound, mp 55-56° C.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](C(OCC)=O)=[CH:11]2.C(OC)(=O)C=C.Cl>C1C=CC=CC=1.O>[Br:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:12][CH2:1][C:2](=[O:5])[C:3]3=[CH:11][C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C=CC(=O)OC
Solvent: O
Solvent: c1ccccc1
Product: O=C1CCn2c1cc1cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of KOtBu (1.0 g, 8.9 mmol) in benzene (20 mL) was added ethyl 5-bromo-1H-indole-2-carboxylate (2.3 g, 8.6 mmol) as a solution in benzene (40 mL) at room temperature. To the resulting white slurry was added methyl acrylate (1.5 mL, 17.1 mmol). The combined solution was heated at 80° C. for 1 h then cooled to room temperature and stirred for an additional 16 h. The reaction mixture was then poured into H2O (100 mL) and the pH was adjusted to 4 with concentrated HCl. The aqueous phase was then extracted with CH2Cl2 (2×200 mL). The combined organic phases were washed with H2O, dried over Na2SO4, filtered and concentrated. The crude residue was then dissolved in EtOH (30 mL), 4M HCl (10 mL) was added, and the mixture was heated to reflux. After stirring at reflux for 3.5 h, the reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The aqueous phase was then washed with Et2O (2×100 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to afford the title compound as an off white solid (1.3 g, 61%).
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 3-(1,1′-biphenyl-4-yloxy)azetidine hydrochloride (100 mg, 382 μmol) in dichloromethane (2.5 mL) was added triethylamine (63 μL, 48 mg, 478 μmol) followed by phenyl isocyanate (35 μL, 38 mg, 320 μmol) and the reaction stirred at room temperature for 2.5 hours. The mixture was loaded directly onto a 2 g pre-packed SCX-2 cartridge and the product eluted with 1:1 dichloromethane:methanol (15 mL). The solvents were evaporated to give the urea (113 mg, 100%) as a white powder; LCMS retention time 2.57 minutes, m/z 345.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ8.54 (s, 1H), 7.62 (d, 4H, J=7.6 Hz), 7.50 (d, 2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.23 (t, 2H, J=7.8 Hz), 7.98-7.91 (m, 3H), 5.09 (m, 1H), 4.46-4.42 (m, 2H) and 3.95-3.91 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[NH2:19][OH:20].[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[OH:20][NH:19][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH:14][C:15](=[O:18])[CH2:16][N:14]3[CH2:15][CH2:24][N:22]([C:23]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=4)[CH2:21][CH2:11]3)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(NC(=O)CCl)cc2s1
Reactant: CN(C)C=O
Reactant: NO
Product: O=C(CN1CCN(c2ccccc2)CC1)Nc1ccc2cc(C(=O)NO)sc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 6-(2-chloro-acetylamino)-benzo[b]thiophene-2-carboxylic acid methyl ester (75 mg, 0.26 mmol) in DMF (2 mL) was added amine (85.8 mg, 0.52 mmol). The reaction mixture was heated to 50° C. After 24 h, NH2OH (50% aq., 1 mL) was added to the solution. The solution was stirred until the disappearance of starting material. After removal of solvent, MeOH/H2O was added until a precipitate forms. The solid was filtered yielding the desired amide. 1H NMR (DMSO-d6) δ 11.32 (br s, 1H), 9.97 (s, 1H), 9.28 (br s, 1H), 8.39 (s, 1H), 7.85-7.72 (m, 2H), 7.55 (d, J=7.0 Hz, 1H), 7.24-7.10 (m, 2H), 6.94-6.84 (m, 2H), 6.72 (t, J=7.0 Hz, 1H), 3.24-3.05 (m, 5H), 2.70-2.58 (m, 4H). MS (EI): cal'd (MH+) 411.14, exp (MH+) 411.33.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC(=O)N=C1N
Reactant: Cc1ccc(N=C=O)s1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
To 1.44 g (12.8 mM) of creatinine in 25 ml of anhydrous DMF was added with stirring 1.78 g (12.8 mM) of 5-methyl-2-thienyl isocyanate in 12 ml of toluene. After 6 hrs. at 60° C., the mixture was cooled, poured into 100 ml of water and filtered. The collected solid was recrystallized twice from ethyl acetate to give 2.4 g of the above urea as a yellow-orange solid, m.p. 207°-209° C.