Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH2:4][CH2:3]1.CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.C(=O)(O)[O-].[Na+]>O>[NH2:29][CH:26]1[C:27](=[O:28])[N:24]2[C:23]([C:32]([OH:34])=[O:33])=[C:22]([CH2:21][S:16][C:15]3[N:11]([CH2:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[N:12]=[N:13][N:14]=3)[CH2:31][S:30][C@H:25]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN1CCN(CCCn2nnnc2S)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)CC1
Temperature: 64 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazole-5-thiol.dihydrochloide (75.32 g) in water (6 l) was added 7-aminocephalosporanic acid (60.0 g) and the mixture was adjusted to pH 5.4 with a saturated aqueous solution of sodium bicarbonate and stirred for 2 hours at 64° C. The reaction mixture was cooled and adjusted to pH 6.84 with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was subjected to column chromatography (CM-Cephadex, H-type: 3 l), eluting with water, 0.5% aqueous solution of sodium chloride and 2% aqueous solution of sodium chloride. The fiactions containing the object compound were collected. The resulting mixture (about 7 l) was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate and then subjected to column chromatography (Non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries: 3l) and eluting with water, 2% isopropyl alcohol and 15% isopropyl alcohol. The fractions containing the object compound were collected and then concentrated. The concentrate was lyophilized to give a powder of 7-amino-3-[1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (34.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:31])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:32]I>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:31])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:32])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Reactant: CI
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC)cc3)CC2)c(C)c1
Yield: 88.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (637 mg) described in Example 307 and methyl iodide (255 mg), the title compound (582 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:50]([S:53]([CH2:56][CH2:57][NH2:58])(=[O:55])=[O:54])([CH3:52])[CH3:51]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:58][CH2:57][CH2:56][S:53]([CH:50]([CH3:52])[CH3:51])(=[O:55])=[O:54])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: CC(C)S(=O)(=O)CCN
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)CCNC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 33.9 %

Procedure:
Prepared according to Procedure I utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.22 g, 0.4 mmol), carbonyldiimidazole (0.58 g,3.6 mmol), and iso-propanesulfonylethylamine (0.24 g, 1.6 mmol) in DMF to afford the title compound (0.088 g). Electrospray MS 649 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:22][C:5]2[C:6]([OH:20])=[C:7]3[C:8](=[C:3]([O:2][CH3:1])[C:4]=2[OH:21])[O:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:12]3=[O:13])[CH2:29][CH2:28]1
Reactant: OCCN1CCNCC1
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: C=O
Solvent: CO
Product: COc1c(O)c(CN2CCN(CCO)CC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), 4-N-hydroxyethyl-piperazine (13.1 g) was stirred under for 4 hours at 50° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 41.7 g of purity 99.5%. MS: (API-ES) m/z 427.5[M+H]+, 449.5[M+Na]+; 1H NMR (DMSO-d6/CF3COOD, 400 MHz): δ 8.11˜8.13 (m, 2H, Ar-2′,6′-H), 7.62˜7.67 (m, 3H, Ar-3′,4′,5′-H), 7.11 (s, 1H, 3-H), 4.45 (s, 2H, CH2), 3.98 (s, 3H, 8-OCH3), 3.78 (t, 2H, —CH2—OH), 3.49-3.69 (m, 8H, CH2), 3.36 (t, 2H, N—CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]=O)=[O:24])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:31]=[CH:32][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)C2
Temperature: 20 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (1.00 g, 6.2 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (1.64 g, 6.2 mmol), sodium triacetoxyborohydride (1.94 g, 9.2 mmol) and dichloromethane (50 ml) was stirred at 20° C. for 18 h. Resulting solution was partitioned between saturated aqueous NAHCO3 (50 ml) and dichloromethane (3×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid. Trituration with 1:1 dichloromethane-ether gave the title compound (0.80 g, 32%).
Reaction SMILES: [Br-:1].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>C(O)C>[BrH:2].[Br-:1].[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:26]
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNCC
Agent: [Br-]
Solvent: CCO
Product: Br
Product: CCN(CC)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Into a one-liter 3-necked flask equipped with stirrer, condenser, addition funnel, and thermometer here was charged, 200 g of the above (3-bromopropyl)triphenylphosphonium bromide, and 650 ml ethanol. There was then added dropwise, 240 ml of diethylamine at 50° C. with stirring. After 18 hours at 65° C., the solution was concentrated to an oil and the residue was redissolved in 500 ml ethanol. The solution was again concentrated to a solid. The resulting brown solid was slurried in 500 ml of hot tetrahydrofuran and filtered. The crystal were recrystallized from tetrahydrofuran containing a small amount of ethanol to give 230 g of (3-diethylaminopropyl)triphenylphosphonium bromide hydrobromide (M.P. 239°-241° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: O=C(Nc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of 4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate. 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Prodedure M to give 550 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 429 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:16][OH:17])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].[Cl:18]N1C(=O)CCC1=O.C(=O)([O-])O.[K+].[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[Cl:45]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:39][C:38]([C:36]4[CH:37]=[C:32]([Cl:31])[C:33]([Cl:45])=[C:34]([Cl:44])[CH:35]=4)([C:40]([F:42])([F:43])[F:41])[O:17][N:16]=3)=[CH:11][C:10]=2[Cl:18])[CH2:6]1)=[O:4]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a stirred solution of 1-[4-(hydroxyimino-methyl)-phenyl]-azetidine-3-carboxylic acid methyl ester (Preparation 10, 0.95 g, 4.059 mmol, 1 eq.) in DMF (10 mL) was added N-chloro succinimide (0.59 g, 4.46 mmol) at room temperature. Resulting reaction mixture was stirred at 45° C. for 30 minutes. After complete consumption of starting material to chloro intermediate, reaction mixture was cooled to room temperature, potassium hydrogen carbonate (0.61 g, 6.089 mmol) was added followed by of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)-benzene (1.33 g, 4.87 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After consumption of chloro intermediate, reaction mixture was quenched with ice cold water (250 mL) and extracted with EtOAc (2×200 mL). Combined organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to 1 g crude. Crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford 0.850 g impure product. Impure product was repurified by column chromatography (silica gel, 100-200 mesh) to afford 0.55 g. 1H NMR (400 MHz, CDCl3): 3.51-3.55 (m, 1H), 3.60 (d, 1H, J=17.08 Hz), 3.75 (s, 3H), 4.0 (d, 1H, J=17.04 Hz), 4.28 (t, 2H, J=7.2 Hz), 4.36 (t, 2H, J=8.36 Hz), 6.45 (d, 1H, J=8.6 Hz), 7.41 (dd, 1H, J1=1.92 Hz, J2=8.6 Hz), 7.46 (d, 1H, J=1.88 Hz), 7.62 (s, 2H); LC-MS (M+H): =542.50.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C1(C)C=CC=CC=1>[CH:10]1([CH2:9][N:8]2[C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][C:3]3[CH2:2][S:1][CH2:6][CH2:5][C:4]2=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCC1CCCCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C1CCSCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(n(CC3CCCCC3)c1=O)CCSC2

Procedure:
After a toluene (40 mL) solution of tetrahydrothiopyran-4-one (5.05 g, 43.5 mmol) and aminomethylcyclohexane (5.41 g, 47.8 mM) was heated and refluxed under azeotropic dehydration for 4 hours, diethyl ethoxymethylenemalonate (9.40 g, 43.5 mmol) was added, and the mixture was further continued to be heated and refluxed for 17 hours. The solvent was removed by distillation under reduced pressure, and the residue was refined with silica gel (160 g) column chromatography (ethyl acetate-toluene of 1:5 in mixing ratio and then that of 2:3), and red oily ethyl 1-cyclohexylmethyl-2-oxo-1,5,7,8,tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08, 8.17 g, 31.5%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[CH3:15])[CH:9]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)/[CH3:15])[CH:9]=1
Reactant: CC(=O)c1cccc(-c2ccccc2Cl)c1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: C/C(=C1/SC(=O)NC1=O)c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-chloro-1,1′-biphenyl-3-yl)ethanone (145 mg, 0.63 mmol) and 2,4-thiazolidinedione (67 mg, 0.57 mmol) in xylene (1.9 mL), sodium acetate (38 mg, 0.28 mmol) and acetic anhydride (53 μL, 0.57 mmol) were added and the solution was heated in a sealed tube for 16 h. It was then cooled to rt, partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Finally filtered, concentrated and purified by chromatography. (hexanes:ethyl acetate; 4:1) to give the product as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[C:42](O)=[O:43])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][N:36]2[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (31) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-2-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 18.5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (20%→40% ethyl acetate in hexanes) affording the desired product (32) as an oil. ESMS: MH+ 590.6
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2

Procedure:
The title compound of step 4 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, 1H), 7.38 (s, 1H), 3.74 (d, J=6.4 Hz, 2H), 3.51 (s, 3H), 3.28 (s, 3H), 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2H), 1.74-1.71 (m, 2H), 1.64-1.59 (m, 2H), 1.13-1.10 (m, 1H), 0.60-0.58 (m, 2H), 0.25-0.24 (m, 2H). LCMS: 405.1 (M+H)+
Reaction SMILES: [C:1]([CH2:3][C:4](C1C=CC(OC)=C(C=1)C=O)(C)C)#N.[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.[C:34]([C:36]1([C:39]2[CH:40]=[CH:41][C:42]([O:59][CH3:60])=[C:43]([CH:58]=2)[CH2:44]N[C@H]2CCCN[C@H]2C2C=CC=CC=2)[CH2:38][CH2:37]1)#[N:35]>>[ClH:17].[ClH:17].[C:34]([C:36]1([C:39]2[CH:40]=[CH:41][C:42]([O:59][CH3:60])=[C:43]([CH:58]=2)[CH2:44][NH:31][C@H:30]2[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:38][CH2:37][CH2:4][CH2:3][CH2:1]1)#[N:35]
Reactant: COc1ccc(C(C)(C)CC#N)cc1C=O
Reactant: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C2(C#N)CCCCC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 47 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.CC([O-])(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 4-amino-2-chlorophenol (Aldrich, 430 mg, 3.0 mmol) in DMF (2.0 mL) at room temperature was added KOt-Bu (352 mg, 3.2 mmol). The mixture was allowed to stir at room temperature for 1 h. To the solution were then added 4-chloropicolinamide (468 mg, 3.0 mmol) and K2CO3 (221 mg, 1.6 mmol). The resulting suspension was heated at 90° C. overnight. After cooling down, the suspension was diluted with 100 mL of EtOAc and 50 mL of H2O. The organic layer was separated and washed with brine (2×25 mL) and dried over MgSO4. After filtration and concentration, the solid was triturated with 50 mL of DCM. The solid was then collected and washed with DCM (2×20 mL), EtOAc (5.0 mL) and dried to give 4-(4-amino-2-chlorophenoxy)picolinamide (320 mg, 40% yield). MS(ESI+): m/z 264.12/266.07 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:12]O>>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Product: COC(=O)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 3-neck round bottom flask equipped with a reflux condenser was added 3,6-dichloropyridine-2-carboxylic acid (50.0 g, 260.42 mmol) in methanol (200 mL). HCl(g) was bubbled in until solution became saturated and stirred at room temperature for 2 hr. The solution was concentrated to dryness in vacuo. Diethyl ether was added to make a slurry that was subsequently added to a flask filled with a 1:1 mixture of saturated sodium bicarbonate/diethyl ether and stirred for 10 min. The aqueous phase was extracted with diethyl ether (3×300 mL). The combined extracts were dried (MgSO4) and concentrated to give 46.6 g of a light yellow solid. 1H NMR(CDCl3): δ 4.00 (s, 3H); 7.41 (d, 1H); 7.80 (d, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:28]([O:27][C:25](=[O:26])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNc1cnc(NCc2ccccc2)cc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 2.03 g (6.7 mmol) N2-benzyl-N5-methyl-4-o-tolyl-pyridine-2,5-diamine in 100 ml dichloromethane and 40 ml N-ethyldiisopropylamine was added dropwise at 0° C. a solution of 2.1 ml (14.09 mmol) benzyl chloroformate in 50 ml dichloromethane. After stirring for 2 h at room temperature the reaction mixture was washed with water (2×50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 2.36 g (80%) of the title compound as light brown crystals. M.p. 110-112° C.
Reaction SMILES: Br[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:22]>>[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]([NH2:21])=[O:22])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: O
Reactant: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
2-(1-Bromocyclohexyl)-8-cyanomethyl-4-oxo-4H-[1]-benzopyran (3.0 g) was added to polyphosphoric acid (120 ml) and the mixture was heated on an oil bath at about 120° C. for 2 hours. After standing overnight, water (about 300 ml) was added to decompose polyphosphoric acid. Crystals deposited were filtered off and recrystallized form the mixed solvent of dichloromethane and methanol to obtain the title compound, yield 57%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([CH:13]=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:15]([C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)[NH2:16].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:18]5[N:19]=[C:20]([C:23]6[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=6)[CH:21]=[N:22][C:17]5=[N:15][N:16]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1
Reactant: O=CC1(c2ccc3ncsc3c2)CC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde (80.0 mg, 0.39 mmol) and methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (96.5 mg, 0.394 mol) in ethanol (2.7 mL) and acetic acid (0.53 mL) was stirred at RT for 3 h. The mixture was concentrated. The residue was dissolved in DCM (5 mL), followed by addition iodobenzene diacetate (150 mg, 0.47 mmol). The mixture was stirred at RT for 6 h, and quenched with saturated sodium bicarbonate (25 mL). The mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with 40% ethyl acetate in DCM to afford the desired product. Analytical LCMS: (M+H)+=429.0.