Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[C:19]2[S:18][C:17]([Cl:20])=[N:16][C:15]=2[C:14]([Cl:21])=[CH:13][C:12]=1[F:22]>O.ClCCl>[Cl:20][C:17]1[S:18][C:19]2[C:11]([N:10]=[C:6]=[S:7])=[C:12]([F:22])[CH:13]=[C:14]([Cl:21])[C:15]=2[N:16]=1
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Cl)c2nc(Cl)sc2c1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 16.9 g calcium carbonate in 100 ml water was added to a solution of 19.4 g thiophosgene in 100 ml dichloromethane. A solution of 40 g 7-amino-2,4-dichloro-6-fluorobenzothiazole in 500 ml dichloromethane was added, dropwise at 5° C., and the mixture stirred for 8 hours at room temperature. The solid was filtered, the phases were separated, and the organic phase dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexane/ethyl acetate). Yield: 16 g=38% of theory m.p.: 80°-81° C.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]([OH:26])[C:22](O)([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8].[BrH:27].O.C(=O)(O)[O-].[Na+].[C:34]([OH:37])(=O)[CH3:35]>>[CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]([O:26][C:34](=[O:37])[CH3:35])[C:22]([Br:27])([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8]
Reactant: C[C@H](CCCn1c(=O)c2c(ncn2C)n(C)c1=O)CCC(O)C(C)(C)O
Reactant: CC(=O)O
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CC[C@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O)C(C)(C)Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-(R)-Methyl-7,8-dihydroxy-8-methylnonyl)-3,7-dimethylxanthine (0.29 g, 0.80 mmol) was stirred with hydrogen bromide (1.00 mL of a 30% solution in acetic acid, 2.40 mmol) for 4 hours. The mixture was then added over 10 minutes to water (10 mL), ice (5 g) and sodium bicarbonate (2 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (2×15 mL), the combined organic phases dried using magnesium sulfate and the solvent evaporated to obtain a residue of 1-(4-(R)-methyl-7-acetoxy-8-bromo-8-methylnonyl)-3,7-dimethylxanthine.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C([Li])CCC.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.Cl>O1CCCC1.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1
Reactant: BrCCCCCCCBr
Reactant: CC1=NCCS1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: BrCCCCCCCCC1=NCCS1
Temperature: -70 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 2-methyl-2-thiazoline (1.01 g) in dry tetrahydrofuran at −70° C. was added a solution of n-butyl lithium in hexanes (2.5M, 4.0 ml) dropwise over 10 min. After stirring at −70° C. for 2 h, 1,7-dibromoheptane (12.9 g) was added in one portion (temperature increased to −45° C.). The mixture was cooled again to −70° C. for 1 h and then allowed to warm to room temperature over 1 h. The mixture was cooled to 0° C. and water (10 ml) added, followed by dilute hydrochloric acid (to pH 2). The organic layer was separated and the aqueous layer extracted with diethyl ethyl (2×20 ml). The organic layers were combined and washed with water and brine and dried over magnesium sulfate. Evaporation under reduced pressure gave an oil that was chromatographed on silica gel using 40-60° C. petroleum ether:ethyl acetate 5:1 to give 1-bromo-8-(2-thiazolinyl)octane (1.06 g). 1H-NMR (CDCl3) δ 1.2-1.5 (6H, m), 1.5-1.75 (4H, m), 1.75-1.95 (2H, m), 2.50 (2H, t), 3.28 (2H, t), 3.40 (2H, t) and 4.21 (2H, dt).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S)-1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:18])[CH3:17])[CH2:12]1>C(O)(=O)C.[Zn]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH2:14][CH:13]([N:16]([CH3:17])[CH3:18])[CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN(C)C1CCN(c2ccc(N)cc2Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (3.0 g) was added in portions to a solution of [1-(2-chloro-4-nitrophenyl)-pyrrolidin-3-yl]dimethylamine (1.9 g) in glacial acetic acid (50 mL) cooled to 0° C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes and then insolubles were filtered off with suction. The filtrate was concentrated in a rotary evaporator, and the residue was partitioned between sodium hydroxide solution and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 239.75 (C12H18ClN3) was obtained in this way; MS (ESI): 240 (M+H+).
Reaction SMILES: [OH-].[Na+].COCCOCCN(CCOCCOC)CCOCCOC.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].Cl[CH:34]([F:36])[F:35]>C1C=CC=CC=1>[F:35][CH:34]([S:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[F:25])[F:36]
Reactant: FC(F)Cl
Reactant: Fc1ccccc1S
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Fc1ccccc1SC(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Powdered NaOH (31.2 g), tris(2-(2-methoxyethoxy)ethyl)amine (5 mL) and 2-fluorobenzene thiol (33.6 mL) in benzene (400 mL) was saturated with chlorodifluoromethane, stirred at 80° C. for 30 minutes and filtered through diatomaceous earth (Celite®). The filtrate was washed with saturated NaHCO3 and the water layer was extracted with diethyl ether. The extracts were combined and dried (MgSO4), filtered and concentrated.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[C:9](O)=[O:10]>C1COCC1>[CH3:12][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH2:9][OH:10]
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccccc1
Yield: 72 %

Procedure:
To a suspension of LiAlH4 (4.64 g, 123.0 mmol) in dry THF (500 mL) was added 2-methyl-2-phenyl-propionic acid (20.0 g, 123.0 mmol) in dry THF (250 mL) dropwise at 55° C. over 10 min. The mixture was quenched with sodium hydroxide aqueous solution (60 mL, 15%). The mixture was filtered and the filtrate was dried over anhydrous sodium sulfate, filtered and evaporated to yield 2-methyl-2-phenyl-propan-1-ol (13.3 g, 72.7%), which was used to the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[N:15]1([CH:24](N2N=C3C=CC=CC3=N2)[NH2:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:15]1([C:24](=[NH:25])[N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(n1nc2ccccc2n1)n1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=N)n2nnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.2 %

Procedure:
A dichloromethane (50 ml) solution of tert-butyl piperidin-4-ylcarbamate (7.50 g, 37.9 mmol) was added dropwise to a dichloromethane (150 ml) solution of 1-(1H-benzotriazol-1-yl)-1-(2H-benzotriazol-2-yl)methanamine (J. Org. Chem. 2000, 65, 8080; and J. Org. Chem. 2003, 68, 4941) (10.0 g, 37.9 mmol) and the resulting mixture was stirred at room temperature for 3 days. 10% Aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 10.6 g (81%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=O.CC1(C)C(C)(C)OB([C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=2)O1.[NH3:31]>>[OH:3][CH2:1][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[C:23]1[NH:31][N:27]=[C:25]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=3)[C:24]=1[CH2:28]2
Reactant: N
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Product: NC(=O)c1ccc(-c2n[nH]c3c2Cc2cc(CO)ccc2-3)cc1

Procedure:
The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 19A and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide in Example 1D. MS (DCI/NH3) m/z: 306.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.90 (s, 2H), 4.57 (s, 2H), 7.32 (d, J=7.49 Hz, 1H), 7.54 (s, 1H), 7.61 (d, J=7.80 Hz, 1H), 7.89 (d, J=8.42 Hz, 2H), 8.00 (d, J=8.42 Hz, 2H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36].[CH3:37][N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>CN1C(=O)CCC1>[CH2:33]([C:20]1[N:19]([CH2:18][CH2:17][CH2:16][NH:15][CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CN1CCC(=O)CC1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC1CCN(C)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (1.07 g) was added to a stirred mixture of the product from example 1 step (vii) (502 mg) and 1-methylpiperidin-4-one (0.21 mL) in NMP (2 mL) at rt. The resulting solution was stirred at 50° C. for 3 h, then purified by SCX, yield 335 mg.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH2:5][CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[N:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][C:4]4[N:10]([CH:1]=[CH:2][N:3]=4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: Nc1ccc2c(c1)-n1ccnc1CCC2
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine was converted to 5-chloro-N*2*-(5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-yl)-N*4*-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.76 (m, 1H), 7.70 (d, 1H), 7.67 (s, 2H), 7.5 (m, 3H), 7.24 (d, 1H), 3.3 (m, 1H), 2.95 (t, 2H), 2.60 (t, 2H), 2.38 (pent, 2H), 1.19 (d, 6H); 19F NMR (282 MHz, CD3OD) δ −77.4, −114.8 (d); MS (m/e) 527 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:32]2[CH2:31][CH2:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccc(O)cc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C2c3cc(O)ccc3C(=O)N2C)CC1
Product: Cl
Yield: 101.5 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(6-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (1.5 g) was coupled to 4-acetamido-4-phenylpiperidine (0.7 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (1.26 g); mp 212°-225° C.; MS: m/z=566(m+1); NMR: 2.00 (s,3), 2.22(m,5), 2.5 (m,2), 2.7(m,2), 2.99(s,3), 3.54(m, 1), 4.54 (d,1, J=3.4), 5.81 (s,1), 6.6 (m,1), 6.7 (m, 1), 6.97 (m, 1), 7.11 (m,2), 7.31 (m,6), 7.50 (d,1, J=8).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol) in methanol (500 mL) was cooled to 0° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜30 min. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to rt, and the reaction was allowed to stir for an additional 2 days at room temperature and the solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (˜500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (˜300 mL), water (˜300 mL), and brine (˜300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[C:15]1[C:10]=3[CH:11]=[CH:12][CH:13]=[CH:14]1>C(Cl)Cl>[CH:5]1[C:6]2[CH:7]=[CH:8][C:9]3[C:18](=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[CH:14]4)[C:19]=2[CH:20]=[C:3]([CH:2]=[O:1])[CH:4]=1
Reactant: OCc1ccc2ccc3c4ccccc4ccc3c2c1
Solvent: ClCCl
Product: O=Cc1ccc2ccc3c4ccccc4ccc3c2c1
Yield: 88.2 %

Procedure:
3-Hydroxymethylchrysene (19F, 14.6 g, 0.057 mol) in CH2Cl2 (2 L) was treated with BaMnO4 (Aldrich, 29 g, 0.113 mol) and refluxed for 15 h. The reaction mixture was filtered, the solvent removed, and the resulting solid eluted through a plug of SiO2 (500 g) using PhCH3 as the eluting solvent. The appropriate fractions were combined and concentrated to 75 mL. Filtration and drying of the precipitate which formed gave 12.88 g (89%) of chrysene-3-carbaldehyde mp 177°-177.5°, (C, H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])=[O:7].Cl>CO>[OH:3][C:4]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 33.8 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.33 mL) was added to a methanol (2.0 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.058 g), followed by stirring at 60° C. for 9 hours and 20 minutes. The reaction mixture was cooled to room temperature, and 6 mol/L hydrochloric acid (0.11 mL) was added thereto. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% chloroform/methanol] to obtain 0.019 g of 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].[H-].[Na+].[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25](OCC)=[S:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]([NH:6][C:5]([NH2:7])=[N:4][C:1](=[O:3])[CH3:2])=[S:26])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)NC(=N)N
Reactant: CCOC(=S)C1CCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N=C(N)NC(=S)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
1-Acetylguanidine (7.20 g, 71.0 mmol) was dissolved in THF (100 mL). The solution was cooled to 0° C. and NaH (1.90 g, 80.0 mmol) was added to the reaction in small batches over 5 mins. Next, 2-ethoxythiocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester (19.6 g, 66.9 mmol) in THF (50 mL) was added to the reaction dropwise over 30 minutes while maintaining the temperature between 0-5° C. The reaction was allowed to return to room temperature, while stirring an additional 12 hours. The product was precipitated by addition of petroleum ether. The organic layer was decanted off and the solid was retained and redissolved in water (300 mL). The pH was adjusted to pH=3 by addition of acetic acid. The resulting solution was transferred to a separatory funnel and extracted with DCM (3×250 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuo to afford 13.0 g (56%) of 2-(N′-acetyl-guanidinocarbothioyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])C.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[CH2:2]([S:4]([N:28]1[CH2:29][CH2:30][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][C:14]3[CH:15]=[CH:16][N:11]4[CH:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[O:31])=[CH:21][CH:22]=2)[CH2:27]1)(=[O:6])=[O:5])[CH3:1]
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: CCS(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 557C, substituting ethane sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (t, J=5.9 Hz, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.88 (m, 3H), 7.52 (d, J=1.2 Hz, 1H), 7.45 (m, 2H), 7.38 (s, 1H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H), 3.75 (dd, J=9.5, 7.5 Hz, 1H), 3.50 (m, 2H), 3.38 (m, 1H), 3.26-3.12 (m, 3H), 2.32 (m, 1H), 2.03 (m, 1H), 1.24 (t, J=7.3 Hz, 3H); MS (ESI(+)) m/e 413 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([CH2:12][CH2:11][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(CCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole-4-carboxaldehyde (6.73 g, 70 mmol) was added portionwise to a suspension of sodium hydride (1.68 g, 60% dispersion in mineral oil, 70 mmol) in tetrahydrofuran (280 ml), and the mixture was then stirred at room temperature for 30 minutes. (2-Bromoethyl)benzene (9.56 ml, 70 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between water (300 ml) and dichloromethane (500 ml), and the layers were separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was pre-adsorbed onto silica gel, and purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (50:50 to 100:0) to afford the title compound, 1.44 g. 1H-NMR (CDCl3, 400 MHz) δ: 3.16 (t, 2H), 4.23 (t, 2H), 7.02 (d, 2H), 7.28 (m, 3H), 7.36 (s, 1H), 7.50 (s, 1H), 9.83 (s, 1H). LRMS: m/z (ES+) 223 [MNa+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:7][C:6]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]1[CH3:20])[CH2:5]2>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[CH2:7][C:6]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]1[CH3:20])[CH2:5]2
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c([N+](=O)[O-])cc1C2
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)NC(=O)C12Cc1cc(N)c(N)cc1C2
Reaction time: 2 h

Procedure:
To a solution of (±)-5′-amino-6′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step A (15 mg, 0.054 mmol) in MeOH (5 mL) was added 10% Pd/C (5 mg) and the reaction mixture was stirred vigorously under hydrogen (ca. 1 atm). After 2 h, the catalyst was filtered off and the filtrate was concentrated in vacuo to yield the title compound. MS: m/z=247 (M+1).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([OH:21])=[O:20])=[CH:6][C:4]=2[O:5]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
The mixture of sesamol (270 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (2.55 ml, 22.9 mmol) and acetone (25 ml) was refluxed for 21 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 20 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the uiixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from chloroform and acetone to give 45 mg 3,4-methylenedioxyphenoxyacetic acid as white crystals, mp 149-151 ° C.