Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([NH2:16])=[CH:10][C:9]=1[OH:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[S:19]([O:17][C:9]1[CH:10]=[C:11]([NH:16][S:19]([CH3:18])(=[O:21])=[O:20])[C:12]([O:14][CH3:15])=[CH:13][C:8]=1[CH3:7])(=[O:21])(=[O:20])[CH3:18]
Reactant: COc1cc(C)c(O)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C)c(OS(C)(=O)=O)cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 175.7 %

Procedure:
20 ml of pyridine was cooled to 0° C. and 2.10 g (3.70 mmol) of 2-methyl-4-methoxy-5-aminophenol and 5.3 g (46.2 mmol) of methanesulfonyl chloride were added thereto. The mixture was adjusted to room temperature followed by stirring for 1 hour. Then 200 ml of water was poured thereto and the mixture was extracted with 300 ml of chloroform, and the extra was washed with 2N hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, brown crystals were obtained. These crystals were purified by column chromatography (the same as the one used in Example 3) and recrystallized from the solvent mixture of ethyl acetate/hexane (2:1). Thus 2.01 g (6.50 mmol) of 2-methyl-4-methoxy-5-mesylaminophenyl mesylate was obtained. The yield was 47%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1
Product: O=C1CCCCC1C(=O)N1CCCCC1
Yield: 96.5 %

Procedure:
Ethyl 2-oxocyclohexane-carboxylate (5.3 g, 31 mmol, 5.0 mL) DMAP (1.05 g, 9.4 mmol) and piperidine (5.3 g, 63 mmol, 6.2 mL) in toluene (100 mL) were heated at reflux for 4 days. The reaction was allowed to cool and the reaction was concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-80% (B), 100 g, 8 CV, 85 mL/min) to afford 6.26 g (96%) of 2-(piperidine-1-carbonyl)-cyclohexanone (19) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 23.5, 24.5, 25.5, 26.2, 27.1, 30.4, 41.9, 42.9, 46.8, 54.2, 167.6, 207.6.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(Cl)c1N
Temperature: 64 °C
Yield: 78.6 %

Procedure:
To a 500 mL round-bottom flask, 0.2 mol of 2-amino-3,5-dichlorobenzoic acid having a structural formula of IV-4, 300 mL of methanol, and 5 mL of concentrated sulfuric acid were added, heated to 64° C. and reacted for 12 hours (into which 3 mL of concentrated sulfuric acid was added twice), after cooling most of the solvent was removed under reduced pressure, and 300 mL of water was added, the pH was adjusted to 9-10 with a saturated sodium hydroxide solution, extracted with 200 mL of ethyl acetate, washed with water for one time, dried over anhydrous sodium sulfate, filtered and the solvent was remove to obtain a crude product, 34.6 grams of 2-amino-3,5-dichlorobenzoic acid methyl ester having a structure as shown by VIII-1 was obtained by column chromatography, and the yield was 78.6%;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: Cc1cc(S(N)(=O)=O)c(N)cc1Br
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1cc(N)c(S(N)(=O)=O)cc1C
Yield: 90 %

Procedure:
3-Bromo-4-methylaniline was transformed by Method B (The isomers were separated by fractional crystallization from MeOH) to give 2-amino4-bromo-5-methylbenzenesulfonamide. A mixture of 2-amino-4-bromo-5-methylbenzenesulfonamide (100 mg, 0.38 mmol), 2-methoxyphenylboronic acid (76 mg, 0.50 mmol), Pd(PPh3)2Cl2 (13 mg, 5 mol %) in 1,2-dimethoxyethane (20 ml) and Na2CO3 (2M, 1 ml, 2 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (10 ml) and extracted with EtOAc (2×25 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 100 mg (90%) of 2-amino-4-(2-methoxyphenyl)-5-methylbenzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 172–175° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].Cl[C:10]([O:12][CH3:13])=[O:11].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2]
Reactant: COC(=O)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(CCCl)CCCl

Procedure:
The starting material N,N-bis-(2-chloroethyl)-carbamic acid methyl ester is prepared by treating a solution of bis-(2-chloroethyl)-amine hydrochloride in methylene chloride at 0° C. with methyl chloroformate (1.0 mole equivalent) and diisopropylethylamine (2.2 mole equivalents).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:36]=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:36]=[CH:35][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(C(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1cnc2ccccc2c1

Procedure:
To a solution of the intermediate from step D (125 mg, 0.24 mmol) in 5 mL of THF was added MeOH (1 mL) followed by sodium hydroxide (5N, 0.5 mL). After stirring the reaction at room temperature for 18 hours, it was concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification. LC-MS: 4.03 min; (M+H)=488.3.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([CH3:15])[N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[N:2][NH:1][C:3]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Reactant: COc1ccc(C(C)=O)cc1
Solvent: CCO
Product: COc1ccc(C(C)=NNc2cc(-c3ccccc3)nc(C)n2)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine (200 mg, 1.0 mmol) and 1-(4-methoxy-phenyl)-ethanone (150 mg, 1.0 mmol) in 10 mL of ethanol by a procedure similar to example 1, step 4 yielding 35 mg (11%) of a cream solid. HPLC Purity: 98%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:18][C:19]2[CH:20]=[C:21]([NH:26][C:27]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[N:35]=[CH:34][CH:33]=[CH:32]4)=[O:28])[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 50 %

Procedure:
Using analogous procedures to those described in the last two paragraphs of the portion of Example 7 which is concerned with the preparation of starting materials, 4-benzyloxybenzoic acid was reacted with N-(3-amino-4-methylphenyl)quinoline-6-carboxamide to give N-[3-(4-benzyloxybenzamido)-4-methylphenyl]quinoline-6-carboxamide in 50% yield, m.p. 227-228° C.; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 5.2 (s, 2H), 7.12 (d, 2H), 7.25 (d, 1H), 7.39 (m, 5H), 7.61 (m, 2H), 7.86 (d, 1H), 8.52 (d, 1H), 8.62 (d, 1H), 8.99 (m, 1H), 9.76 (s, 1H), 10.47 (s, 1H); and that compound was hydrogenolysed to give the required starting material in 93% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 6.83 (d, 2H), 7.23 (d, 1H), 7.61 (m, 2H), 7.85 (m, 3H), 8.12 (d, 1H), 8.25 (d, 1H), 8.52 (d, 1H), 8.62 (s, 1H), 8.99 (d, 1H), 9.61 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 396.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N+:6]([O-])[CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(F)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(F)c(Cl)n1
Temperature: 0 °C
Yield: 79 %

Procedure:
5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (100 mg, 0.584 mmol) was dissolved in POCl3 (2 ml), and then heated at reflux under nitrogen stream for 4 hours. The resulting reaction liquid was slowly added to ice (15 g), and then extracted with MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 88 mg of white solid (79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([OH:13])=[O:12].N1C=CC=CC=1.[C:21]([C@@H:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)#[N:22]>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C@H:23]([C:21]#[N:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)=[O:12]
Reactant: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
7 g of the product of Step C, 7.3 g of dicyclohexylcarbodiiumide and 3 ml of pyridine were added to 50 ml of methylene chloride and after the addition of 8 g of (S)α-cyano-3-phenoxy-benzyl alcohol, the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The 20 g of residue were crystallized from isopropyl ether to obtain 10.5 g of (S)-α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(methoxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 98° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:34].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, 2.37 mmol) (obtained as described in Reference Example 62(1)) in methanol (53 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (53.2 ml). To the mixture were added p-nitrobenzyl chloroformate (0.76 g, 3.52 mmol) and triethylamine (0.5 ml, 3.59 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (3:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (867.2 mg, yield 61%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Li+].CC([N-]C(C)C)C.B(OC)(OC)[O:18]C>C1COCC1.CCCCCCC.C1COCC1>[OH:18][C:7]1[C:2]([F:1])=[N:3][C:4]([F:8])=[CH:5][CH:6]=1
Reactant: Fc1cccc(F)n1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(F)nc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 2, 6-difluoropyridine (6.7 mL, 73.8 mmole) in THF (100 mL, cooled to -78° C.) was added a 2M solution of LDA in heptane/THF/ethylbenene (38 mL, 76 mmol). The mixture was stirred at -78° C. for 1 hour, and trimethyl borate (6.8 mL, 89.7 mmol) was added. The mixture was stirred for 1 hour and allowed to warm to 20° C., then the reaction was quenched with HOAc (10 mL). The solution was made basic with 20% aq NaOH (20 mL), H2O2 (50%, 200 mL) was added, and the mixture stirred for 16 hours. The mixture was neutralized by addition of HCl (2M, aq) and extracted with EtOAc. The combined EtOAc extracts were dried (MgSO4). The solvent was evaporated under vacuum, and the crude product was chromatographed (silica gel; hexane/EtOAc 9:1 to 6:4) to yield 2.7g (28%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ: 6.75 (dd, J=3.0, 5.5 Hz, 1H), 7.48 (m, 1H). MS (DCI/NH3) m/e 149 (M+NH4)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>C(O)C.ClCCl.[Pd]>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A stirred suspension of tert-butyl 2-hydroxyethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (590 mg, 1.539 mmol) and palladium, 10 wt. % on activated carbon (164 mg, 0.154 mmol) in ethanol (10 mL) was stirred at room temperature under an atmosphere of hydrogen (1 atm) for 2 hours (yellow color disappears). To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (878 mg, 3.08 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and then filtered through Celite. The filtrate was then diluted with water and extracted with dichloromethane (4×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, giving the desired product (339 mg, 47.6%) as a yellow foam. 1H NMR (DMSO-d6) δ 7.69 (s, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.07 (t, J=4.2 Hz, 1H), 6.41-6.25 (m, 3H), 6.08 (d, J=8.1 Hz, 1H), 4.71-4.65 (m, 1H), 3.63-3.54 (m, 2H), 3.49-3.33 (m, 6H), 3.27-3.15 (m, 2H), 3.02-2.94 (m, 2H), 1.39-1.29 (m, 9H); ESI-MS (m/z, %): 463 (MH+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: NCCSc1ccc(CCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCc1ccc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-[4-(2-aminoethylthio)phenyl]propionic acid (0.8 g), triethylamine (1.6 ml) and methylene chloride (50 ml) was added 4-chlorophenylsulfonyl chloride (0.79 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 3% hydrochloric acid and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue, which was then crystallized from ethyl acetate - n-hexane to give 3-{4-[2-(4-chlorophenylsulfonylamino)ethylthio]phenyl}propionic acid (Compound No. 52) (1.07 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:38])[N:17]([CH3:37])[C:18]([C:22]3[CH:36]=[CH:35][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)=[N:19]2)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:37][N:17]1[C:16](=[O:38])[C:15]2[C:20](=[CH:21][C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)[N:19]=[C:18]1[C:22]1[CH:23]=[CH:24][C:25]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:35][CH:36]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(N)ccc3c(=O)n2C)cc1)OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(-c2nc3cc(NS(=O)(=O)c4ccccc4)ccc3c(=O)n2C)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Benzenesulfonyl chloride (0.57 ml) was slowly added dropwise at 0° C. to 10 ml of pyridine containing 1.5 g of the compound obtained in Example 66. The mixture was stirred at room temperature for 12 hours. After adding a saturated sodium bicarbonate solution, the reaction mixture was extracted with dichloromethane. The organic layer was washed with diluted hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 1.75 g of the desired compound as colorless crystals. Table 3 shows the chemical structure and physical property (melting point) of the compound obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCc2ccccn2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 2-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].S(Cl)(Cl)=O.C[N:27](C=O)C>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:27])=[O:11]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of compound (1B) (53 g, 0.18 mol), thionyl chloride (51.3 mL) and DMF (1 mL) was stirred at room temperature for 18 h, then concentrated in vacuo to dryness. This acid chloride (60.7 g) was dissolved in THF (400 mL), and NH4OH (235 mL) was added. The mixture was then stirred for 18 h and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane:EtOAc (4:1) to afford 27.7 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzamide (1C).
Reaction SMILES: C(O[C:4]([C:6]1([NH:10][C:11]([C:13]2[C:14]3[CH2:15][C@@H:16]4[CH2:29][C@@H:17]4[C:18]=3[N:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:20]=2)=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[NH3:30]>CO>[C:4]([C:6]1([NH:10][C:11]([CH:13]2[NH:20][N:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[C:18]3[C@H:17]4[CH2:29][C@H:16]4[CH2:15][C:14]2=3)=[O:12])[CH2:7][CH2:8][CH2:9]1)(=[O:5])[NH2:30]
Reactant: N
Reactant: CCOC(=O)C1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@@H]2C[C@H]32)CCC1
Solvent: CO
Product: NC(=O)C1(NC(=O)C2NN(c3ccc(F)cc3F)C3=C2C[C@@H]2C[C@H]32)CCC1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
1-{[(1aS,5aS)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-cyclobutanecarboxylic acid ethyl ester (20 mg, 0.05 mmol) was dissolved in 7 N ammonia in methanol (4 mL). The sealed reaction vial was stirred at 65° C. for 48 h. The solvent was evaporated, and the residue was purified by preparative TLC plate to give the title compound (14 mg) as a white solid. LCMS m/z=373.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (td, J=4.6 and 3.5 Hz, 1H), 1.16-1.20 (m, 1H), 1.82-1.94 (m, 1H), 2.18-2.31 (m, 4H), 2.50 (m, buried, 3H), 2.80 (d, J=16.3 Hz, 1H), 2.92 (dd, J=16.3 and 6.3 Hz, 1H), 6.85 (s, 1H), 6.96 (s, 1H), 7.32-7.38 (m, 1H), 7.61-7.68 (m, 1H), 7.81-7.88 (m, 1H), 8.28 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24].Cl.[OH-].[Na+]>O.C(O)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(O)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 26.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and neutralized with aqueous 2N NaOH to pH 6-7. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow solid (18 mg, 27%). 1H NMR (Acetone-d6): 9.53-9.51 (m, 1H), 8.85 (s, 1H), 8.71 (dd, J=1.8, 4.8 Hz, 1H), 8.67-8.63 (m, 1H), 8.49 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 2.23 (s, 3H).