Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19](O)=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)[C:15]=2[CH3:32])=[CH:10][CH:9]=1.[CH2:33]([N:35]([CH2:38]C)[CH2:36]C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>ClCCl.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][C:17]([C:19]([N:42]([O:43][CH3:44])[CH3:41])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[N:29]=[CH:33][N:35]([CH3:38])[CH3:36])=[CH:24][CH:23]=3)[C:15]=2[CH3:32])=[CH:12][CH:13]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CCN(CC)CC
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Oxalyl chloride (2.1 g, 1.4 ml, 16.2 mmol) was added dropwise at 0° C. to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 1c, 2.2 g, 5.4 mmol) in a mixture of dichloromethane (40 ml) and DMF (0.8 g, 0.8 ml, 10.8 m mol). The resulting mixture was allowed to warm to room temperature and stirred for 1.5 hr, under a nitrogen atmosphere. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and used directly for further reaction. The residue so obtained was dissolved in dry dichloromethane (40 ml) and to this was added triethylamine (2.8 g, 3.9 ml, 27.0 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (1.06 g, 10.8 mmol) under stirring. The reaction mixture was stirred at room temperature for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was washed with water (2×20 ml) and the organic layer obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using 80% ethylacetate in hexane as an eluent to obtain the title compound (2.36 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To 2,4-difluoro-phenylamine (1, 11.8 g, 91.4 mmol) in 110 mL of dichloromethane, pyridine (8.13 mL, 100 mmol) and propane-1-sulfonyl chloride (4, 11.3 mL, 100 mmol) were added. The reaction was stirred at room temperature overnight, then poured into 1 M aqueous hydrochloric acid, the aqueous layer separated and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography to give the desired compound (11, 19.98 g, 92.9%). MS(ESI)=[M−H+]−=234.06.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH2:19])([CH2:12]3)[CH2:10]1)[CH2:16]2)([O-:3])=[O:2].[Cl:23][CH2:24][C:25]([N:27]1[CH2:31][C:30]([F:33])([F:32])[CH2:29][C@H:28]1[C:34]#[N:35])=[O:26].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C(#N)C>[ClH:23].[ClH:23].[ClH:23].[F:33][C:30]1([F:32])[CH2:31][N:27]([C:25](=[O:26])[CH2:24][NH:19][C:11]23[CH2:12][CH:13]4[CH2:14][CH:15]([CH2:16][C:9]([NH:8][CH2:7][C:6]5[CH:20]=[CH:21][CH:22]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)([CH2:18]4)[CH2:10]2)[CH2:17]3)[C@H:28]([C:34]#[N:35])[CH2:29]1
Reactant: NC12CC3CC(C1)CC(NCc1cccc([N+](=O)[O-])c1)(C3)C2
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)CCl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: Cl
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CNC12CC3CC(C1)CC(NCc1cccc([N+](=O)[O-])c1)(C3)C2
Reaction time: 4 h

Procedure:
90 mg (0.3 mmole) of N-(3-nitrobenzyl)adamantane-1,3-diamine and 50 mg (0.24 mmole) of (2S)-1-(chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile are dissolved in acetonitrile, to the solution 300 mg (0.75 mmole) of polimer bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) are added. The mixture is sirred at 70° C. for 4 hours, then at room temperature for 20 hours. The scavanger resin is fitered off and the filtrate is evapotared, the residue is purified by column chromatography (chloroform-methanol 6:1). After acidification of the formed oil with ethereal hydrochloride acide the title compound is obtained: 41 mg (29%), m.p.: 226-229° C. 1H-NMR (DMSO-d6): 1.57 (s, 2H), 1.95 (d, 8H), 2.45 (d, 4H), 2.91 (m, 2H), 4.14 (m, 2H), 4.33 (m, 4H), 5.21 (m, 1H), 7.74 (t, 1H), 8.15 (t, 1H), 8.27 (dd, 1H), 8.58 (s, 1H), 9.41 (b, 2H), 9.77 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2ncccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
Under nitrogen atmosphere, the 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (5.0 g, 0.022 mole) was added to a suspension of sodium hydride (0.96 g of 60% in oil, 0.024 mole, washed once with hexanes) in dimethylformamide (100 ml). The mixture was heated at 70°-85° C. for 1.5 hr before adding the α-bromoacetophenone (4.38 g, 0.022 mole) at room temperature. The reaction mixture was stirred at room temperature overnight, then poured into water. The precipitate was collected by filtration, washed with water, and dried under high vacuum. A sample was dissolved in isopropyl alcohol, then concentrated to initiate crystallization. The crystals were collected by filtration, washed with isopropyl alcohol, and dried under high vacuum at 70° C. over a weekend to give 1.5 g (20%) of title compound, mp. 262°-263° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:10]=1[F:25])[O:6][CH2:7][CH3:8])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=1.[F-].[Cs+]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:9]1[C:10]([F:25])=[CH:11][C:12]([C:31]2[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=2)=[CH:13][C:14]=1[F:15])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(OCC)c1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(OCC)c1c(F)cc(-c2ccc(N)nc2)cc1F
Temperature: 25 °C

Procedure:
A solution of (RS)-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethoxy-acetic acid ethyl ester in 1,2-dimethoxyethane was treated with 2-amino-5-bromopyridine and CsF. The reaction mixture was deoxygenated by passing a stream of argon through it. Tetrakis(triphenylphosphine)palladium(0) was added. The reaction mixture was heated to 80° for 2 days, then cooled to rt and concentrated. The crude product was isolated by flash chromatography (cyclohexane/EtOAc 2:1=>EtOAc) to give (RS)-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester as amorphous brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:26]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:25]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic arthydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2 Cl2/MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+1042.
Reaction SMILES: CCO[CH:4]([OH:9])[C:5](Cl)(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+].[Br:17][C:18]1[C:19]([CH3:25])=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].Cl.N[OH:28].Cl>O>[Br:17][C:18]1[C:19]([CH3:25])=[C:20]2[C:22]([C:4](=[O:9])[C:5](=[O:28])[NH:21]2)=[CH:23][CH:24]=1
Reactant: Cc1c(N)cccc1Br
Reactant: NO
Reactant: CCOC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)ccc2c1NC(=O)C2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Chloral alcoholate (0.43 g, 1.05 eq) and Na2SO4 (2.84 g, 20 mmol) were dissolved in 10 mL water. 3-Bromo-2-methylaniline (0.33 g, 1.77 mmol) was added to the solution followed by 0.16 mL conc. HCl aqueous solution and NH2OH.HCl (0.38 g, 3.0 eq). The mixture was refluxed for 15 min and stirring was continued for additional 1 hr at RT. The precipitate was collected by filtration, washed with water and dried under vacuum. This precipitate was dissolved in 1 mL H2SO4 and the solution was heated (80° C.) for 15 min. After cooling down to RT, the mixture was poured into ice-water mixture and the precipitate was collected, washed with water and dried under vacuum to give the title compound (0.26 g, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]3[CH:8]2[C:7]1=[O:19].Cl.[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[N:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:21].[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]5[CH:8]4[C:7]3=[O:19])[CH2:32][CH2:33]2)[CH:25]=[N:24][CH:23]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 5-(4-bromobutyl)tetrahydro-1H-thieno-[3',4':3,4]cyclobuta[1,2-c]pyrrole-4,6(3H,5H)dione 2,2-dioxide in 50 ml of dimethylformamide is added to a stirred solution 2.0 g (0.007 mol) of 1-(6-chloro-2-pyrazinyl)-piperazine hydrochloride and 4 ml of triethylamine. The reaction mixture is stirred overnight and the solvent is removed under vacuum. The residue is partitioned between water and methlene chloride. The methylene chloride extracts are combined, washed with brine and dried over anhydrous sodium sulfate. Filtration and roto-evaporation gives the crude free base. Preparative HPLC [silica gel; ethyl acetate:methylene chloride (9:1)] followed by evaporation of the appropriate fractions (TLC Rf=0.4), treatment with ethanolic hydrogen chloride and recrystallization from ethanol gives the title compound: m.p. 154°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:24]([Cl:23])=[O:26])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cl)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 1M solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.84 g, 2.88 mmol) in anhydrous THF was added dropwise triphosgene (1.28 g, 4.32 mmol) and triethylamine (0.92 mL, 6.62 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure to give the desired product, 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbonyl chloride as an orange solid was used immediately in the next step without any further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[C:24]2[CH:35]=[C:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][C:25]=2[N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O>[N:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:22][C:23]3[C:24]4[CH:35]=[C:34]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[S:33][C:25]=4[N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)OC(C)(C)C)sc21
Temperature: 5 °C
Yield: 41.9 %

Procedure:
Oxalyl chloride (20.2 mL, 231 mmol) was added to a suspension of 4-morpholin-4-ylbenzoic acid (7.98 g, 38.5 mmol) in dry dichloromethane (DCM, 210 mL) and dimethylformamide (DMF, 0.04 mL). After refluxing the mixture for 6.5 hours, volatiles were carefully removed under reduced pressure (taking up the residue three times with toluene). The resulting 4-morpholin-4-ylbenzoyl chloride hydrochloride was added portion-wise (in about 0.5 hours) to a suspension of 5-tert-butyl 1-ethyl 3-amino-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (6.0 g, 19.3 mmol) in dry DCM (200 mL) and pyridine (23.2 mL, 289 mmol), under stirring at 5° C. The resulting suspension was stirred for 20 hours at room temperature. 300 mL of DCM and 300 mL of aqueous sodium bicarbonate were then added to the reaction mixture; the organic layer was separated, washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (DCM/ethyl acetate 7:3) gave 4.05 g of the title compound.
Reaction SMILES: N1C=CC=C(CN)C=1.[S:9]1[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10]1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][N:46]2[CH2:50][C@@H:49]([CH3:51])[N:48]([C:52]3[S:53][C:54]([C:58](O)=[O:59])=[C:55]([CH3:57])[N:56]=3)[C:47]2=[O:61])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][N:46]2[CH2:50][C@@H:49]([CH3:51])[N:48]([C:52]3[S:53][C:54]([C:58]([NH:15][CH2:14][C:13]4[S:9][CH:10]=[N:11][CH:12]=4)=[O:59])=[C:55]([CH3:57])[N:56]=3)[C:47]2=[O:61])=[CH:43][CH:42]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)O
Reactant: NCc1cncs1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)NCc1cncs1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with thiazol-5-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (67%): mp 70-73° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.62 (t, J=5.4 Hz, 1H), 7.76 (s, 1H), 7.33-7.28 (m, 2H), 7.18-7.13 (m, 2H), 4.56-4.39 (m, 5H), 3.59-3.56 (m, 1H), 3.00 (dd, J=9.0, 2.7 Hz, 1H), 2.45 (s, 3H), 1.35 (d, J=6.0 Hz, 3H); MS (ES+) m/z 445.7 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=O.O.[NH2:24][NH2:25].CC(O)=O>CCO.O>[NH:24]([C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)=[O:2])[NH2:25]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NNC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a suspension of 4-{[4-(methoxycarbonyl)benzoyl]amino}benzoic acid (300 mg g, 1 mmol) in EtOH (4.5 mL) was added hydrazine hydrate (0.73 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave a white solid. This residue was taken up in water (25 mL) and AcOH (5 mL) was added. A white solid precipitated out which was further washed with water (3×2 mL). Drying at 80° C. for 1 hr gave 220 mg of the title compound (73%) as a white solid in 91.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([S:5]([CH2:7][C@@:8]1([CH3:15])[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])=[O:6])(C)(C)C.C(O)(=O)C.[OH2:20].[Cl:21]Cl.C1(C)C=CC=CC=1.CCCC(C)C>>[CH3:15][C@@:8]1([CH2:7][S:5]([Cl:21])(=[O:20])=[O:6])[C:9](=[O:14])[NH:10][C:11](=[O:13])[NH:12]1
Reactant: O
Reactant: ClCl
Reactant: CC(C)(C)S(=O)C[C@@]1(C)NC(=O)NC1=O
Solvent: CC(=O)O
Solvent: CCCC(C)C
Solvent: Cc1ccccc1
Product: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Temperature: 6 °C
Reaction time: 0.02 h
Yield: 87.1 %

Procedure:
A stirred (350 rpm) solution of (5S)-5-[(tert-butylsulfinyl)methyl]-5-methylimidazolidine-2,4-dione (1.00 eq, 22.5 mmol, 5.22 g) in acetic acid (1.75 mol, 100 mL, 105 g) and water (555 mmol, 10.0 mL, 10.0 g) was cooled to 6° C. and purged with nitrogen. The nitrogen purge was stopped and chlorine gas (59.2 mmol, 4.2 g, 1.33 L at STP) was then bubbled through the mixture over a period of 25 min, maintaining the jacket temperature at 6° C. The temperature of the reaction mixture reached a maximum of 9.5° C. The end of reaction was determined by a persistent green colouration of the mixture and a fall in temperature from 9.1 to 7.8° C. over 1 min. The supply of chlorine was shut off and a nitrogen purge applied. HPLC analysis of the mixture at this point revealed complete conversion of the sulfoxide intermediates. The mixture was heated to 15° C., discharged from the vessel and concentrated under reduced pressure (bath temperature 45° C.). The residue was suspended in toluene (469 mmol, 50.0 mL, 43.3 g) and evaporated to low volume. Further toluene (469 mmol, 50.0 mL, 43.3 g) was added and the evaporation procedure repeated. The residue was triturated with iso-hexane (377 mmol, 50.0 mL, 32.5 g) and then collected by filtration. The resulting solid was washed with iso-hexane (151 mmol, 20.0 mL, 13.0 g), sucked dry on the filter and dried in vacuo for 24 h at 40° C. to give [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride as a white crystalline solid (0.874 eq, 19.6 mmol, 4.45 g) in 87% yield.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]2[C:27]([F:30])([F:29])[F:28].CC(S(N=[C:38]([C:45]1[N:49]([CH3:50])[CH:48]=[N:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=O)(C)C.C1C[O:54]CC1>>[CH3:50][N:49]1[C:45]([C:38]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]3[C:27]([F:30])([F:29])[F:28])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[OH:54])=[CH:46][N:47]=[CH:48]1
Reactant: C1CCOC1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: Cn1cncc1C(=NS(=O)C(C)(C)C)c1ccccn1
Agent: [Li]CCCC
Product: Cn1cncc1C(O)(c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.10 mL, 0.25 mmol) was added dropwise by syringe to a solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (122 mg, 0.261 mmol, Intermediate 8, step d) in dry THF (4.5 mL) in a dry ice-acetone bath. After 2 min, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.0540 g, 0.288 mmol, Intermediate 11, step b) in dry THF (0.25 mL) was added dropwise. The reaction mixture was stirred for 5 min in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 5 min, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by reverse-phase chromatography (acetonitrile w/0.05% TFA in water). Saturated sodium bicarbonate was used to form the free-base product, which was extracted with DCM and concentrated to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.4 Hz, 1H), 8.32 (d, J=8.9 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.9, 1.8 Hz, 1H), 7.75 (td, J=7.7, 1.7 Hz, 1H), 7.51 (s, 1H), 7.49-7.40 (m, 3H), 7.35 (dd, J=7.0, 5.3 Hz, 1H), 7.28 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 6.72 (s, 1H), 6.39 (s, 1H), 3.44 (s, 3H). MS m/e 529.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])C=C.Cl[C:8](N(C)C)=[C:9]([CH3:11])[CH3:10].C1C[O:18][CH2:17][CH2:16]1>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.O>[CH3:10][C:9]1([CH3:11])[C:17](=[O:18])[CH2:16][CH:8]1[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C1CCOC1
Reactant: CC(C)=C(Cl)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: O
Product: COC(=O)C1CC(=O)C1(C)C
Yield: 29 %

Procedure:
The suspension of methyl acrylate (1.3 equiv.), 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.0 equiv.), and zinc trifluoromethanesulfonate (0.25 equiv.) was stirred to blend its contents for 15 min at room temperature under N2. Then the mixture was sonicated (100 W) at 36-39° C. for 24 h. A mixture of THF:H2O=10:1 was added to the mixture and sonicated. The mixture was concentrated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether; petroleum ether:ethyl acetate=50:1, 10:1) to afford the title compound methyl 2,2-dimethyl-3-oxocyclobutanecarboxylate (29% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.73 (s, 3H), 3.51 (dd, J=7.6 Hz, 18.4 Hz, 1H), 3.07 (q, J=9.2 Hz, 18 Hz 1H), 2.94 (t, J=7.2 Hz, 8.8 Hz, 1H), 1.29 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:16][NH2:17].CO>CC(O)C.O>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1)[NH2:17]
Reactant: NN
Reactant: Cn1cc(-c2ccc(Cl)nc2)ccc1=O
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2ccc(NN)nc2)ccc1=O
Temperature: 140 °C
Yield: 126.1 %

Procedure:
A mixture of 5-(6-chloropyridin-3-yl)-1-methylpyridin-2(1 H)-one (1.2 g, 5.44 mmol) and hydrazine (870 mg, 2.2 mmol) in 2-propanol (5ml) was heated in a microwave at 140° C. for 5 hrs. The reaction mixture was co-evaporated with MeOH (3×) and then suspended in water (50 ml). Solid product was collected by filtration and dried under high vacuum for 24 hrs to provide the title compound, 5-(6-hydrazinylpyridin-3-yl)-1-methylpyridin-2(1 H)-one (600 mg, 51% yield).