Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([O:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)=[C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][CH3:26])[S:6][C:5]=2[CH:7]=1
Reactant: COCc1ccccc1B(O)O
Reactant: COC(=O)/C=C/c1ccc(Oc2c(Br)sc3cc(OC)ccc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCc1ccccc1-c1sc2cc(OC)ccc2c1Oc1ccc(/C=C/C(=O)OC)cc1
Yield: 79 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.238 mmol) in 1,2-dimethoxyethane (3.0 mL) was added (2-(methoxymethyl)phenyl)boronic acid (79 mg, 0.477 mmol). [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.5 mg, 0.024 mmol) and Na2CO3 (2.0N aqueous, 0.358 mL, 0.715 mmol). The resulting mixture was subjected to microwave irradiation at 100° C. for 20 min after which time the reaction was diluted with EtOAc, added anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (86.6 mg, 0.188 mmol, 79% yield). LC/MS (m/z, M+H2O): 478.0.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.C([Li])(C)(C)C.C([Cu])#N.[C:40]([O:44][C:45]([N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([CH2:56]Cl)=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC.O>[C:40]([O:44][C:45]([N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([CH2:56][C:2]2[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Clc1ccc(CNc2ccc(Br)nn2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Agent: N#C[Cu]
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(Cc2ccc(NCc3ccc(Cl)cc3)nn2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.8 %

Procedure:
To (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine (522, 0.560 g, 1.88 mmol) in tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at −78° C., was added n-butyllithium (2.50 M in hexane, 0.760 mL) slowly. After 10 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.201 g, 0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction was cooled to −78° C., followed by addition of 1.70 M of tert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirred for 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 M in tetrahydrofuran, 3.00 mL) and 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 0.47 g, 1.8 mol) in tetrahydrofuran (10.0 mL). After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was treated with trifluoroacetic acid (1.0 mL) dissolved in dichloromethane (10.0 mL) for 10 minutes. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the desired compound (523, 0.10 g, 23.8%). MS (ESI) [M+H+]+=450.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:57])([CH3:56])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:55])([C@@:17]4([CH3:54])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:45][C@H:44]5[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:41]([CH2:42][CH2:43]5)[CH2:40]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59].[OH-].[Li+]>C1COCC1.CO>[C:50]([O:49][C:47]([N:46]1[C@H:41]2[CH2:42][CH2:43][C@@H:44]1[CH2:45][N:39]([CH2:38][CH2:37][NH:36][C@:20]13[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:54])([CH2:18][CH2:19]3)[C@@:16]3([CH3:55])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:57])([CH3:56])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23]1)[CH2:40]2)=[O:48])([CH3:51])([CH3:52])[CH3:53].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4CC[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4CC[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 2 TFA (30 mg, 0.030 mmol) in THF (0.75 mL) and MeOH (0.25 mL) was added a solution of lithium hydroxide (1N) (0.148 mL, 0.148 mmol). The reaction mixture was stirred at 75° C. After 1 h, the reaction mixture was cooled to rt and purified by reverse phase prep-HPLC using HPLC method 7 and dried to give 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, 2 TFA (22.2 mg, 0.021 mmol, 69.0% yield) as pale yellow solid. LC/MS: m/e 768.8 (M+H)+, 2.34 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 5.13 (d, J=5.4 Hz, 1H), 4.84 (br. s., 1H), 4.68 (s, 1H), 4.36 (br. s., 2H), 3.68-3.32 (m, 6H), 2.98 (d, J=10.3 Hz, 2H), 2.70 (br. s., 1H), 2.08 (br. s., 7H), 1.97-1.82 (m, 2H), 1.70 (d, J=5.9 Hz, 1H), 1.66 (s, 3H), 1.63-1.51 (m, 5H), 1.49 (s, 9H), 1.47-1.39 (m, 5H), 1.39-1.27 (m, 4H), 1.27-1.15 (m, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.97-0.94 (m, 3H), 0.89 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.CO.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 90 °C

Procedure:
The following reaction was split into 3 separate sealed tubes and worked up separately. The material was then combined following purification. Ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (10 g, 25.7 mmol), methanol (10.5 mL, 259 mmol) and TFA (100 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen and the resulting mixture was sealed, stirred vigorously and heated at 90° C. with an oil bath for 18.5 h. The resulting mixture was diluted with methanol and all the solvent was removed under reduced pressure. Methanol (100 mL) was added and all the solvent was removed under reduced pressure again. Methanol (100 mL) and sodium bicarbonate (12.4 g, 147 mmol) were added. The resulting mixture was stirred at room temperature until pH=6 (in water). The mixture was concentrated nearly to dryness. Water (100 mL) was added. The resulting brown solids were collected by vacuum filtration and washed with water. The brown solids were dissolved in hot methanol and acetonitrile and purified using reverse-phase C18 flash column chromatography (20-100% acetonitrile in water). Fractions containing the desired product were combined and concentrated nearly to dryness under reduced pressure. Solids were collected by vacuum filtration, washed with water and dried under high vacuum to give the desired product (4.88 g, 14.3 mmol, 55% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.71 (s, 1H), 7.59 (s, 1H), 4.66 (tt, J=3.61, 12.20 Hz, 1H), 4.07 (d, J=1.56 Hz, 2H), 3.25 (s, 3H), 3.06-3.17 (m, 1H), 2.42 (qd, J=3.51, 12.89 Hz, 2H), 2.10 (d, J=10.93 Hz, 2H), 1.61 (d, J=10.93 Hz, 2H), 1.10-1.24 (m, 2H); MS (ESI) m/z 341.3 [M]+, 343.1 [M+2]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:29]4[CH2:28][CH2:27][NH:26][CH:25]([C:21]5[O:20][CH:24]=[CH:23][CH:22]=5)[CH2:30]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1coc(C2CNCCN2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccco4)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 843 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.28 g of 2-furanylpiperazine and 10 ml of pyridine was heated in a pressure bottle for 24 hours, then cooled first to room temperature and then at 0° C. The pyridine was removed under reduced pressure and the residue purified by flash column chromatography using chloroform:methanol:water:triethylamine (95:5:.1:.1), giving 280 mg of the desired product, mp 176° C.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.CCCCCC.[NH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(OCC)(=O)C>[CH3:26][C:25]1[C:20]([NH:19][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1cccnc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccnc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 64.3 %

Procedure:
To di t-butylcarbonate (32.29 g, 147.95 mmol) was added hexane (35 ml) and the solution was refluxed under heating at 80° C. Under refluxing, 2-amino-3-methylpyridine (10.00 g, 92.47 mmol) in ethyl acetate (10 ml) was dropped in a period of 15 minutes. After the mixture was refluxed for 2 hours and cooled to room temperature, thereto was added hexane (20 ml). The resulting crystals were filtered and dried in vacuo to give the subject compound (12.39 g, 64%).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1.CCN(CC)CC.CC(N(C)C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Stir 3-phenyl-2,3-dihydro-1H indole (0.233 g, 1.19 mmol), 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1 equiv.), Et3N (0.50 mL, 0.36 g, 3.57 mmol), DMA (0.015 g, 0.123 mmol) in CH2Cl2 (45 mL) overnight under N2. Dilute the CH2Cl2 to 150 mL and pour into a saturated solution of NaHCO3 (50 mL) and stir for 15 minutes. Separate the organic layer and wash with H2O (100 mL), extract with 1N HCl (2×75 mL), wash with brine, separate and dry (MgSO4). Filter and evaporate followed by chromatography on the ISCO using a 40 g silica gel column and elute with EtOAc-hexane 90-100%) to give 0.33 g of the racemic compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCC(O)CO
Reactant: COc1cscc1OC
Product: CCCCCCCCCCC1COc2cscc2O1

Procedure:
Racemic 2-n-decyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-dodecanediol as described in EXAMPLE 1. It was characterized by GC-MS and H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)N3CCOCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and morpholine to give 7-methoxy-2-morpholinocarbonylbenzofuran (Compound 329a). Successively, it was formylated to give 4-formyl-7-methoxy-2-morpholinocarbonylbenzofuran (Compound 329b), then compound 329b was reacted with methylamine hydrochloride to give compound 329 as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1.[C-:23]#[N:24].[Na+]>CCO.O>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][C:23]#[N:24])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: ClCc1ccccc1-c1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1-c1cccc(OCc2ccccc2)c1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-chloromethyl-3′-benzyloxybiphenyl from Step A (188 mg, 0.61 mmol) in EtOH (4 mL) was added a solution of NaCN (60 mg, 1.22 mmol) in water (4 mL). The resulting solution was heated to reflux for 12 h, stood at ambient temperature for 48 h, then concentrated under reduced pressure. The residue was partitioned between sat. aq. NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 2-10% EtOAc in hexane to give the titled product.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=2)[C:11](=[O:25])[CH2:10]1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>ClCCl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:8][CH:9]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=2)[C:11](=[O:25])[CH2:10]1
Reactant: COC(=O)c1ccc(N2CC(NC(=O)OC(C)(C)C)CC2=O)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(N2CC(N)CC2=O)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.9 g (75%, 5.5 mmol) methyl 4-(4-tert.-butoxycarbonylamino-2-oxo-pyrrolidin-1-yl)-2-methyl-benzoate are dissolved in 25 ml dichloromethane and combined with 4.4 ml TFA. The mixture is stirred for 18 hours at ambient temperature, then evaporated to dryness and the residue is purified by chromatography on silica gel (eluant: gradient dichloromethane/isopropanol/ammonia 90:10:0.2-dichloromethane/methanol/ammonia 50:50:0.4).
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:34]1([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[S:41]([CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:43])=[O:42])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 105.9 %

Procedure:
To a solution of 500 mg of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 10 ml of tetrahydrofuran are added 0.27 ml of triethylamine and 343 mg of phenylmethanesulfonyl chloride under ice-cooling in nitrogen atmosphere, and the mixture stirred for 25 minutes. The reaction mixture is poured into ice water and extracted with ethyl acetate, and the extract washed with water, dried on sodium sulfate and concentrated under reduced pressure to yield 756 mg of benzyl α-(3ξ-carbomethoxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8](O)=[O:9])[S:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:31]2=[O:39])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC#N>[O:1]=[C:2]1[CH:6]([CH2:7][C:8]([N:24]2[CH2:25][CH2:26][CH:27]([N:30]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[NH:32][C:31]3=[O:39])[CH2:28][CH2:29]2)=[O:9])[S:5][CH:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(O)CC1SC(c2ccccc2)N(Cc2ccncc2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1SC(c2ccccc2)N(Cc2ccncc2)C1=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-oxo-2-phenyl-3-((pyridin-4-yl)methyl)thiazolidin-5-yl)acetic acid (0.15 mmol, 49 mg), 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (0.15 mmol, 33 mg) and DIPEA (0.375 mmol, 65.3 μl) in 4:1 CH3CN:DMF (0.5 ml) was added HATU (0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=528.1; tR=2.28. H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.60 (d, J=6.3 Hz, 2H), 7.40-7.38 (m, 2H), 7.33-7.29 (m, 5H), 7.06-6.92 (m, 4H), 5.55-5.53 (m, 1H), 4.55 (d, J=4.4 Hz, 2H), 4.45-4.42 (m, 3H), 4.07 (d, m, 2H), 3.42-3.41 (m, 1H), 3.20-3.15 (m, 1H), 3.01-2.90 (m, 1H), 2.66 (m, 2H), 1.88 (m, 2H) ppm.
Reaction SMILES: ClC1C=CC(S(=O)(=O)NC)=CC=1C(O)=O.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([OH:28])=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH:32][CH:29]([CH3:31])[CH3:30])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CC(C)N
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 74 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and isopropylamine and obtained in 74% yield. MS (m/e): 276.1 (MH−, 100%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:7][N:6]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5]1)[CH3:2]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl (3R,5S)-3-acetyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (0.40 g) in ethanol (10 ml) was added sodium borohydride (29 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was acidified with 5% aqueous potassium hydrogen sulfate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:1) was concentrated under reduced pressure to give the object product (0.40 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 81 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (613 mg, 1.49 mmol, 81%) was obtained.