Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:35](=[O:36])[CH2:34][C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: Cn1cnc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)Cc2cn(C)cn2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
4-Amino-2-phenylbenzoyl methionine methyl ester hydrochloride (compound 8, 111.8 mg, 0.2833 mmol) and N-methylimidazole-4-yl-acetic acid hydrochloride (50 mg, 0.2832 mmol) were suspended in 10 mL of methylene chloride. To this solution was added diisopropylethylamine (197 μL, 4.0 eq) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (107.4 mg, 0.2833 mmol). After stirring at ambient temperature for 2 days, the reaction was worked up by washing with dilute HCl (PH=3.0) and concentrated sodium bicarbonate. After evaporating solvents, the residue was purified by flash column chromatography (CH2Cl2-Methanol, 10:1) to give [4-(1-Methylimidazole-4-ylacetamido)-2-phenylbenzoyl]methionine methyl ester (106 mg, 78%); m.p. 69-70° C.; 1H NMR (CDCl3) δ 9.89 (s, 1H, amide), 7.67 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.46 (s, 1H, imidazole), 7.34-7.42 (m, 5H), 6.81 (s, 1H, imidazole), 5.90 (d, J=7.7 Hz, 1H, amide), 4.63 (ddd, J=5.1, 7.3 and 7.7 Hz, 1H, Met α H), 3.72 (s, 3H, OCH3), 3.64 (s, 5H, N-methyl and imidazole acetyl), 2.10 (t, J=7.6 Hz, 2H), 1.98 (s, 3H), 1.83-1.94 (m, 1H), 1.66-1.75 (m, 1H); 13C NMR (CDCl3) δ 171.7, 169.0, 168.9, 140.3, 140.1, 139.8, 137.3, 135.3, 129.6, 129.3, 128.5, 128.3, 127.5, 120.6, 118.5, 118.0, 52.1, 51.6, 36.3, 33.3, 30.8, 29.4, 15.0; LRMS (EI) for C25H28O4N4S 480 (M+, 20), 406 (100), 318 (50); HRMS (EI) calcd 480.1813, obsd 480.1829.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([S:9][CH2:10][C:11]([NH:13][CH2:14][C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:16]2)=[O:12])[S:7][CH:8]=1)(O)=[O:2].Cl.[CH2:31]([NH2:33])[CH3:32].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[ClH:28].[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][N:17]1[CH2:18][CH2:19][O:20][C@@H:15]([CH2:14][NH:13][C:11](=[O:12])[CH2:10][S:9][C:6]2[S:7][CH:8]=[C:4]([C:1]([NH:33][CH2:31][CH3:32])=[O:2])[N:5]=2)[CH2:16]1
Reactant: CCN
Reactant: O=C(CSc1nc(C(=O)O)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (476 mg) of (1-5) and ethylamine hydrochloride (98 mg) were dissolved in dimethylformamide (2 mL), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg), hydroxybenzotriazole hydrate (230 mg) and triethylamine (167 μL) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (free form, 441 mg) as a pale-yellow amorphous solid. By a similar method as in (1-2), the title compound (357 mg) was obtained as pale-yellow crystals from the obtained residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30](Cl)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:30]([O:29][CH3:28])=[O:31])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: COC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 52 %

Procedure:
According to the procedure for compound 398 using methylchloroformate (20 mg, 0.21 mmol) afforded 13.6 mg (52% yield) of 476, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(#N)C.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>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:44]3[CH:45]=[C:40]([F:39])[CH:41]=[CH:42][C:43]=3[F:46])=[O:16])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Yield: 93 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (2.00 g, 3.63 mmol) in 5 mL of degassed acetonitrile and add 2,5-difluorophenyl boronic acid (1.15 g, 7.26 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.51 g, 0.73 mmol) and sonicate briefly. Next add cesium fluoride (4.96 g, 32.76 mmol) and heat to 75° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol to give 1.74 g (93%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][N:9]([CH2:12][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(F)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Yield: 178 %

Procedure:
To a microwave vial was added tert-butyl 4-(3-bromo-5-fluorophenoxy)piperidine-1-carboxylate (215 mg, 0.574 mmol), cesium carbonate (562 mg, 1.72 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (130 mg, 0.27 mmol), potassium [(dimethylamino)methyl](trifluoro)borate(1-) (114 mg, 0.689 mmol), palladium acetate (30.7 mg, 0.137 mmol) and 5.05M water in THF (3.5 mL). The tube was sealed and evacuated and refilled with N2 (3×). The sealed tube was then heated at 80° C. for 20 hours. The reaction was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with preparative LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford the desired product (180 mg, 89%). LCMS (M+H)+: 353.2.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[N:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(#N)C>[N:33]1([CH2:32][CH2:31][NH:12][C:9]2[C:8](=[N:13][NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][N:10]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: NC1=NN=C(c2ccccc2)C1=NNc1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: c1ccc(NN=C2C(NCCN3CCOCC3)=NN=C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine (65 mg, 0.25 mmol) was dissolved in 5 mL of acetonitrile. Potassium carbonate (70 mg, 0.5 mmol) and a catalytic amount of sodium iodide were added and the solution was heated to reflux. 4-(2-chloroethyl)morpholine hyrdochloride (50 mg, 0.25 mmol) was added in small portions over 30 min. After heating at reflux for 6 hours, the reaction was allowed to cool to ambient temperature and was stirred overnight. Some of the residual 4-(2-chloroethyl)morpholine was removed by stirring the solution over 50 mg of polystyrene bound thiophenol with 1 drop of diethylisopropylamine. The solution was filtered through celite and evaporated to a tan solid. The solid was then dissolved in ethyl acetate and precipitated with hexanes. The solid was isolated by filtration and air dried. The material was purified by column chromatography (CH2Cl2:MeOH=10:1) to yield two fractions in amounts of 28 mg and 35 mg (total 67%). 1H NMR (ppm, 200 MHz, CDCl3) δ 2.60 (t, 4H), 2.80 (t, 2H), 3.70 (t, 4H), 4.18 (t, 2H), 7.25-7.50 (m, 8H), 7.78 (d, 2H), 8.15 (d, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15](=[CH2:28])[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])(C)(C)C>ClCCl>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH:16]([CH3:17])[C:15](=[CH2:28])[C:13]([OH:14])=[O:12])=[CH:19][CH:20]=1)=[O:23]
Reactant: C=C(C(=O)OC(C)(C)C)C(C)c1ccc(C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C(=O)O)C(C)c1ccc(C(=O)OC)cc1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (21.7 mL, 283 mmol) was added to a solution of methyl 4-(3-(tert-butoxycarbonyl)but-3-en-2-yl)benzoate (8.7 g, 30 mmol) in anhydrous dichloromethane (85 mL), and the mixture was stirred at 23° C. for 5 h. The solvents were removed under reduced pressure and the residue was triturated with hexane. The solid was collected by filtration and dried under vacuo to give the title compound. MS: m/z=233.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)OS1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[CH2:1]([NH:8][CH2:12][C@H:11]([N:21]=[N+:22]=[N-:23])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1O[C@@H](c2ccc(Cl)cc2)CN1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H](CNCc1ccccc1)c1ccc(Cl)cc1
Yield: 84.2 %

Procedure:
A solution of (2RS,5S)-3-benzyl-5-(4-chlorophenyl)-1,2,3-oxathiazolidine 2-oxide (16.2 g, 52.6 mmol) and sodium azide (17.11 g, 263.2 mmol) in N,N-dimethylformamide (100 ml) was heated at 70° C. for 24 hours. The reaction mixture was partitioned between ether and water, and the organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-20% ethyl acetate-hexane) to afford (R)-N-benzyl-2-azido-2-(4-chlorophenyl)ethylamine (12.7 g, 83.8%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C@@H:17]1[C:31]([O:33]C)=[O:32].[OH-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C@@H:17]1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)[C@H]1CN(CCSc2ccccc2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4ccccc4)C[C@@H]3C(=O)O)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A suspension of 0.7 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(phenylthio)ethyl]piperidine-3-carboxylate in 5 cm3 of methanol, to which methanol had been added 2.9 Cm3 of N aqueous sodium hydroxide, was stirred for 2 hours at a temperature in the region of 80° C. The solution obtained was neutralized with 0.18 cm3 of acetic acid and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63 μm; diameter 3 cm; height 20 cm), elution was carried out with a dichloromethane/ethanol (90/10 by volume) mixture, and 20-cm3 fractions were collected. Fractions 21 to 52 were region of 40° C. 0.53 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(phenylthio)ethyl]piperidine-3-carboxylic acid was obtained in the form of an oil with a beige color.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[N:10]([CH2:30][C:31](=[O:40])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([CH2:30][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=[C:11]2[C:14](=[O:29])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C:23]3=[O:28])=[CH:18][CH:17]=2)=[O:40])=[N:34][CH:35]=1
Reactant: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2CC(=O)Nc1ccc(Cl)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cn1c(C(=O)Nc2ccc(N3CCOCC3=O)cc2)nc2c(C(=O)O)cccc21)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
127 mg (0.20 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 15 mL CH2Cl2. At 0° C. 1.8 mL (1.8 mmol) of a 1 M BBr3-solution were added. The reaction mixture was stirred for 24 h at room temperature. Because of incomplete conversion further 0.9 mL (0.9 mmol) of a 1 M BBr3-solution were added. After stirring for 24 h at room temperature the reaction mixture was concentrated and purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid). 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid was obtained as a light brown, amorphous solid. Yield: 73 mg MS (ES+): m/e=549, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: Sc1ccc(Br)cn1
Solvent: CS(C)=O
Product: Brc1ccc(SC2CCCC2)nc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
5-bromopyridine-2-thiol (0.5 g, 3.44 mmol) was dissolved in anhydrous DMSO (10 mL). CS2CO3 (2.23 g, 6.89 mmol) was added and stirred for 5 minutes followed by addition of bromocyclopentane (0.73 mL, 6.89 mmol). The reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was poured on ice cold water (25 mL) and extracted with MTBE (2×25 mL) washed with water and brine dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 2-5% ethyl acetate in hexanes as eluent to provide 5-bromo-2-cyclopentylsulfanyl-pyridine (0.7 g).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH:7]2[O:16][CH:10]3[O:11][C:12]([CH3:15])([CH3:14])[O:13][CH:9]3[CH:8]2[OH:17])[NH:5][C:4](=O)[CH2:3]1.[H-].[Al+3].[H-].[H-]>>[OH:17][CH:8]1[CH:9]2[CH:10]([O:11][C:12]([CH3:15])([CH3:14])[O:13]2)[O:16][CH:7]1[CH:6]1[CH:2]([OH:1])[CH2:3][CH2:4][NH:5]1
Reactant: CC1(C)OC2OC(C3NC(=O)CC3O)C(O)C2O1
Agent: [Al+3]
Agent: [H-]
Product: CC1(C)OC2OC(C3NCCC3O)C(O)C2O1

Procedure:
A process for converting 5-(t-BOC)amino-5-deoxy-l,2 O-isopropylidene-α-D-glucuronolactone to castanospermine which comprises (a) reacting 5-(t-BOC)amino-5-deoxy-l,2-O?isopropylidene-α-D-glucuronolactone (I) with ethyl acetate and a strong base in an inert solvent at low temperature whereby the ethyl acetate adds across the carbonyl group of the lactone to give the corresponding cyclic hemiketal of a β-keto ester (II); (b) hydrogenating the hemiketal catalytically under pressure over a platinum catalyst in ethyl acetate to reduce the β-keto function and give β-hydroxy ester (III); (c) treating the β-hydroxy ester with formic acid in an inert solvent with cooling to remove the protecting group from the amine followed by basification to provide internal cyclization of the amine to give lactam (IV); (d) reducing the lactam with an aluminum hydride reducing agent to give the corresponding pyrrolidine (V); and (e) treating the pyrrolidine first with trifluoroacetic acid with cooling and then hydrogenating over platinum catalyst under pressure to give castanospermine (VI).
Reaction SMILES: C([O:3][C:4](=[O:26])[C@H:5]([OH:25])[CH2:6][C@H:7]([NH:16][C:17]([C:19]1[N:20]=[N:21][N:22]([OH:24])[CH:23]=1)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)C.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].CCO.O.[Li+].[OH-]>[Pd]>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([F:37])=[C:30]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:16][C:17]([C:19]3[N:20]=[N:21][N:22]([OH:24])[CH:23]=3)=[O:18])[CH2:6][C@@H:5]([OH:25])[C:4]([OH:3])=[O:26])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1cn(O)nn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
(2R,4R)-5-(4-Bromophenyl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid ethyl ester (30 mg, 70 μmol) was combined with 5-chloro-2-fluorophenylboronic acid (22 mg, 126 μmol), K2CO3 (29.1 mg, 211 μmol), EtOH (0.8 mL, 10 mmol), and water (0.2 mL, 10 mmol). SilicaCat DPP-Pd (0.28 mmol/g loading; 25.1 mg, 7.0 μmol) was added the last. The resulting mixture was microwaved at 100° C. for 10 minutes. 1 M LiOH in water (281 μL, 281 μmol) was added, and the resulting mixture was stirred for 1 hour. The mixture was filtered, concentrated, and purified by preparative HPLC to yield the title compound (17 mg). MS m/z [M+H]+ calc'd for C20H18ClFN4O5, 449.10. found 449.2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]([CH2:21][CH2:22][CH3:23])[C:12]([CH2:14][O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])=[O:13])[CH2:9][CH3:10].Cl[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26].O.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:11]([CH2:8][CH2:9][CH3:10])[C:12]([CH2:14][O:15][C:16]([CH2:17][CH2:18][NH:19][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26])=[O:20])=[O:13])[CH2:22][CH3:23]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCN(CCC)C(=O)COC(=O)CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)COC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-propionic acid dipropylcarbamoylmethyl ester (step 2) (20.1 g, 75 mmol) in DCM (240 ml) at 0° C. under N2 was added DMAP (0.46 g, 3.76 mmol) followed by TEA (38.8 ml, 278 mmol). The reaction mixture was treated with a solution of 3-chlorosulfonylbenzoic acid (16.6 g, 75 mmol) in DCM (200 ml). The mixture was allowed to stir at 0° C. for 1 h and then warmed up to RT for 1 h. Water (200 ml) was added and the pH adjusted with 1N HCl (100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification by C18 reverse phase chromatography, eluting with MeCN/water (1% HCl) afforded the title product; LC-MS Rt 1.01 mins; 415.2 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32](O)=O)[N:17]=1>>[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:19]=[C:18]([C:32]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:14]=2)[N:17]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C(=O)O)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.12 g, 0.55 mmol) and 4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.8) (0.104 g, 0.37 mmol) according to the general procedure V. Obtained as a white solid (0.025 g, 15%). MS (ISP) 462.4 [(M+H)+]; mp 326° C.
Reaction SMILES: CCOC1C=CC(N)=CC=1.Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:21]([C:20]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])([O-:23])=[O:22]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CCOc1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 28.0 g (0.20 mol) of p-phenetidine, 23.6 g (0.10 mol) of 2,6-dichloro-3-nitrobenzoic acid, and 80 ml of N,N-dimethylaniline was heated five hours on a steam bath. The resulting mixture was diluted with chloroform and extracted with 1N aq. NaOH. Acidification of the aqueous extract yielded 6-chloro-2-[4-ethoxyphenyl)amino]-3-nitrobenzoic acid as reddish brown crystals, mp 174°-176° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C@@H:11]1[CH2:30][N:14]2[C:15](=[O:29])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:17][C@@H:13]2[CH2:12]1>>[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([S:9][C@H:11]2[CH2:30][N:14]3[C:15](=[O:29])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH2:17][C@@H:13]3[CH2:12]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Br)CN12
Agent: [Na]
Product: Cc1ccc(S[C@@H]2C[C@H]3CN(c4ccc(OC(F)(F)F)cc4)C(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 893.6 %

Procedure:
Na (112 mg, 0.548 mmol) was added to anhydrous enthanol (10 ml). Until the sodium was dissolved. 4-methylbenzenethiol (34 mg, 0.0274 mmol) was added in the ice-bath. Subsequently (6S,7aS)-6-Bromo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (100 mg, 0.274 mmol) was added. After the addition, the ice bath was removed and the reaction was stirred for overnight at the room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 100 mg (85%) of the title compounds as white solid. 1H NMR (300 MHz, CDCl3): δ 7.61-7.56 (m, 2H), 7.33-7.29 (m, 2H), 7.20-7.12 (m, 4H), 4.28-4.00 (m, 3H), 3.85-3.83 (m, 1H), 3.69 (dd, 1H, J1=2.7 Hz, J2=9.6 Hz), 3.11 (dd, 1H, J1=4.2 Hz, J2=12.9 Hz), 2.32 (s, 3H), 2.19-2.12 (m, 1H), 1.93-1.83 (m, 1H); LC-MS: 409 [M+1]+.