Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH:22][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCC3(N)CCCC3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)Nc2cccc(OCC3(NC(=O)c4ccncc4)CCCC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a stirred suspension of 4-amino-5-((1-aminocyclopentyl)methoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (346.83 mg, 1 mmol) in DMF (6 mL) was added triethylamine (0.278 mL, 2 mmol). After being stirred at room temperature for 10 min., a mixture of isonicotinic acid (123.11 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) and HOBt (149 mg, 1.1 mmol) in 4 ml of DMF was added and the reaction mixture was then stirred at room temperature overnight. The resulting solution was purified by reverse phase HPLC, and then the product was re-crystallized from ethanol/water, after dry to give the title compound as a white solid (300 mg) in 72% yield. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.67 (m, 2H), 1.75-1.78 (m, 2H), 1.83-1.88 (m, 2H), 2.19-2.24 (m, 2H), 4.43 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.85 (s, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 8.66 (d, J=8 Hz, 2H), 10.96 (s, 1H). MS 416 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]([OH:9])[CH2:7][CH2:6][CH2:5][C:4]1(CC)[CH:10]([C:14]([O-:16])=[O:15])[C:11]([O-:13])=[O:12])C.[OH-].[Na+].Cl>C1COCC1.O>[C:19]1([CH:3]2[CH:8]([OH:9])[CH2:7][CH2:6][CH2:5][CH:4]2[CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC1(C(C(=O)[O-])C(=O)[O-])CCCC(O)C1(CC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(=O)O)C1CCCC(O)C1c1ccccc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
A solution of 0.87 g (2.6 mmole) of diethyl-2-(SR)-phenyl-3-(SR)-hydroxy-(SR)-cyclohexylmalonate in 12 mL of THF and 7 mL of water was treated with 3.1 mL (7.8 mmole) of 10% aqueous sodium hydroxide and the mixture was heated in an oil bath at 70° C. under nitrogen for 24 hr. The mixture was cooled, 10 mL of water was added and the pH was adjusted to 2 with 2N aqueous HCl. The mixture was extracted with 3×35 mL of ethyl acetate, and the organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give 700 mg of a light yellow foam. This material was carried on in Step F below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)/[CH:21]=[CH:22]/[N:23](C)C)=[CH:16][CH:15]=3.O.[NH2:35]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][NH:23][N:35]=1)=[CH:16][CH:15]=3
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C(F)F)c21

Procedure:
The process is carried out as indicated in Example 40 above, with the compound from Example 151B, 3-(2,4-dichlorophenyl)-9-difluoromethyl-6-((E)-3-dimethylamino-acryloyl)-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one, and hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].CC[O-].[Na+].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=O)[CH3:15]>CCO>[O:8]=[C:7]1[NH:9][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:23])=[N:1][C:2]2[CH:6]=[CH:5][S:4][C:3]1=2
Reactant: NC(=O)c1sccc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccsc2c(=O)[nH]1
Yield: 73.7 %

Procedure:
A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR νmax Nujol)/cm−1 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δH (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]>C(O)C.CO>[CH3:1][NH:2][C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]
Reactant: CN
Reactant: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CO
Product: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)NC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reaction time: 48 h

Procedure:
3 ml of a 8M solution of methylamine in ethanol are added to 2.9 g of 2-[[[(1-methyl-2-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-[ethoxyimino]ethylidene) amino]oxy]-methyl]-α-(methoxyimino)-phenylacetic acid methyl ester in 30 ml of methanol and stirring is carried out for 2 days at room temperature. The reaction mixture is concentrated to dryness by evaporation. Recrystallisation of the residue from hexane yields the title compound having a melting point of 88-90° C. (compound 5.23).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: Cc1cccc(C=O)c1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methylbenzaldehyde (0.5 g, 4.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.092, 73%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14](O)[C:13]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=3[C:11]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.CCO>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][C:13]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=3[C:11]2=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)C(O)N(CCCc1ccccc1)C2=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CN(CCCc1ccccc1)C2=O
Reaction time: 3 h

Procedure:
2-(3-Phenylpropyl)-5-methoxy-3-hydroxy-1-oxo-1,3-dihydrobenzo[c]pyrrole (2.49 g, 8.38 mmol) is dissolved in HCl/EtOH (50 ml concentrated HCl, 150 ml EtOH), and N2 is bubbled through the solution for 10 minutes followed by the addition of the catalyst, 10% Pd/C (200 mg). The mixture is hydrogenated on a Parr-Shaker apparatus at 3 atmospheres pressure for 3 hours. After filtering the reaction through a pad of Celite, the filtrate is concentrated in vacuo, and the residue is dissolved in EtOAc (200 ml). The EtOAc is washed with 2N HCl (200 ml), H2O (200 ml), saturated NaHCO3 solution (200 ml) and saturated NaCl solution (200 ml) dried over MgSO4 and evaporated. The product is purified by chromatography (SiO2 ; 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) to yield 2-(3-phenylpropyl)-5-methoxy-1-oxo-1,3-dihydrobenzo[c]pyrrole. Treatment with BBr3 yields 2-(3-phenylpropyl)-5 -hydroxy-1-oxo-1,3-dihydrobenzo[c]pyrrole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][CH2:8][C:6]1[O:7][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(CO)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(CBr)o1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 3.4 g (26.7 mmol) of 5-(hydroxymethyl)furan-2-carboxaldehyde and 7.78 g (29.4 mmol) of triphenylphosphine in 300 ml of dichloromethane at −5° C. are added 5.28 g (29.4 mmol) of N-bromosuccinimide in 10 min. The mixture is stirred at −5° C. for 30 min. The mixture is then concentrated and the residue is purified by chromatography on silica (cyclohexane/AcOet: 7:3) to yield 4.38 g (87%) of 5-(bromomethyl)furan-2-carboxaldehyde in the form of a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[Na].[CH2:14]([O:16][CH2:17][CH2:18][OH:19])[CH3:15]>>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:7]=[C:2]([O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])[N:3]=1
Reactant: CCOCCO
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [Na]
Product: CCOCCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1

Procedure:
To a solution of 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 150 ml of 2-ethoxyethanol was added over a 35 minute period, a solution of 2.53 grams (0.11 mole) of sodium metal dissolved in ~100 ml of 2-ethoxyethanol. The mixture was heated for 5 hours at 65°-75° C. The insoluble by-products were filtered off and the 2-ethoxyethanol was removed by evaporation under reduced pressure. The residue which remained was diluted with water and extracted with methylene chloride and the extract dried with sodium sulfate. The extract was filtered and the methylene chloride evaporated off leaving the 2-chloro-6-(2-ethoxyethoxy)-4-(trichloromethyl)pyridine product as an oil. The product had a refractive index of n 25/d = 1.5395 and was recovered in a yield of 23.8 grams (75 percent of theoretical). Upon analysis, the compound was found to have carbon, hydrogen, nitrogen and chlorine contents of 37.72, 3.25, 4.55 and 44.61 percent, respectively, as compared with the theoretical contents of 37.64, 3.48, 4.39 and 44.45 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:45][CH2:44][CH:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:42][CH2:41]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCOCC4)CC3)ccc2[nH]1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-(piperidin-4-yl)-morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (72%).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH3:30]>>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([NH2:30])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(N)=O)cc1

Procedure:
As in the method described in Example 31, 4-(hexadecylamino)hydrocinnamic acid chloride hydrochloride is treated with anhydrous ammonia to yield 4-(hexadecylamino)hydrocinnamamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:2]1.C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: N[C@@H](Cc1ccsc1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(3-Thienyl)-L-alanine (2.45 g., 14.3 mmol.) was suspended in water/p-dioxane (22 ml/11 ml.) at room temperature under argon. Sodium carbonate (1.52 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (3.14 g.) was added, and the resulting mixture was stirred for 3.0 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 3.22 g. of title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-146.8° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.31.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].OS(O)(=O)=O.[N:17]([O-])=O.[Na+]>O>[CH:7]1[C:6]([NH:9][NH2:17])=[CH:5][CH:4]=[C:3]([S:1]([OH:11])(=[O:10])=[O:2])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(=O)(=O)O)cc1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Sulfanilic acid (52 g, 0.3 mol) was dissolved in 200 ml H2O containing 16.5 g Na2CO3. The resulting solution was cooled to 10° C. and 35 g of conc. H2SO4 was then added dropwise, followed by the addition of 75 ml 4N NaNO2. The diazotization step was carried out for 15 min at 10°-12° C., then the diazonium salt was collected by filtration, washed with a small amount of cold water and added, at 5° C., to a stirred solution of 85 g of Na2 SO3 in 250 ml H2O. After stirring the reaction mixture for 1 h, the temperature was raised to 95° C. and 240 ml of concentrated H2SO4 was added over a period of 30 min. The reaction mixture was left overnight and the precipitated product was collected, washed with cold water and dried. The phenylhydrazine-4-sulfonic acid obtained (52 g) was dissolved in 500 ml H2O containing 60 ml 30% NaOH, and 30 g (0.28 mol) of benzaldehyde was added at 50°-55° C. Stirring was continued for 1 h, the temperature was reduced to 30° C., and the product was precipitated by acidification with 36 ml 30% HCl. The product was collected, washed with a small amount of cold water and dried, to give 50 g of benzaldehyde phenylhydrazone-4-sulfonic acid.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[NH:11][C:10]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][C@H:14]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]3)=[N:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Xe](F)[F:33]>C(#N)C>[CH:1]1([C:5]([C:7]2[NH:11][C:10]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:30][CH2:31]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][C@H:14]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]3)=[N:9][C:8]=2[F:33])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ncc(C(=O)C3CCC3)[nH]2)C1
Reactant: F[Xe]F
Solvent: CC#N
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2nc(F)c(C(=O)C3CCC3)[nH]2)C1
Temperature: 0 °C
Yield: 4.7 %

Procedure:
To a solution (16 mL) of (3R)-3-{2-[5-(cyclobutylcarbonyl)-1H-imidazol-2-yl]-2-[4-(cyclopropylsulfonyl)phenyl]ethyl}cyclopentanone (0.720 g) in acetonitrile was added xenon difluoride (0.552 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio), and recrystallized from diethyl ether-hexane to give the title compound (0.035 g, yield 5%) as colorless crystals. melting point 85-88° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]=[CH2:16]
Reactant: Cc1c(F)cccc1Cl
Reactant: C=CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C=CC[C@H](Oc1cccc(Cl)c1C)[C@H]1CCNC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (31 mg, 130 μmol) was dissolved in DMF (470 μL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 10.1 mg, 169 μmol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0 μL, 390 μmol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the solvent was removed. 1.2M HCl in EtOH (630 μL, 760 μmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H20C1NO, 266.12. found 266.0.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:22]1([C:2]2[CH:3]=[C:4]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=3[CH3:21])[CH:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:10])=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Temperature: 135 °C

Procedure:
A stirred mixture of N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (AF1) (5.0 g, 15 mmol), imidazole (2.07 g, 30 mmol) and caesium carbonate (9.93 g, 30 mmol) in dry NMP (30 ml) is heated under argon at 135° C. for 18 hours. The reaction mixture is then poured onto water (50 ml) whereupon the titled product precipitates and is recrystalfised from ethanol-water.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3dione (10.0 g, 36.6 mmol) in anhydrous DMF (180 ml) were added DBU (8.2 mL, 54.9 mmol) and methyl bromoacetate (5.1 mL, 54.9 mmol). After stirring at rt for 45 min, the reaction mixture was quenched with water (600 mL) and HCl (1N, 100 mL). Extraction with EtOAc (3×500 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Recrystallization from AcOEt 150 mL) gave the title compound as an orange powder (6.45 g, 51%) in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).