Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C@H:4]([CH2:44][CH2:45][S:46][CH3:47])[NH:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:36])[C@H:14]([CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:9][C:8]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OCC)C>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:48])[C@H:4]([CH2:44][CH2:45][S:46][CH3:47])[NH:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:36])[C@H:14]([CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)[NH2:15])=[CH:9][C:8]=1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@H](Cc2c[nH]cn2)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1
Reaction time: 6 h

Procedure:
[4-(bis-tert-butoxycarbonyl-L-histidyl)-2-phenylbenzoyl methionine methyl ester (0.992 g, 1.42 mmol), prepared as in Example 184A, was dissolved in 4 M HCl/dioxane (15 mL), upon which gas evolution was observed. The clear amber solution was stirred for 6 hours, during which time a white precipitate formed. The mixture was treated with ethyl ether and the precipitate was isolated by filtration to provide 0.779 g (100%) of [4-(L-histidyl)-2-phenylbenzoyl methionine methyl ester (believed to be the mono-hydrochloride salt); 1H NMR (CD3OD) δ 1.72-1.87 (m, 1H), 1.95-2.03 (comp, 4H), 2.08-2.28 (comp, 2H), 3.38-3.60 (comp, 2H), 3.67 (s, 3H), 4.45-4.57 (comp, 2H), 7.30-7.46 (comp, 6H), 7.53 (d, 1H), 7.69 (d, 1H), 7.77 (app s, 1H), 8.90 (s, 1H). LRMS (CI): 496 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[F:15])[CH2:2][CH2:3][CH3:4].C(Cl)Cl>[Pd].CO>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of N,N-di-n-butyl-2-fluoro-4-nitroaniline (4.03 g, 15 mmol) in mixed solvents of CH2Cl2 (70 mL) and MeOH (20 mL) was added catalyst Pd/C (0.40 g). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=8:1) to give the title compound as colorless oil (2.32 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Li])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1.O1CCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]([CH2:17][CH3:18])([OH:19])[C:13]2[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: [Li]c1ccc(Br)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
To 400 ml. of a 0.5 molar ethereal 4-bromophenyl-lithium solution a solution of 7.5 g. of 4'-hydroxy-propiophenone in 37 ml. of dry tetrahydrofurane is added dropwise, with stirring at a temperature between -50° C. and -40° C. The reaction mixture is stirred at 0° C. for an additional hour, and is then decomposed with a mixture of ice and glacial acetic acid. The aqueous phase is extracted with ether, the ethereal phases are combined, and washed to neutral with water. After drying over anhydrous magnesium sulfate the solvent is distilled off under reduced pressure, and the residue is chromatographed on a silica gel column with a 7:3 mixture of benzene and ethyl acetate as an eluting agent. The solvent is distilled off in vacuo, and the residue is crystallized from a mixture of ethyl acetate and dichloromethane. 4.2 g. of the named compound are obtained, melting at 161° to 162° C.
Reaction SMILES: [C:1]([C:23](OC)=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:27][NH:28][CH2:29][CH2:30][OH:31]>C1COCC1>[C:1]([C:23]([N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:20])([F:22])[F:21])([F:18])[F:17])([F:15])[F:14])([F:11])[F:12])([F:8])[F:9])([F:6])[F:5])([F:2])[F:3]
Reactant: CNCCO
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: CN(CCO)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 76.4 %

Procedure:
C7F15C(O)N(CH3)C2H4OH was prepared by combining n-C7F15CO2CH3 (85 grams) and CH3NHCH2CH2OH (16.5 grams) in THF (50 grams) at 50° C. Progress of the reaction was monitered by GC and FTIR spectra. The isolated yield was 76.4% of C7F15C(O)N(CH3)C2H4OH. (b.p.: 110–125° C./1.5–3 mmHg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[N:12]=[N:13][C:14]([Cl:18])=[CH:15][C:16]=1Cl)=[O:10])[CH3:7]>C(OCC)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[N:12]=[N:13][C:14]([Cl:18])=[CH:15][C:16]=1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:10])[CH3:7]
Reactant: CCNCC
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(Cl)cc1N(CC)CC
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Diethylamine (86 mg, 1.3 equivalents, 1.2 mmol) is added to a solution of 4,6-dichloro-pyridazine-3-carboxylic acid ethyl ester (0.2 g, 0.91 mmol) in ethyl acetate (10 mL) at room temperature. After overnight stirring, the reaction is quenched with water (6 mL). The organic layer is separated and the aqueous layer extracted (2×15 mL) with ethyl acetate. The combined organic layers are dried and solvent removed to give 230 mg of 6-chloro-4-diethylamino-pyridazine-3-carboxylic acid ethyl ester as a yellowish oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]3[C:10](=[N:11][N:12]=[CH:13]3)[CH2:9][N:8]=2)=[CH:5][CH:6]=1.[CH2:22]=[O:23]>C1(C)C(C)=CC=CC=1>[OH:23][CH2:22][C:13]1[N:14]2[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[N:8][CH2:9][C:10]2=[N:11][N:12]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A process according to claim 2 wherein estazolam is reacted with paraformaldehyde in xylene at 120° C. to 140° C. for a time sufficient to form 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH2:12][Br:21])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)ccc(=O)n1Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)ccc(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 1-benzyl-3-methyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid ethyl ester (158 mg, 0.58 mmol), N-bromosuccinimide (114 mg, 0.64 mmol) and benzoyl peroxide (14 mg, 0.058 mmol) in CCl4 (6 mL) was refluxed for 16 h. After cooling to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-35% EtOAc/hexanes) to give 147 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=7.10-7.40 (m, 6H), 6.72 (d, 1H, J=9.2 Hz), 5.32 (s, 2H), 4.24, (s, 2H), 4.19 (q, 2H, J=7.0 Hz), 1.16 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[Br:29][CH2:30][CH2:31]Br>C(C(C)=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH2:30][Br:29])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OCCBr)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A mixture of 93.5 g (0.25 mole) of 2-n-Butyl-3-(4-hydroxy-benzoyl)-benzofuran, 69 g (0.5 mole) of finely ground anhydrous potassium carbonate and 500 ml of methyl ethyl ketone was stirred and refluxed for 30 minutes. The mixture was allowed to cool to about 50° C. and 187.8 g (1 mole) of 1,2-dibromo-ethane were added in one operation. Stirring and refluxing were continued for 18 h and a further increment of 47 g of 1,2-dibromo-ethane was added. Refluxing was continued for 6 h, the course of the reaction being monitored by thin-layer chromatography (TLC). Filtration and evaporation to dryness under reduced pressure then followed. The residue was taken up in diethyl ether after which the ethereal solution was washed, first with water, then with a 10% aqueous solution of sodium hydroxide and once again with water. Drying was carried out over sodium sulphate, followed by evaporation to dryness under reduced pressure. In this way 56.5 g of 2-n-butyl-3-[ 4-(2-bromo-ethoxy)-benzoyl]-benzofuran in the form of an oil were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.O.Cl>[Fe].C1(C)C=CC=CC=1>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(Sc2ccsc2)cc1N
Reaction time: 3 h

Procedure:
1.6 G. of 2-amino-4-(3-thienylthio)-1-nitrobenzene is treated with 1.6 g. of iron powder in a refluxing mixture of 1.6 ml. of water, 0.16 ml. of conc. hydrochloric acid and 100 ml. of toluene. After 3 hours when the reaction is complete, the iron residue is filtered off and the filtrate stripped under vacuum to afford 1,2-diamino-4-(3-thienylthio)-benzene.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:38])([O:17][C:18]1[CH:37]=[CH:36][C:21]2[NH:22][C:23]([S:25][CH:26]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=3)[CH3:27])=[N:24][C:20]=2[CH:19]=1)[CH:14]([F:16])[F:15].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:38][C:13]([F:12])([O:17][C:18]1[CH:37]=[CH:36][C:21]2[NH:22][C:23]([S:25]([CH:26]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=3)[CH3:27])=[O:6])=[N:24][C:20]=2[CH:19]=1)[CH:14]([F:15])[F:16]
Reactant: COc1ccnc(C(C)Sc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc(C(C)S(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
9.8 g of 80% m-chloroperoxybenzoic acid in 200 ml of dichloromethane are added dropwise at -65° C. to a solution of 19.5 g of ±-5-(1,1,2,2-tetrafluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]thio}-1H-benzimidazole in 1.5 l of dichloromethane. The reaction mixture is stirred for a further 2 h at -40° C. and then stirred into a sodium carbonate solution. The organic phase is separated off, and the aqueous phase is extracted once more with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated. A sparingly soluble diastereomer thus crystallises. The other diastereomer remains in the mother liquor and can either be purified by chromatography or can, by leaving it to stand, preferably in the presence of bases, be rearranged into the less soluble diastereomer. Recrystallisation of sparingly soluble product from ethyl acetate/diisopropyl ether gives 10 g (51%) of the title compound of m.p. 156°-157° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=O)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][NH:34][C:35]([C:37]1[S:38][C:39]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][CH:41]=1)=[NH:36]>>[F:32][C:2]([F:1])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[N:18]3[N:25]=[CH:26][C:27]([C:28]4[O:33][N:34]=[C:35]([C:37]5[S:38][C:39]([S:42]([NH2:43])(=[O:45])=[O:44])=[CH:40][CH:41]=5)[N:36]=4)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) (237 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/hexane) and crystallization (dichloromethane) as a yellow solid (220 mg, 67%). MS (ISP) 659.3 [(M+H)+]; mp 255° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccnc2ccccc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(Nc2ccnc3ccccc23)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of 4-aminoquinoline (H. Shinkai et al., J. Med. Chem., 2000, 43, pp. 4667-4677) (251 mg), chlorotriphenylmethane (533 mg), and triethylamine (266 μL) in methylene chloride (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give quinolin-4-yltritylamine as a pale yellow foam (610 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:22]4[NH:23][C:24]([CH3:35])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 102 mg (80%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.27 (br s, 1H, NH), 11.66 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.43 (m, 4H, 2×CH2), 2.30 (s, 3H, CH3), 2.27 (m, 4H, 2×CH2), 2.18 (s, 3H, CH3), 2.12 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.64 g) in dichloromethane (7 mL) was added TFA (7 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.051 g, 12%). MS (ISP) 426.1 [(M+H)+]; mp 312° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.O>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (35.1 g) was dissolved in DMF (200 mL) and to the resulting solution was added N-ethylmorpholine (17.0 mL) followed by TBTU (28.8 g). The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. 0.88 Ammonia (11.1 mL) was added and the mixture was allowed to warm to room temperature. The mixture was allowed to stir at room temperature for 16 h and was then poured into water and the resulting precipitate removed by filtration. The solid was dried in vacuo to give the sub-titled compound (34.2 g).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THE is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.0 mg (0.21 mmol) of 3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 51 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([SH:16])=[C:11]([C:13]([NH2:15])=[O:14])[S:12][C:8]=2[CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CN(C=O)C>C1COCC1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][S:16][C:10]1[C:9]2[CH:17]=[CH:18][C:6]([O:5][CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])=[CH:7][C:8]=2[S:12][C:11]=1[C:13](=[O:14])[NH2:15])[CH3:35]
Reactant: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1S
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1c(C(N)=O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-((2,4-dichlorobenzyl)oxy)-3-sulfanyl-1-benzothiophene-2-carboxamide (40 mg) in THF (dry) (4.0 mL) were added sodium hydrogen carbonate (13.1 mg) and ethyl 2-bromoacetate (0.017 mL). The mixture was stirred overnight at room temperature. To the mixture was added DMF (1.0 mL) and stirred at room temperature over weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (25.2 mg).
Reaction SMILES: C[Si](C)(C)Cl.Br[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.N>CCOCC.[Zn]>[OH:18][C:14]1([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)C(C)Br
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylchlorosilane (950 μL, 7.43 mmol) was added by syringe to a suspension of zinc powder (6.65 g, 0.102 mol) in absolute Et2O (170 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source removed, and ethyl 2-bromopropionate (10.1 mL, 77.8 mmol) was added at such a rate that the ether gently boiled. After being heated to reflux for 1 hour, the mixture was stirred for 1 hour at room temperature. A solution of cyclobutanone (5.00 g, 63.2 mmol) in Et2O (10 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. After stirring for 1 hour at room temperature, the mixture was poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3, and concentrated. the title compound was given as a colorless oil (12.9 g, 100%). 1H-NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J=6.8 Hz), 1.29 (3H, t, J=7.3 Hz), 1.51-1.64 (1H, m), 1.80-1.90 (1H, m), 1.96-2.17 (4H, m), 2.70 (1H, q, J=7.3 Hz), 3.44 (1H, s), 4.18 (2H, qd, J=7.3 and 1.2 Hz).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([OH:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:26][O+](C)C.O>ClCCl>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([O:14][CH3:26])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nc(SCc2ccccc2)nn1-c1ccccc1
Reaction time: 18 h
Yield: 51.5 %

Procedure:
3-Benzylthio-5-hydroxy-1-phenyl-1,2,4-triazole (15 g) in dichloromethane (60 ml) was treated with trimethyloxonium tetrafluoroborate (15.7 g) and allowed to stand for 18 hours at room temperature. The reaction mixture was poured into water (200 ml) and the aqueous layer was washed with dichloromethane (2×100 ml). The dried organic layer was evaporated and then purified by column chromatography (silica/petroleum ether:ether), to give 8.1 g of the desired product.
Reaction SMILES: Br[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[O:4][CH:3]=1.[Cl:15]C1C2NC(C(OCC)=O)=CC=2SC=1>CCCCCCC.CCOC(C)=O>[Cl:15][C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)c1cc2occ(Br)c2[nH]1
Reactant: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc2occ(Cl)c2[nH]1
Yield: 42 %

Procedure:
The title compound was synthesized from ethyl 3-bromo-4H-furo[3,2-b]pyrrole-5-carboxylate (200 mg, 0.774 mmol) using the conditions to synthesize ethyl 3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate. Chromatography (silica gel, heptane/EtOAc) yielded ethyl 3-chloro-4H-furo[3,2-b]pyrrole-5-carboxylate (70 mg, 42% yield).