Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[N:11]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.Br[CH2:35][CH2:36][CH:37]=[CH2:38].O>O1CCCC1>[CH2:38]([C:14]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12][N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15]1)[CH2:37][CH:36]=[CH2:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
Lithium hexamethyldisilazide (1M in tetrahydrofuran, 15.7 mL, 15.7 mmol) was added dropwise to a stirred, cooled (−78° C.) solution of 1-(1,1-dimethylethyl) 4-phenylmethyl 1,4-piperidinedicarboxylate (2.50 g, 7.83 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at −78° C. for 2 hours. 4-Bromo-1-butene (1.99 mL, 19.6 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 hour, then at room temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10) to give the title compound (1.07 g, 37%). 1H NMR (400 MHz CDCl3) δ 7.4–7.3 (5H, m), 5.75–5.6 (1H, m), 5.15 (2H, s), 4.93 (1H, br d, J 7 Hz), 4.90 (1H, br s), 3.95–3.75 (2H, m), 2.93–2.78 (2H, m), 2.13 (2H, br d, J 10 Hz), 1.95–1.85 (2H, m), 1.65–1.55 (2H, m), 1.44 (9H, s), and 1.43–1.30 (2H, m).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>N1C=CC=CC=1.CCOCC>[Br:20][CH2:1][C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCC#CCC#CCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC#CCC#CCC#CCC#CCBr
Temperature: 0 °C

Procedure:
A mixture of 5 g of 2,5,8,11-heptadecatetrayn-1-ol, 1.25 c3 of phosphorus tribromide and one drop of pyridine in 15 cm3 of anhydrous ether, stirred in the absence of light, is heated under reflux for 2 hours. The solution is then poured into 100 cm3 of ice water and extracted twice with ethyl ether. The ether phases are washed initially with a solution of sodium bicarbonate and then with water, and finally dried over sodium sulphate.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=[O:14])[C:7]([CH:16]1[CH2:18][CH2:17]1)=[CH:6]2)#[N:2].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([NH:30][NH2:31])=O>>[CH:16]1([C:7]2[N:8]([CH2:12][C:13]3[O:14][C:28]([C:27]4[CH:32]=[CH:33][CH:34]=[C:25]([C:24]([F:23])([F:35])[F:36])[CH:26]=4)=[N:30][N:31]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:19]([F:21])([F:22])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:17][CH2:18]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2nnc(-c3cccc(C(F)(F)F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid (Example 362B) and 3-(trifluoromethyl)benzohydrazide: 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.64 (t, J=7.8 Hz 1H), 7.38 (d, J=8.5 Hz 1H), 6.51 (s, 1H), 5.79 (s, 2H), 2.08 (m, 1H), 1.22 (m, 2H), 0.93 (m, 2H); MS (ES) m/z 477 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2cc(CO)ccc2c1
Solvent: c1ccccc1
Product: Cc1ccc2cc(CCl)ccc2c1
Reaction time: 1 h

Procedure:
20.3 g. of 6-methyl-2-naphthalenemethanol is dissolved in 100 ml. of dry benzene and to this solution is added 30 ml. of thionyl chloride. The solution is stirred for about one hour and concentrated to yield 2-chloromethyl 6-methylnaphthalene.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].ClCCl.[CH:8]1([CH2:14][CH:15]2[CH2:26][C:25]3[C:17](=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=3)[C:16]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:28]Br>>[CH:8]1([CH2:14][CH:15]2[CH2:26][C:25]3[C:17](=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][C:23]=4[C:24]=3[Br:28])[C:16]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrBr
Reactant: O=C1c2cc3c(cc2CC1CC1CCCCC1)CCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cc3c(c(Br)c2CC1CC1CCCCC1)CCC3
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 40.9 g (0.305 mol) of AlCl3 in 180 ml of dichloromethane 32.7 g (0.122 mol) of 2-(cyclohexylmethyl)-3,5,6,7-tetrahydro-s-indacen-1(2H)-one was added. To this mixture cooled to 0° C. 21.5 g (0.134 mol) of bromine was added dropwise by vigorous stirring for 45 min at 0-5° C. The resulting mixture was stirred for 12 h at ambient temperature and then poured on 1000 cm3 of ice. The organic layer was separated, and the aqueous layer was extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. This product was further used without an additional purification. Yield 39.5 g (93%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[C@H:32]([CH3:31])[CH2:36][O:35][C:34]4=[O:37])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 39 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (184 mg) described in Preparation Example 127 and (R)-4-methyloxazolidin-2-one (47.8 mg) described in Preparation Example 25, the title compound (82.6 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8](=[O:18])[C:7]12[CH2:20][CH2:19]1)([O-])=O.O>CCOC(C)=O.Cl[Sn]Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8](=[O:18])[C:7]12[CH2:20][CH2:19]1
Reactant: CCCCCN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCN1C(=O)C2(CC2)c2cc(N)ccc21
Yield: 11.1 %

Procedure:
5′-Nitro-1′-pentyl-spiro[cyclopropane-1,3′-indoline]-2′-one (29.3 g) is dissolved in EtOAc (266 ml) and SnCl2.2 H2O (96.0 g; 427 mmol) is added. The reaction mixture is refluxed overnight, cooled and filtered over Al2O3. After an aqueous work-up of the filtrate the compound (2.9 g) is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH2:7].II.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25]Cl)(=[O:24])=[O:23])=[CH:20][CH:21]=1>C(#N)C.O>[S:22]([N:25]1[CH2:7][CH:6]1[C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C=Cc1cccc(C(F)(F)F)c1
Agent: II
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC2c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
3-(Trifluoromethyl)styrene (1.70 mL, 11.5 mmol) is added to a mixture of iodine (0.29 g, 1.15 mmol) and Chloramine-T (3.12 g, 11.5 mmol) in acetonitrile (35 mL). The reaction mixture is stirred at room temperature under a nitrogen atmosphere overnight, then taken in H2O (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated and purified by silica gel chromatography (0˜20% EtOAc/Hexanes) to provide 1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine (3.44 g, 88% yield) as a colorless oil product.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+].O>CO>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-iodo-3-nitrobenzoic acid (3 g, 10 mmol) in methanol (30 ml) cooled to 0° C., sulfuric acid (3.4 g, 34.6 mmol) is added slowly. The reaction mixture is warmed to room temperature and then refluxed (˜70° C.) for 8 hours. After cooling, the reaction mixture is neutralized with solid NaHCO3 and the salts are filtered. The filtrate is evaporated under reduced pressure. To the residue obtained, water (30 ml) is added and the mixture extracted with MTBE (30 ml×2). The combined organic phase is washed with brine, dried using anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, 4-iodo-3-nitro-benzoic acid methyl ester is obtained as a yellow solid (2.67 g, 85% yield, 98% HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O(C1C=CC(C(C=CC(O)=O)=O)=CC=1)[C:23]1C=CC=C[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])=[O:12])=[CH:18][CH:19]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The procedure in Example 13(1) was followed, except that 6.05 g of 3-[4-(4-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-(4-phenoxybenzoyl)acrylic acid, to give 5.51 g of ethyl 3-[4-(4-chlorophenoxy)benzoyl]acrylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:26][CH3:27])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([O:26][CH3:27])=[C:21]([NH:22][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Yield: 27.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-methoxyaniline (26.1 g, 64.7 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.8 g, 64.7 mmol) the title compound of Step C was obtained (10.2 g, 27.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=5.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.38-7.45 (m, 1H), 7.15-7.30 (m, 4H), 6.40 (d, J=5.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.50-3.61 (m, 4H), 3.18 (s, 3H). MS (ES+): 580 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[O:28][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
8.0 g (35.7 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 20 ml of DMF. 4.0 g (17.7 mmol) of 4-benzyloxy-3-hydroxybenzonitrile and 7.4 g (41.3 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 100° C. for 3 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[O:12][C:11]([C:13]3[O:14][C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[C:16]=4[C:17]=3[CH3:18])=[N:10][C@H:9]2[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([CH2:7][C@@H:8]2[O:12][C:11]([C:13]3[O:14][C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[C:16]=4[C:17]=3[CH3:18])=[N:10][C@H:9]2[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C2=N[C@@H](C(=O)N3CCN(C)CC3)[C@H](CC3CCCCC3)O2)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C2=N[C@@H](C(=O)N3CCN(C)CC3)[C@H](CC3CCCCC3)O2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 0.75 h
Yield: 75.7 %

Procedure:
dl-[5-Cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazol-4-yl]-(4-methyl-piperazin-1-yl)-methanone (11.9 mg) was dissolved in 1:1 mixture of trifluoroacetic acid and dichloromethane (1 ml) and was allowed to stand at room temperature for 45 minutes. The resulted solution was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. After evaporation of the solvent the crude product was purified by silica gel column chromatography (Fuji Silysia, DU-3050) using 1000:10:1 mixture of dichloromethane, methanol and triethylamine as an eluent to give the title compound (7.7 mg) as a white solid. FAB-MS: m/z 588 (MH+); NMR (CDCl3): δ 0.9-2.0 (13H, m), 2.06 (2H, quintet, J=6.27 Hz), 2.34 (3H, s), 2.43 (2H, t, J=4.95 Hz), 2.55 (2H, m), 2.62 (3H, s), 2.89 (2H, t, J=6.93 Hz), 3.70 (2H, m), 3.81 (1H, m), 3.84 (2H, s), 4.07 (1H, m), 4.16 (2H, t, J=5.93 Hz), 4.55 (1H, d, J=6.60 Hz), 5.54 (1H, m), 6.61 (1H, d, J=7.92 Hz), 7.10 (1H, d, J=8.25 Hz), 7.15-7.30 (2H, m), 7.67 (1H, dt, J=7.92 Hz, 1.98 Hz), 8.49 (1H, dd, J=1.65 Hz, 4.95 Hz), 8.57 (1H, d, J=1.98 Hz).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=1)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=1
Reactant: CN(C)CCCCC(=O)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN(C)CCCCC(=O)Nc1ccc(N)cc1
Yield: 82.9 %

Procedure:
Compound 3 (1.94 g, 0.005 mol) was stirred in 48% w/v hydrobromic acid in acetic acid (11 mL) for 1 h. Diethylether was added till a cream precipitate appeared and the ethereal solution decanted. The resulting white sticky solid was suspended in dichloromethane (100 mL) and 1 M aqueous sodium hydroxide (20 mL). The aqueous layer was extracted with dichloromethane (1×50 mL) and the combined organic layers were washed with saturated brine (1×50 mL), dried (MgSO4) and concentrated in vacuo to give 4 as a pale yellow oil (975 mg, 82%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH3:21].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:6]2[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:3]([CH3:21])[C:4]([C:17]([O:19][CH3:20])=[O:18])=[CH:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(F)cc2)c(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(F)cc2)c(-c2ccccc2)c1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Under an argon atmosphere, a suspension of methyl 5-bromo-1-[(4-fluorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate (2.10 g), phenylboronic acid (1.42 g), tetrakis(triphenylphosphine)palladium (0.65 g), sodium carbonate (1.77 g) in 1,2-dimethoxyethane (11 mL)-water (11 mL) was stirred at 70° C. for 12 hr. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a colorless oil (yield 1.75 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:15])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: [K+]
Solvent: CI
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Yield: 97.3 %

Procedure:
4-Chloro-5-methyl-2-nitroanisole was prepared by the same procedure as described for Step 2 of Preparation 2a except using 4-chloro-5-methyl-2-nitrophenol (50 g), methyl iodide (75.8 g), and potassium carbonate (44 g). Workup gave crude 4-chloro-5-methyl-2-nitroanisole (52.3 g, 97%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.85 (s, 1 H), 6.95 (s, 1 H), 3.94 (s, 3 H), 2.45 (s, 3 H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([CH:38]([F:40])[F:39])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:30][C:31]=1[CH:38]([F:40])[F:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 63.3 %

Procedure:
A solution of 5-cyclopropyl-6-(N-(3-(difluoromethyl)-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.45 g, 2.53 mmol) and 10% Pd/C (catalytic) in MeOH (15 mL) was stirred under a hydrogen atmosphere (20 psi) for 3 h. The reaction mixture was filtered through celite, evaporated, and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.87 g, 63%) as a white solid. LCMS (m/z, ES+)=544.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14]Br)[CH3:2].[CH3:17][C:18]([SH:21])([CH3:20])[CH3:19].[H-].[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14][S:21][C:18]([CH3:20])([CH3:19])[CH3:17])[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1CSC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Bromomethyl-4-nitro-benzoic acid ethyl ester (8.0 g, 27.8 mmol) and 2-methyl-2-propanethiol (3.74 mL, 33.3 mmol) were combined in MeCN (100 mL) at 0° C. Sodium hydride (60% in mineral oil; 1.39 g, 34.8 mmol) was added, and the reaction was stirred for 5 minutes at 0° C., and then at room temperature until no starting material was seen by analytical tlc. The mixture was quenched by adding ice chips and diluted with H2O (100 mL) and 1N aqueous HCl (30 mL), and then extracted with EtOAc. The combined organic layers were washed with H2O, dried, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:20])=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=1)#[N:24]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.30 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=584 ([M+H]+, 3), 109 (100); IR (KBr): 2165 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystalised from isopropanol/ether; m.p.: 109° C. (isopropanol/ether).