Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([NH:12][C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[CH:18]3)=[O:14])[CH2:7][CH2:6][CH2:5]2.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([S:43]([NH:46][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][C:19]2[N:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:25])[C:22]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([NH:12][C@H:8]2[C:9]4[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]2)=[O:14])=[CH:24][CH:23]=3)(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: O=C(O)CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of (R)-5-(6-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (10 mg, 0.019 mmol), cyclopropanesulfonamide (3.43 mg, 0.028 mmol, 1.50 equiv.), DMAP (4.61 mg, 0.038 mmol, 2.0 equiv.) and EDC (7.23 mg, 0.038 mmol, 2.0 equiv.) in DCM (1 mL) was stirred at room temperature overnight. The residue was purified by column chromatography on silica gel eluting with 0-3% CH2Cl2/MeOH to give 7.8 mg of (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide as a white solid. LCMS [M+H]+=634. 1H NMR (DMSO, 500 MHz) δ ppm: 8.18 (dd, J=8.0, 3.5 Hz, 2H), 7.91 (d, J=8.0 Hz, 1H), 7.43-7.36 (m, 4H), 7.26 (t, J=7.0 Hz, 1H), 7.00 (t, J=8.5 Hz, 2H), 6.66 (s, 1H), 5.26-5.22 (m, 1H), 2.85-2.74 (m, 3H), 2.30-2.15 (m, 4H), 2.09 (t, J=7.0 Hz, 2H), 2.00-1.96 (m, 2H), 1.91-1.76 (m, 2H), 1.45-1.39 (m, 4H), 1.10-1.00 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ccc(Cl)n3ncnc23)cc1
Reactant: COc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Temperature: 110 °C
Yield: 77.2 %

Procedure:
A suspension of 4-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (50 mg, 132 μmol), 2-methoxypyridin-4-boronic acid (40 mg, 260 μmol), Pd(PPh3)4 (46 mg, 40 μmol) and NaOtBu (51 mg, 530 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for five hours. After evaporation of the solvents, the residue is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3) affording the title compound (46 mg), which is isolated as a mixture containing 50% of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[Br:13][C:10]1[C:11]2[O:12][C:14]([C:15]([CH3:20])([CH3:19])[CH3:16])=[N:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: CC(C)(C)C(=O)O
Reactant: COC(=O)c1cc(N)c(O)c(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c2oc(C(C)(C)C)nc2c1
Temperature: 150 °C
Yield: 19.3 %

Procedure:
To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (2.00 g, 4.06 mmol, 50% purity), 2,2-dimethylpropanoic acid (0.83 g, 8.13 mmol), and solid support triphenylphosphine (75% by weight; 4.26 g, 12.2 mmol) in acetonitrile (20 mL) was added trichloroacetonitrile (815 μL, 8.13 mmol). The mixture was heated in a microwave reactor for 10 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (245 mg). LC-MS [M]=312.1.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-methylbenzyl bromide (0.54 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (NaSO4), evaporation in vacuo afforded 1.41 g (100%) of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.4-7.05 (m, 6H), 6.8 (m, 1H), 5.3 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.7-2.3 (m, 4H), 2.3 (s, 1H), 1.2 (d, J=7 Hz, 3H). MS (ES) m/e 362.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[CH3:10]>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: BrCCCCCCBr
Reactant: CCc1ccc(CCO)cc1
Product: CCc1ccc(CCOCCCCCCBr)cc1

Procedure:
(2.6 g), T.l.c. [B] Rf 0.25, from 1,6-dibromohexane (9.8 g) and 4-ethylbenzeneethanol (2.0 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])=[CH:19][CH:18]=1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(Cl)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (11.79 g, 75.15 mmol) in dry THF (100 mL), n-BuLi (14.08 mL, 22.54 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 30 min at −78° C., a solution of 4-chloro-N-methoxy-N-methylbenzamide (5.0 g, 25.0 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4C solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography elating with 5-7% EtOAc in hexanes to afford 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.8 g, 57%) as a light green oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([CH2:16][CH2:17][C:18](OCCCC)=[O:19])[CH:9]=1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([CH2:16][CH2:17][CH2:18][OH:19])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: CCCCOC(=O)CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(OC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(CCCO)n1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
A solution of butyl 3-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)-2-pyridinyl]propanoate (4.76 g, 12.49 mmol) in THF (120 ml) was treated with LiAlH4 soln (1M in THF, 12.49 ml, 12.49 mmol) at −78° C. The reaction mixture was allowed warm to −20° C. and after stirring at −20° C. for 15 min, the mixture was treated with water (9 ml) and allowed to stir for 1 h before being filtered and evaporated to give a slightly impure product (3.98 g, 102%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([C:33]=1[OH:34])=[CH:31][CH:30]=[C:29]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:28]=2)=[O:23])[C:17]([OH:19])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([C:33]=1[OH:34])=[CH:31][CH:30]=[C:29]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:28]=2)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 75.2 %

Procedure:
TFA (0.4 mL) was added to a mixture of 2-(S)-tert-Butoxycarbonylamino-3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid (99 mg, 0.21 mmol) in CH2Cl2 (2 mL). The resultant mixture was stirred at room temperature for 3 h and concentrated. Residue was taken up with water (100 mL) and the pH was adjusted by 1 N NaOH aq. Solution to 9-10, then acidified by 1 N HCl to pH=5. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 58 mg (0.158 mmol) in 75% yield. LC-MS ESI−: 366.10 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5]P(=O)([O-])[O-].[Li]CCCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)CCCC#C>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([CH:5]=[CH:23][CH2:22][CH2:21][CH2:20][C:19]#[CH:18])[CH:3]=1
Reactant: O=P([O-])([O-])Cc1cccc(Cl)c1
Reactant: CCCCCC
Agent: C#CCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
An oven-dried 250 mL three-necked round-bottomed flask under a nitrogen atmosphere was charged with 3-chlorobenzylphosphonate (4.74 g, 18 mmol) and dry THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) was added dropwise over 10 min, via syringe. The mixture was stirred at 0° C. for 30 min, then 5-hexynal (1.0 g, 10 mmol) in dry THF (40 mL) was added. The solution was warmed to room temperature and was stirred for 3 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). The reaction was quenched by adding saturated aqueous ammonium chloride solution (70 mL). The layers were separated and the aqueous phase was extracted with ether (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, gravity filtered and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 1.9 g of the title compound as a colorless oil in a 93% yield.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=C[C:16]([C:17]#[N:18])=CC=1.O1C=CC(B(O)O)=C1>>[C:17]([C:16]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1)#[N:18]
Reactant: c1cc(-c2ccoc2)ccn1
Reactant: N#Cc1ccc(Br)cc1
Agent: OB(O)c1ccoc1
Product: N#Cc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 3-(pyridin-4-yl)furan, 4-bromobenzonitrile (4.00 g, 22.0 mmol) was coupled to 3-furanboronic acid to furnish in high yield crude 3-(4-cyanophenyl)-furan as a brown solid, mp 55-7° C., which was used immediately without further purification. 1H NMR (CDCl3): δ 7.82 (bs, 1H), 7.67 (d, 2H, J=8.4 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.52 (t, 1H, J=1.9 Hz), 6.72 (bs, 1H). IR (KBr): 2214, 1608, 1160, 796 cm-1. Anal. Calculated for C11H7NO.0.1 C6H6 : C, 78.72; H, 4.33; N, 7.91. Found: C, 78.32; H, 4.60; N, 7.65.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 80.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (65 mg, 0.093 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 35% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (390 mg, 81%) as a white solid: LC/MS m/e calcd for C28H28N2O4S2 [M+H]+ 521.67, observed 520.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:20][OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](OC(=O)C)(=O)[CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1F
Product: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Yield: 30 %

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole was prepared in 30% yield from 1-(3-fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one oxime from Step 2 and acetic anhydride by the procedure described in Example 4, Step 1 and used directly in the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41]([C:7]2[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[C:12]([C:22]([NH:23][CH3:24])=[O:25])[C:11]=3[CH:26]=2)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC(C)(C)C)cc([N+](=O)[O-])c3)cc12
Temperature: 99 °C
Yield: 75.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (400 mg), (3-(tert-butylcarbamoyl)-5-nitrophenyl)boronic acid (345 mg) and Cs2CO3 (846 mg) in dioxane (8 mL) and water (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (150 mg). The mixture was flushed with nitrogen and then heated at 99° C. for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column (hexanes/EtOAc=3:1) to give 5-(3-(tert-butylcarbamoyl)-5-nitrophenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide 2 (350 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH2:30]([O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)=[O:28])[CH3:31]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminobenzoate in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[C:25]=1[NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH3:23].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:25]2[C:35]([CH2:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:24]=2[CH2:22][CH3:23])=[O:14])=[O:7])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCCNc1c(CC)cccc1CC
Reactant: CCC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(CC)c1N(CCCC(=O)O)C(=O)CCCN(C(=O)c1ccc(Cl)cc1)C(C)(C)CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-[(1,1-dimethylpropyl)amino]butyric acid and ethyl γ-(2,6-diethylanilino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1,1-dimethylpropylamino)butyryl]-4-(2,6-diethylanilino)butyric acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])=S)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]2[N:28]=[C:29]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(I)cnc1NCc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a stirred solution of ethyl N-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate (2.30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (0.93 g, 5.27 mmol). The resulting mixture was allowed to stir at room temperature. After 12 h, a precipitate had formed. The mixture was filtered, and the filtercake was washed with water (2×10 mL) and methanol (10 mL). The solids were dried to provide 1.50 g (69%) of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1C(OC)=O.[Cl:37]C1C=CC(OC)=C(B(O)O)C=1>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>[Cl:37][C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccc(Cl)c1OC
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (0.58 g, 2.2 mmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro-2-methoxyphenylboronic acid (0.54 g, 2.9 mmol) to afford 245 mg (35%) of methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) as a clear oil. Data for methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.79 (d, J=2.4, 1H), 8.40 (dd, J=8.4, 2.4, 1H), 7.57 (d, J=8.5, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.75 (s, 3H), 3.47 (s, 3H).